Role of Lipids in Brain Injury and Diseases

Future Lipidology
ISSN: 1746-0875 (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/tlip19
Role Of Lipids In Brain Injury And Diseases
Rao Muralikrishna Adibhatla & James F Hatcher
To cite this article: Rao Muralikrishna Adibhatla & James F Hatcher (2007) Role Of Lipids In Brain
Injury And Diseases, Future Lipidology, 2:4, 403-422
To link to this article: http://dx.doi.org/10.2217/17460875.2.4.403
Copyright 2007 Future Medicine Ltd
Published online: 18 Jan 2017.
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Download by: [U Catolica Santiago de Guayaquil ] Date: 23 August 2017, At: 09:10
REVIEW
Role of lipids in brain injury and diseases

Rao Muralikrishna
Lipid metabolism in CNS is of particular interest because of the high concentration of lipids.
Adibhatla &
The importance of lipids in cell signaling and tissue physiology is demonstrated by many
James F Hatcher
CNS disorders and injuries that involve deregulated metabolism. The long-suffering lipid field
Author for correspondence is gaining reputation and respect, as evidenced through the Center of Biomedical Research
Department of Neurological
Excellence in Lipidomics and Pathobiology (COBRE), Lipid MAPS (Metabolites And Pathways
Surgery, H4330 Clinical
Science Center, 600 Highland Strategy) Consortium sponsored by NIH, European initiatives for decoding the lipids through
Avenue, University of genomic approaches, and Genomics Of Lipid-associated Disorder (GOLD) project initiated
Downloaded by [U Catolica Santiago de Guayaquil ] at 09:10 23 August 2017
Wisconsin School of Medicine by the Austrian government. This review attempts to provide an overview of the lipid
and Pulic Health-Madison, imbalances associated with neurological disorders (Alzheimers disease, Parkinsons
Madison, WI 537923232,
USA disease, Niemann-Pick disease, multiple sclerosis, Huntingtons disease, amyotrophic lateral
Tel.: +1 608 263 1791; sclerosis, schizophrenia, bipolar disorders and epilepsy) and CNS injury (stroke, traumatic
Fax: +1 608 263 1409; brain injury and spinal cord injury), as well as a few provocative thoughts. Lipidomic
adibhatl@neurosurg.wisc.edu analyses along with RNA silencing will provide new insights into the role of lipid intermediates
in cell signaling and hopefully open new avenues for prevention or treatment options.
Lipids & the CNS statistics). The crucial role of lipids in tissue phys-
Phospholipids are important components of all iology and cell signaling is demonstrated by the
mammalian cells and have a variety of biological many neurological disorders, including bipolar
functions: disorders, schizophrenia, neurodegenerative dis-
Formation of lipid bilayers that provide struc- eases such as Alzheimers, Parkinsons, Niemann-
tural integrity necessary for protein function; Pick (NP) and Huntington diseases (HDs), that
involve deregulated lipid metabolism [1]. Altered
Function as an energy reservoir (for example,
lipid metabolism is also believed to be a key event
triglycerides);
which contributes to CNS injury [3].
Serve as precursors for various second messen-
gers, such as arachidonic acid (ArAc), docosa- Reactive oxygen species &
hexaenoic acid (DHA), ceramide, lipid peroxidation
1,2-diacylglycerol (DAG), phosphatidic acid Reactive oxygen species (ROS), including super-
and lyso-phosphatidic acid. oxide anion radical and hydrogen peroxide, are
Lipids comprise a large number of chemically produced by a number of cellular oxidative meta-
distinct molecules arising from combinations of bolic processes including oxidative phosphoryla-
fatty acids with various backbone structures. tion by the mitochondrial respiratory chain,
Overall, mammalian cells may contain approxi- xanthine oxidase, NAD(P)H oxidases, mono-
mately 10002000 lipid species [1]. Lipids are amine oxidases and metabolism of ArAc by
classified into eight categories (fatty acyls, glycer- cyclooxygenases (COX)/lipoxygenases (LOX) [4].
olipids, glycerophospholipids, sphingolipids, However, recent literature suggests that COX
sterol lipids, prenol lipids, saccharolipids and does not directly produce ROS during ArAc oxi-
polyketides) [2]. Subtypes of these eight lipid dative metabolism, but does form free radicals
Keywords: Alzheimers
classes are given in Table 1. Lipid metabolism may (i.e., carbon-centered radicals on ArAc).
disease, arachidonic acid, be of particular importance for the CNS, as this Although there are many reports in the literature
CDP-choline, CNS injury, organ has a high concentration of lipids, second of ROS production by COX, this is probably due
docosahexaenoic acid,
Huntington disease, lipid
only to adipose tissue. to secondary ROS generation induced by various
peroxidation, Neurodegenerative diseases, mental disorders, eicosanoids. Disruption of mitochondria during
neurodegenerative diseases, stroke and CNS traumas are problems of vast clin- COX-2-associated apoptosis is a likely source of
phospholipases,
phospholipids, stroke
ical importance. Currently no cure exists for these ROS production, as has been established for a
CNS injuries and disorders, resulting in a huge number of different cells [57]. ROS then cause
part of impact on quality of life and an economic burden oxidative damage to nucleic acids, proteins,
on society (Table 2, based on US population carbohydrates and lipids. Beyond damage to
10.2217/17460875.2.4.403 2007 Future Medicine Ltd ISSN 1746-0875 Future Lipidol. (2007) 2(4), 403422 403
REVIEW Adibhatla & Hatcher
Table 1. Major lipid classes and representative subtypes.

Lipid class Subtypes
Fatty acyls Free fatty acids and conjugates; eicosanoids; docosanoids; fatty alcohols,
aldehydes and esters
Glycerolipids Mono-, di-, and tri-acylglycerols
Glycerophospholipids Phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and
phosphatidylinositol
Sphingolipids Ceramide, sphingobases, sphingomyelin and glycosphingolipids (gangliosides)
Sterol lipids Sterols including cholesterol, steroids and bile acids
Prenol lipids Isoprenoids, polyprenols, quinones and hopanoids
Saccharolipids Acylaminosugars and acylaminosugar glycans
Polyketides Macrolide and aromatic polyketides
A comprehensive listing of lipids is provided in [2].
membranes, lipid peroxides give rise to reactive insoluble A40 species [8]. A two-step cleavage of
,-unsaturated aldehydes, including malondial- the neuronal membrane protein amyloid precur-
dehyde, 4-hydroxynonenal (HNE) and acrolein. sor protein (APP) [9] results in two products,
These aldehydes covalently bind to proteins A40 and A42. Strong evidence for the role of
through reaction with thiol groups and alter their A in the pathogenesis of AD was provided by
function. Although there are intracellular the observation that, in familial or early onset
defenses against ROS, increased production of AD, mutations in APP or the enzymes that
ROS or loss of antioxidant defenses leads to pro- cleave it lead to over-production of A42 and
gressive cell damage and decline in physiological rapid progression of the disease [10]. Late-onset
function. Oxidative stress occurs when genera- AD is also characterized by accumulation of A
tion of ROS exceeds the cells capacity to detoxify and formation of plaques but is not inherited in
them. The brain is believed to be particularly any simple pattern. The second hallmark of AD
vulnerable to oxidative stress as it contains high is formation of neurofibrillary tangles due to
concentrations of polyunsaturated fatty acids hyperphosphorylation of tau protein.
(PUFAs) that are susceptible to lipid peroxida- There has been debate concerning the roles of
tion, consumes relatively large amounts of oxygen A versus tau protein in AD. Transgenic mouse
for energy production, and has lower antioxidant models of AD require two or more mutations to
defenses compared with other organs. reproduce all the physical features of AD (A
plaques and tau tangles), however these models
Lipids in CNS disorders have not provided any leads to the relationship
A summary of CNS disorders, their symptoms between A plaques and tau tangles. Transgenic
and lipid systems involved is presented in Table 3 mice that overexpress APP do not form neuro-
as a quick reference guide. fibrillary tangles and more closely resemble age-
related memory impairment than AD. Some tau
Alzheimers disease models express little amyloid but develop severe
Alzheimers disease (AD), the most common form memory problems associated with AD [10]. So far
of dementia, is a progressive brain disorder affect- most of the efforts in developing treatments for
ing regions that control memory and cognitive AD are directed to attenuating A plaques.
functions, gradually destroying a persons memory Mouse models based on overexpression of A
and ability to learn, reason, communicate and may be useful in developing strategies to limit
carry out daily activities. AD is broadly divided formation of A plaques, but these are consid-
into sporadic or late-onset AD (9095% of AD) ered limited/incomplete models for AD. APP
and early-onset (occurring in persons under age and APP/PS1 mutant mouse models develop
65 years, 510% of AD). One of the hallmarks of amyloid deposition at a young age, but fail to
AD is overproduction of a 4-kDa peptide, amy- develop neurofibrillary tangles that are the essen-
loid -peptide (A), resulting in the formation of tial hallmark of AD. Neuritic atrophy is found in
plaques. AD encompasses a range of phenotypes, some transgenics, but of nearly one dozen mouse
extending from cases with exclusively aggregated models, only one has reported the loss of neu-
A42 to cases with, in addition, large quantities of rons characteristic of AD [11], which may limit
404 Future Lipidol. (2007) 2(4) future science group

Role of lipids in brain injury and diseases REVIEW
the usefulness of these models for developing increase production of A42. Recent studies sug-
therapeutic strategies for AD [12]. Development gest that A40 inhibits HMG-CoA reductase
of therapeutic strategies directed to tau patho- while A42 activates N-SMase and increases
logy will require identifying which phosphory- ceramide production, which can accelerate the
lation sites are linked to tau aggregation and neurodegenerative process [17,18]. However, it is
filament formation, and the specific kinases and unclear what regulates the cleavage to A42 ver-
phosphatases involved [13,14]. sus A40 and whether the ratio of A42 to A40
While the etiology of late-onset AD is not can be lowered such that attenuation of
clearly understood, there is growing evidence HMG-CoA reductase and N-SMase will be
that cholesterol is of particular importance in simultaneously achieved. Prospective trials evalu-
development and progression of the disease. ating statin therapy did not demonstrate
Apolipoprotein (Apo)E is one of the major improvement in cognitive function in AD
Apos in plasma and the principal cholesterol patients [19]. It is also unknown whether genetic
carrier protein in the brain. Identification of the differences such as presence of the APOE 4
gene encoding the variant ApoE4 (APOE 4
allele affects clinical outcome.

allele) as a significant risk factor for late-onset Recent studies have shown that mRNA
AD provided evidence for a role of cholesterol expression of proinflammatory secretory phos-
in the pathogenesis of AD [15]. Elevated choles- pholipase A2 (sPLA2) group IIA (IIA) was
terol levels increase A in cellular and animal upregulated in AD brains compared with non-
models, and drugs such as statins that inhibit dementia elderly brains and also found
cholesterol synthesis lower A levels [14,16]. Stat- sPLA2 IIA immunoreactive astrocytes in AD
ins inhibit 3-hydroxy-3-methylglutaryl-coen- hippocampus that were associated with A
zyme A (HMG-CoA) reductase that initiates plaques [20].
cholesterol and isoprenoid lipid synthesis. Chol-
esterol is needed to make the cellular membrane AD, oxidative stress & lipid peroxidation
micro-domains referred to as lipid rafts. APP, A number of studies demonstrating increased
-secretase, -secretase complex and neutral lipid peroxidation in AD provide mounting evi-
sphingomyelinase (N-SMase) are present in the dence supporting a role for oxidative damage in
lipid rafts that are rich in cholesterol and this disorder [21]. Recent studies demonstrated
sphingomyelin (SM). Genetic mutations in APP increased levels of hydroxynonenal (HNE) and
or presenilins (part of the -secretase complex) acrolein [21] in the brain tissue from patients
affected by mild cognitive disorder and early
Table 2. Annual cost* of selected CNS disorders and injuries AD, indicating that lipid peroxidation occurs
in USA. early in the pathogenesis of AD [21]. Acrolein, by
far the strongest electrophile among all
CNS disorders or injury Cases Costs/year
,-unsaturated aldehydes, reacts with DNA
(in millions) (in $ billions)
bases including guanine, adenine, cytosine and
Neurological illnesses 50 400 thymidine to form cyclic adducts, the major exo-
Mental disorders (in addition to 44 148 cyclic adduct being acrolein-deoxyguanosine.
neurological illnesses above but Increased levels of acrolein-deoxyguanosine
excluding alcohol and drug problems) adducts were recently demonstrated in brain tis-
Alzheimers disease 4.5 100 sue from AD patients [22]. ROS may also play a
Stroke 4.7 57 role in amyloid deposition in AD as oxidizing
Traumatic brain injury 5 56.3 conditions cause protein cross-linking and aggre-
All depressive disorders 20.5 44 gation of A peptides, and also contribute to tau
Schizophrenia 2 32.5 protein aggregation [23]. A aggregation has been
shown to induce accumulation of ROS, which
Spinal cord injury 0.25 10
may lead to cyclic or self-propagating oxidative
Multiple sclerosis 2.5 9.5
damage. AD and mild cognitive disorder sub-
Parkinsons disease 1 5.6 jects also showed lower levels of antioxidant
Huntingtons disease 0.3 2 defense systems [23].
Amyotrophic lateral sclerosis 0.03 - There may not be any simple answer for the
(Lou Gehrigs disease) complexity of AD. Are the familiar and sporadic
*Data from National Institutes of Health (NIH) and voluntary organizations. forms of AD distinct? Is the research field on the
More than 1000 brain and CNS disorders are known. wrong track studying the familial form and not
future science group www.futuremedicine.com 405

406
Table 3. Lipid systems affected by the CNS disorders and injuries .
Disorder/injury Symptoms/ CNS region(s) affected Mechanism of damage Possible treatments
pathologic features
Alzheimers disease [10] Memory loss/dementia; Amygdala; Altered cholesterol [104] and lipid [105] Ganglioside treatments prevent
Difficulties in communicating; Hippocampus; homeostasis; neuronal death [25]
Problems learning, thinking, Cerebral cortical areas APP cleavage in lipid rafts [9]; ApoE protects against oxidative injury
reasoning; controlling reasoning, Decreased DHA levels; upregulation of by mediating A [105]
Difficulty with familiar tasks; learning and language PLA2; Statins [16]
Disorientation; Increased lipid peroxidation [21,25,106]
Amyloid plaques and tau protein sPLA2-IIA expression increased [20]
aggregation [13,14]
Parkinsons disease [27] Movement disorder; Substantia nigra Although a direct role of PLA2 in PD is not PLA2 inhibition [25]
Resting tremors; yet clearly demonstrated, cPLA2 knock Ganglioside treatments [25]
Muscle rigidity; out mice showed protection against Quinacrine [25]
Bradykinesia (slow movements); MPTP toxicity [25];
Impaired posture, balance PUFAs promote -synuclein
and coordination; aggregation [27]
Lewy bodies/-synuclein aggregates
Niemann-Pick disease Type A: progressive loss of early Lysosomal storage disorder Type A: <1% of normal A-SMase Enzyme replacement was shown to
[30,31,33] motor skills, early fatality typically that leads to SM and activity leads to lysosomal be effective in a mouse model for Type B
within the first few years; cholesterol accumulation sphingomyelin accumulation; [108]
Type B: enlarged liver and spleen; Type B: <10% of normal A-SMase; D609, a SM synthase inhibitor, may be
respiratory problems; Type C: defect in cholesterol transport an option not yet explored [32]
Type C: Inability to move eyes up with secondary defect in A-SMase Inhibition of glycosphingolipid synthesis
Future Lipidol. (2007) 2(4)

and down. Learning and activity; prolonged lifespan in mouse model of
cognitive impairment Excessive accumulation of cholesterol type C [33]
and sphingolipids [107]
Multiple sclerosis- Unpredictable and varies from Demyelination of axons Lipid peroxidation products from ROS Antioxidants [36]
experimental person to person; cPLA2 is highly expressed in EAE [25]; sPLA2 inhibition by CHEC-9 blocks
autoimmune Loss of balance; sPLA2 levels increased prior to onset inflammation [41]
encephalomyelitis Loss of muscle coordination, of symptoms; Ganglioside treatments prevent
[38,109] resulting in tremors, bladder T cells and auto-antibodies to lipids [109]; neuronal death
problems and slurred speech; Decreased DHA levels [106]
Problems with memory, attention,
cognitive functions
Apo: Apolipoprotein; COX: Cyclooxygenase; DHA: Docosahexaenoic acid; EAE: Encephalomyelitis; EPA: Eicosapentaenoic acid; HD: Huntington disease; GABA: -aminobutyric acid; LOX: Lipoxygenase;
MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PLA2: Phospholipase A2; PUFA: Polyunsaturated fatty acids; ROS: Reactive oxygen species; SM: Sphingomyelin.
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Table 3. Lipid systems affected by the CNS disorders and injuries (cont.).
Disorder/injury Symptoms/ CNS region(s) affected Mechanism of damage Possible treatments
pathologic features
Huntington disease Movement disorder; Striatal (caudate and Trinucleotide CAG repeat expansion in Inhibiting
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[43,110] Uncontrollable muscle movements; putamen) neurons; the Huntingtin (Htt) gene is responsible 1) fatty acid amide hydrolase
Lack of concentration; Degeneration of medium for this polyglutamine disease 2) monoacylglycerol lipase or
Memory loss; spiny striato-efferent 3) endocannabinoid membrane
Nuclear and cytoplasmic GABAergic neurons, atrophy transporter provided relief to HD patients
inclusion/Huntingtin of caudate nucleus [43,46]; Ethyl-eicosapentaenoic acid [48]
Combination therapy (minocycline and
coenzyme Q10) [50]
Amyotrophic lateral Limb and muscle weakness, Progressive loss of cortical Lipid peroxidation [56] Riluzole is the only available clinical
sclerosis twitching and cramping of muscles; and spinal cord agent [51]
Lewy body like hyaline motorneurons COX-2 inhibition was beneficial in
inclusion/SOD1 mutation mouse model [54]
Schizophrenia Disturbances in thinking, emotional Dorsalateral prefrontal Altered lipid metabolism may be Antipsychotic drugs;
reactions and social behavior cortex responsible for defects in neurological Eicosapentaenoic acid
development [57,58] supplementation [57]
Bipolar disorder (manic Mood disorders characterized Combination of EPA and DHA [57]
depressiive illness) by episodes of mania and
major depression
Epilepsy Wide range of severity; Focal cortical area, later Decreased DHA levels [106] Ketogenic diet [64]
Violent convulsions; transferred to the thalamus Phenytoin [61]
Loss of conciousness; Second-generation antiepileptic
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Minimal or no movements drugs [62]
Stroke [69] Sudden weakness on one side of Cerebral cortical areas; Activation of phospholipases (A2, C, D) CDP-choline attenuated sPLA2 [68]
the body, loss of balance and Striatum [4,68], increased sPLA2 [111]; Neuroprotectin D1 reduces infarct in
coordination, trouble with cognition cPLA2 knockout mice showed protection MCAO model [91]
[4, and reference cited therein] sPLA2 inhibitors [112]
Decreased DHA levels [106]
Traumatic brain injury Loss of CA3 hippocampal A deposition, tau pathology [84] Corticosteroids [81]
[113] neurons ApoE mimetic peptide showed benefit
in experimental TBI [88]
Spinal cord injury [89] Weakness and sensory loss; Activation of PLA2, COX/LOX pathways; High-dose methylprednisolone in
paralysis Corticosteroids inhibit these clinical use [89]
activations [81] DHA treatment is beneficial [106]
Apo: Apolipoprotein; COX: Cyclooxygenase; DHA: Docosahexaenoic acid; EAE: Encephalomyelitis; EPA: Eicosapentaenoic acid; HD: Huntington disease; GABA: -aminobutyric acid; LOX: Lipoxygenase;
MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PLA2: Phospholipase A2; PUFA: Polyunsaturated fatty acids; ROS: Reactive oxygen species; SM: Sphingomyelin.
407
paying more attention to the sporadic form? Are dopamine agonists, catechol-O-methyltransferase
the animal models good enough to provide con- inhibitors and amantadine [26]. The mechanism
crete answers? Mouse models are based on of action of amantadine remains unknown; how-
mutations in familial AD (the rare form of the ever, it has been suggested to have anticholinergic
disease) and may not model the more common properties in addition to acting as a NMDA
sporadic form. Furthermore, most models do receptor antagonist to increase dopamine release
not exhibit the extent of neurodegeneration seen and inhibit its reuptake. These treatments, how-
in AD patients [10]. The amyloid vaccine ever, remain focused on achieving symptomatic
AN-1792 effectively cleared plaques and relief while minimizing adverse effects.
improved memory in animal models while
Phase 2 trials were abandoned after some PD, oxidative stress & lipid peroxidation
participants developed meningoencephalitis, a In PD, the accelerated metabolism of dopamine
potentially fatal inflammation of the brain. Are by monoamine-oxidase-B may result in excessive
these treatments (e.g., AN-1792) more compat- ROS formation. A role for oxidative stress in PD
ible with the familial form compared with spo- was demonstrated by marked increases in
radic? The triple transgenic mouse (amyloid 8-hydroxy-2-deoxyguanosine, a hydroxyl radi-
precursor protein/PS1/tau) studies raise the pos- cal-damaged guanine nucleotide commonly used
sibility that a multi-antibody-based approach to evaluate oxidative damage to DNA. Further-
(i.e., one targeted against A and one against more, several markers of lipid peroxidation were
tau) may provide the most significant clinical found to be significantly increased in PD brain
benefit for the treatment of AD [24]. The real regions [23].
issue will be how the patients respond to the
combination treatment without developing PD & -synuclein
clinical complications. PD is associated with the presence of Lewy
bodies containing insoluble aggregates of
Parkinsons disease -synuclein in association with other proteins.
Parkinsons disease (PD) is characterized by selec- Recently, the PUFAs were linked to the appear-
tive degeneration of dopaminergic neurons of the ance of soluble oligomers of -synuclein that
substantia nigra, resulting in bradykinesis, tremor ultimately promote the formation of insoluble
and rigidity. The etiology of PD is unknown. -synuclein aggregates [27]. Docosahexaenoic
Oxidative stress caused by free-radical generation acid (DHA) was shown to stimulate oligomeriza-
and lipid peroxidation plays a significant role in tion of -synuclein. Recent studies have shown
pathogenesis of PD. One of the factors responsi- increased levels of DHA in PD brains compared
ble for this stress is believed to be phospholipase with controls [28], suggesting that DHA could
activation in substantia nigra, supported by the have a role in formation of -synuclein
fact that cPLA2 null mice are resistant to aggregates. Interestingly, DHA reduced levo-
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine dopa-induced dyskinesias in MPTP-treated
(MPTP)-induced neurotoxicity [25]. The MPTP monkeys, indicating that DHA can reduce the
metabolite MPP+ is taken up by nigrostriatal neu- severity or delay the development of levodopa-
rons, where it inhibits mitochondrial oxidative induced dyskinesias [29]. It was suggested that
phosphorylation and causes neuronal death. DHA may represent a new approach to improve
MPTP neurotoxicity has been used as an animal the quality of life of Parkinsons disease patients.
model for PD. It should be noted that, while This apparent discrepancy for the role of DHA
MPTP is capable of producing virtually all the in PD (beneficial or harmful?) could be due to
signs and symptoms of PD, strictly speaking, it is the use of MPTP animal models and warrants
not PD and is a separate disease. further investigation.
Treatment of PD Niemann-Pick diseases

No therapy has been demonstrated to slow the NP diseases are genetic pediatric neurodegenera-
loss of dopamine neurons in PD. The dopamine tive conditions characterized by specific disor-
prodrug levodopa remains the gold standard for ders in lipid metabolism and are categorized as
the treatment of PD. However, long-term levo- types A, B and C. NP types A (NPA) and B
dopa therapy leads to development of dyskinesia. (NPB) are caused by deficiencies in acidic
Alternatives to the use of levodopa in early PD sphingomyelinase (A-SMase) [30]. NPA, the most
include monoamine oxidase B inhibitors, common type, is caused by a nearly complete

lack of A-SMase (<1% of normal activity) and is Symptoms range from relatively benign to
characterized by jaundice, an enlarged liver and severely disabling, in which communication
profound brain damage. Infants with NPA rarely between the brain and other parts of the body is
live beyond 18 months. Since A-SMase is local- disrupted, rendering a person unable to write,
ized to the lysosomes, NPA results in accumula- speak or walk. In MS, the immune system
tion of sphingomyelin (SM) and is classified as a attacks the myelin sheath of nerve cell fibers in
lysosomal storage disorder [31]. Those with NPB the brain and spinal cord. MS is predominantly a
have approximately 10% of the normal level of T-lymphocyte-mediated disorder, and cytokines
A-SMase, generally have little or no neurologic may therefore have a key role in the pathogenesis
involvement and may survive into late childhood of the disease. MS is the only neurological dis-
or adulthood. Tricyclodecan-9-yl potassium xan- order where therapeutic manipulation of the
thate (D609), a widely known phosphatidyl- cytokine system influences development of the
choline-phospholipase C (PC-PLC) inhibitor, disease [35]. Thiobarbituric acid reactive sub-
also inhibits SM synthase [32] and may help pre- stances and F2-isoprostane levels were shown to
vent accumulation of SM in NPB, a therapeutic be elevated in CSF of MS patients, and HNE

possibility not yet explored. was associated with MS lesions, indicative that
NP type C (NPC) is also always fatal but it lipid peroxidation also occurs in MS [36].
differs from NPA and NPB at the biochemical
and genetic level. NPC is caused by mutations Experimental autoimmune
in either the NPC1 gene (95% of cases) or encephalomyelitis
NPC2 gene (5% of cases) [33]. While the precise Experimental autoimmune encephalomyelitis
functions of the NPC1 and NPC2 proteins are (EAE) can be induced in animals by immunizing
not clear, these are involved in transport of lip- against myelin antigens [37] and is an animal
ids, particularly cholesterol, from the late endo- model for MS due to similarities in its histo-
somes/lysosomes [34]. Deficiencies in these pathology and clinical course. Recent studies
proteins result in lysosomal accumulation of demonstrated a key role for cPLA2 in EAE [37,38].
cholesterol and other lipids. In NPC, choles- cPLA2, which can be induced by the cytokine
terol accumulates in all tissues except the brain, TNF- [39,40], was highly expressed in EAE
where cholesterol levels decrease with age [33]. lesions. Blocking cPLA2 showed a remarkable
Since 7080% of cholesterol in the brain is con- decrease in both the onset and progression of the
tained in myelin, the extensive demyelination disease [37], indicating that cPLA2 has a signifi-
that occurs in NPC probably accounts for the cant role in both the induction and effector
loss of cholesterol in the brain, which would phases of EAE. A second study showed that
likely mask accumulation of cholesterol in neu- cPLA2 null mice were resistant to EAE [38]. It
rons or astrocytes. Currently there are no treat- should be noted that these studies were con-
ments for NPC. Despite the accumulation of ducted using C57BL/6 or SV127 mouse strains
cholesterol in late endosomes/lysosomes, neither that are naturally deficient in inflammatory
cholesterol- lowering agents nor dietary meas- PLA2 or sPLA2 IIA [4]. Treatment of EAE rats
ures slowed the progression of the disease. with the nonapeptide sPLA2 inhibitor CHEC-9
Neurosteroids and enzymes involved in steroid (CHEASAAQC) significantly attenuated sPLA2
synthesis were significantly reduced in activity, EAE symptoms and ED-1 positive
NPC1-deficient mice. Administration of the microglia/macrophages [41]. Recently, MS patients
neurosteroid allopregnanolone alleviated pro- were shown to have elevated sPLA2 activity [41].
gression of the disease [33], suggesting that neu- These studies suggest that both cPLA2 and
rosteroid therapy might be a treatment option sPLA2 inhibition may be treatment options
for NPC. Since NP diseases have a known for MS.
genetic origin, it is possible that gene therapy to Previous studies have focused on the immuno-
replace the defective genes may eventually pro- logical aspects of MS and the immune systems
vide a cure since that would be directed to the involvement in the disease has been elucidated.
root causes of the diseases. Future studies seeking deeper insights into the
molecular mechanisms of T-cell activation (what
Multiple sclerosis causes the immune system to attack the myelin?)
Multiple sclerosis (MS) is an inflammatory and the signaling cascades responsible for neurode-
demyelinating autoimmune disease affecting the generation will help to further identify molecular
CNS, but its underlying cause remains elusive. targets for efficient treatment strategies [42].

Huntingtons disease R6/2 transgenic HD mouse models also pro-

HD is a relatively rare (eight per 100,000 peo- vided benefit by acting synergistically (mino-
ple) inherited neurological disorder character- cycline attenuated microglia proliferation and
ized by abnormal body movements (chorea, or CoQ10 reduced htt protein aggregation) [50].
jerky, random, uncontrollable movements) and
a lack of coordination; cognition and personal- HD & lipid peroxidation
ity may also be affected. HD is caused by a In HD, one study reported no increase in
trinucleotide repeat expansion in the Hunting- 8-hydroxy-2-deoxyguanosine or other markers
tin (Htt) gene. The normal gene has fewer than of DNA oxidation, and no change in lipid per-
36 repeats, whereas the mutated Htt gene has oxidation (as measured by thiobarbituric acid
40 or more CAG repeats. Since CAG is the reactive substances, a relatively nonspecific
codon for glutamine, HD is one of the marker for lipid peroxidation). By contrast,
polyglutamine diseases. other studies have shown increases in the lipid
Endocannabinoids are endogenous agonists of peroxidation markers F2-isoprostane and
cannabinoid receptors comprised of amides, malondialdehyde in HD [23].

esters and ethers of long-chain PUFAs. N-Ara-
chidonoylethanolamine (AEA, anandamide) and Amyotrophic lateral sclerosis
2-arachidonylglycerol (2-AG) are well character- Amyotrophic lateral sclerosis (ALS) is an adult-
ized lipid mediators of the endocannabinoid sys- onset neurodegenerative disease characterized by
tem [43]. The endocannabinoid system has been progressive loss of spinal cord and cortical
found to have an important neuroprotective role motorneurons and is usually fatal within
in CNS injury and neurodegenerative diseases 25 years of diagnosis. Approximately 10% of
and an extensive review of these studies was ALS cases are familial (inherited), with the remain-
recently published [44]. ing 90% of cases being sporadic in origin [51]. The
Endocannabinoids act as retrograde messen- underlying cause of sporadic ALS still remains
gers and, upon release from postsynaptic neu- elusive. Of the familial cases, approximately 20%
rons, regulate further neurotransmitter release by (i.e., 2% of all ALS) are due to mutations in the
activating presynaptic cannabinoid receptors [45]. gene for the cytosolic copper-zinc superoxide
Cannabinoid receptor 1 (CB1) expression in the dismutase (SOD1). SOD is responsible for
brain is highest in the basal ganglia, globus pal- detoxifying superoxide radicals to hydrogen
lidus and substantia nigra; it is also moderate in peroxide. Expression of a mutant SOD1 pro-
the cerebellum, hippocampus, caudate nucleus, tein, with or without residual SOD activity, is
putamen, hypothalamus and amygdala. The necessary to cause ALS phenotype, suggesting a
endocannabinoid system is hypoactive in HD dominant negative mechanism [51]. There is
[43], which may underlie the neurotransmission strong evidence that the toxicity of mutant
abnormalities of HD and may be the cause of the SOD1 in ALS is not due to loss of activity, but
clinical manifestations of the disease. Inhibition to the gain of one or more toxic functions that
of fatty acid amide hydrolase, monoacylglycerol are independent of SOD1 activity [52]. It is
lipase or the endocannabinoid membrane trans- hypothesized that mutant SOD1 stimulates
porter can enhance endocannabinoid levels and oxidative stress and induces mitochondrial
counteract neurochemical deficits and the hyper- dysfunction, excitotoxicity, inflammation and
kinetic effects of HD [46]. Other studies have protein aggregation [51].
shown that dietary supplementation with essen- The role of glutamate-mediated excitotoxicity
tial fatty acids protected against motor deficits in in ALS was supported by the efficacy of riluzole,
a transgenic mouse model of HD [47]. Recent (a benzothiazole derivative that acts by reducing
studies using ethyl-eicosapetaenoate (Ethyl-EPA, glutamate excitotoxicity) in slowing the progres-
LAX-101 or Miraxion) showed promise in sion of ALS [51]. Riluzole is the only available
clinical trials and its action is presumed to be treatment for ALS, but is now known to have
through c-Jun amino-terminal kinase (JNK) limited therapeutic benefits with minimal effects
pathway [48]. HD is associated with upregulated on survival [53]. Several inflammatory markers,
transglutaminase activity in selectively vulnera- such as caspase 1, COX-2 and TNF-, are
ble brain regions and transglutaminase-catalyzed increased in spinal cord tissue in transgenic
cross-links colocalize with huntingtin (htt) pro- mouse models of ALS. Inhibition of COX-2
tein aggregates [49]. Combination therapy using reduced spinal neurodegeneration and prolonged
minocycline and coenzyme Q10 (CoQ10) in the survival of ALS transgenic mice [54]. The role

of COX-2 in ALS as well as the presence of proteins, availability of cell signaling molecules,
TNF- suggests that cPLA2 and/or sPLA2 may and the behavior of neurotransmitter systems.
also be upregulated in ALS to supply the ArAc This hypothesis is supported by animal studies
substrate to the COX pathway. TNF- induces demonstrating that application of PLA2 into the
cPLA2, sPLA2 as well as COX-2. This suggests brain produces alterations in the dopamine
that anti-TNF- therapy could attenuate the system [57]. In addition, since phospholipid
progression of ALS, an option that does not metabolism has a crucial role in neuronal and syn-
appear to have been tested. aptic growth and remodeling, it is plausible that
defects in this system result in failure of normal
ALS & lipid peroxidation neurodevelopment in schizophrenia. There is also
Evidence of increased oxidative DNA damage evidence that schizophrenia is associated with
in ALS was indicated by elevated levels of alterations in lipid transport proteins and mem-
8-hydroxy-2-deoxyguanosine in plasma, urine brane phospholipid composition (increase in
and CSF [23]. Several studies have shown phosphatidylserine and decrease in phosphatidyl-
increased lipid peroxidation and DNA damage choline and phosphatidylethanolamine) [58].
in transgenic mice expressing mutant SOD1 Genome studies have found that several genes
(an animal model for ALS) and in neural tissue involved in myelination have decreased expression
or sera from ALS patients [55,56]. levels in schizophrenia [59].
Although studies demonstrate that oxidative From a therapeutic perspective, a number of
damage occurs in a number of neurodegenera- reports indicate that at least a portion of schizo-
tive diseases, in chronic conditions such as these phrenic patients have reduced levels of PUFAs,
it is difficult to determine if this damage relates particularly ArAc and DHA, in red cell phos-
directly to the underlying cause of the disease or pholipids, with low levels particularly associated
represents secondary damage in cells with with negative symptoms [57]. ArAc, DHA and
otherwise compromised function [55]. Interpre- eicosapentaenoic acid (EPA) are important for
tation of data from patients is complicated by monoaminergic neurotransmission, brain devel-
the fact that observations are usually obtained at opment and synaptic functioning [58]. This sug-
the end stage of neurological disease and thus gests that supplementation with essential fatty
the time course of oxidative damage relative to acids could alleviate symptoms of schizophrenia.
the progression of the disease is not obtained. In In preliminary studies, however, DHA essen-
addition, these oxidative modifications are not tially had no effect and ArAc appeared to worsen
disease specific, but occur in a number of symptoms in some schizophrenia patients.
neurodegenerative diseases. Unexpectedly, EPA provided significant
improvement, comparable in magnitude to that
Schizophrenia, epilepsy & produced by new atypical antipsychotic drugs,
bipolar disorders without any of the side effects characteristic of
Schizophrenia is marked by disturbances in drug treatment. The combination of EPA and
thinking, emotional reactions and social behav- DHA was also beneficial in bipolar disorder
ior, with delusions and hallucinations. Drugs that (manic-depressive illness) [57].
block dopamine receptors alleviate symptoms of
schizophrenia, indicative of excess dopaminergic Epilepsy
function, while agents that block glutamate Epilepsy is a neurological disorder characterized
receptors induce some of the symptoms of by recurrent spontaneous seizures due to an
schizophrenia in otherwise normal persons [57]. imbalance between cerebral excitability and inhi-
Recent theories on the neurological deficits of bition, with a tendency towards uncontrolled
schizophrenia have focused on abnormalities in excitability [60]. Recurrent severe seizures can
phospholipid metabolism, particularly increased lead to death of brain cells. The usual treatment
activity of PLA2 enzymes and reduced activity of for epilepsy is administration of anti-epileptic
the system that incorporates PUFAs into phos- drugs. Phenytoin (US brand names: Dilantin,
pholipids (a simultaneous increase in phospho- Phenytek) is the generic name of a widely used
lipid hydrolysis and decrease in synthesis) [57,58]. antiseizure medicine [61]. The primary site of
Neither abnormality alone produces schizophre- action appears to be the motor cortex, where
nia but the presence of both does [57]. These spread of seizure activity is inhibited possibly by
abnormalities lead to changes in membrane struc- promoting sodium efflux from neurons. Pheny-
ture and thus the function of membrane-bound toin tends to stabilize the threshold against

hyper-excitability caused by excessive stimula- subsequent production of eicosanoids, ceramide

tion. The current status of new (second genera- and free radicals (ROS, RNS and other radicals)
tion) anti-epileptic drugs has been recently that may potentiate brain injury [74].
reviewed [6163].
The ketogenic diet is an established and effec- CDP-choline
tive nonpharmacological symptomatic treatment CDP-choline, the rate-limiting intermediate in
for epilepsy that has been in clinical use for more phosphatidylcholine (PC) biosynthesis, has
than 80 years [60,64,65]. The ketogenic diet is a shown beneficial effects in cerebral ischemia,
high fat, low protein and low carbohydrate diet TBI, hypoxia, AD, PD, learning and memory
in which over 90% of calories are derived from disorders, alcoholism, drug addiction, amblyopia
fat and dietary availability of glucose is minimal and glaucoma, and has undergone several clinical
[60,64,65]. The hallmark feature of the ketogenic trials for stroke treatment worldwide (Box 1) [67].
diet is production of ketone bodies (-hydroxy- An extensive review of CDP-choline studies was
butyrate, acetoacetate and acetone) in the liver recently published [75]. Owing to the complexity
with a concomitant rise in plasma levels. Since of stroke biochemistry, targeting a single path-
glucose (the preferred source of energy, particu- way may never prove efficacious. Drug cocktails
larly in the brain) is severely restricted, the or combinational therapies have been suggested
ketone bodies are used as the energy source in but have not yet been initiated in clinical trials.
extrahepatic tissues [64]. Despite its many years of In experimental paradigms, CDP-choline in
use, there is still considerable debate over how combination with urokinase, basic fibroblast
the ketogenic diet works; several major hypo- growth factor, or nimodipine provided synergis-
theses have been advanced, but none are tic benefits [67]. The failure of NXY-059 SAINT
widely accepted. II trials [76] reiterates the need for combinational
treatment. CDP-choline is a safe drug (virtually
Lipids in CNS injury no side effects even when given at 2 g/day in
Focal cerebral ischemia (stroke) clinical trials) and should be considered as one
Focal cerebral ischemia caused by obstruction of component in combination therapy.
blood flow (ischemia) to the brain, is the leading
cause of long-lasting disability and third leading Stroke, ROS & lipid peroxidation
cause of death. Presently, tissue plasminogen Until now, it has been generally accepted that the
activator (tPA) is the only US FDA approved oxidative metabolism of ArAc thorough COX
drug for the treatment of ischemic stroke. tPA generates prostaglandins and ROS. Recent stud-
administration beyond 3 h presents hemor- ies have clarified that COX-2 produces tyrosyl
rhagic risk. The recent failure of NXY-059 (a radicals on the protein and carbon centered radi-
nitrone spin trap agent developed by Astra- cals on the substrate ArAc, but does not generate
Zeneca) in Phase III stroke clinical trials empha- ROS [5,6]. It has been shown recently that ROS
sizes the need for careful preclinical scrutiny of production was elevated in a stroke model but
test agents before embarking into major clinical that COX-2 inhibition did not attenuate ROS
trials [66]. production. Also, ROS generation was not
The initial event in cerebral ischemia is energy reduced in COX-2 deficient mice [7]. These stud-
failure, resulting in excessive release of the ies indicated that NADPH oxidase was a signifi-
neurotransmitters such as dopamine and gluta- cant source of ROS in the stroke model [7]. The
mate [67]. Over-stimulation of glutamate receptors role of ROS in activation of various signaling
results in elevated intracellular Ca2+ and activa- pathways such as p38, JNK, p53, ERK1/2, Akt,
tion of phospholipases A2, C, and D (Figure 1A) NFB [77], matrix metaloproteinases [78] and
and sphingomyelinases (Figure 1B). Activation of stroke injury [4,79] have been recently reviewed.
these phospholipases causes hydrolysis of Generation of HNE has been demonstrated by
membrane phospholipids and release of second both ourselves and others in brain tissue after stroke
messengers [4,68,69]. TNF- and IL-1, major [4]. Recently, elevated levels of an acroleinprotein
proinflammatory cytokines, are rapidly upregu- conjugate (N-[3-formyl-3,4-dehydropiperidino]-
lated in the brain following cerebral ischemia lysine, FDP-lysine) were demonstrated in plasma
and activate phospholipases [7073]. The nature of of stroke patients [80]. The time-course of altera-
the inflammatory response after stroke suggests tions in lipid metabolism and formation of lipid
that cytokines, particularly TNF- and IL-1/, metabolites and lipid peroxidation products after
affect the phospholipid metabolism and transient cerebral ischemia is presented in Figure 2.

Figure 1. Lipid metabolism in ischemic neuronal death.
Glutamate release Ischemia

A
Extracellular Ca++ mGluR 1
NMDA and 5
G protein
PI-PLC
Ca++ [Ca++]i IP3 PIP2

PC
PC-PLC 1,2-diacylglycerol (DAG)

PLA2
DAG FFA,
DHA
ArAc Anti-inflammatory
Lyso-PA
PLD PA
DHA LOX Resolvins and protectins
G protein
ArAc LOX Lipoxins
Reincorporation
into membrane Proinflammatory
COX/LOX Prostaglandins, leukotrienes

Neuronal and thromboxanes
mGluR death
Free radicals including ROS, lipid

peroxidation and the formation of
B TNF- and IL-1
MDA, HNE and acrolein
PLA2 PC-PLC
PC
ArAc DAG SM
N-SMase A-SMase
SM synthase
SM
Ceramide PC
(A) Activation of phospholipases (PLA2, PC-PLC, PI-PLC and PLD) following cerebral ischemia results in release of lipid second messengers
DAG, PA, lyso-PA, DHA and ArAc. PA and DAG can be readily interconverted by phosphohydrolases and DAG-kinases. ArAc undergoes
further metabolism by COX/LOX to generate important signaling and vasoactive eicosanoids. Free radicals are formed during ArAc
metabolism by COX/LOX and free radical generation can be induced by eicosanoids. Recent studies indicate that ArAc oxidative
metabolism by COX-2 produces free radicals but does not directly generate ROS [7]. ArAc generates proinflammatory prostaglandins,
leukotrienes and thromboxanes as well as LOX-generated anti-inflammatory lipoxins. Through the LOX pathway, DHA is metabolized to
anti-inflammatory resolvins and protectins, including 10,17S-docosatriene (neuroprotectin D1), an endogenous neuroprotectant.
(B) Glycerophospholipid and sphingolipid relationship. TNF- and IL-1 activate N-SMase and A-SMase through stimulation of PLA2 and
PC-PLC and release of ArAc and DAG, respectively. N-SMase and A-SMase hydrolyze SM to liberate ceramide. SM synthase transfers the
phosphocholine head-group of PC to ceramide to form SM and DAG.
ArAc: Arachidonic acid; A-SMase: acidic sphingomyelinase; COX/LOX: Cyclooxygenases/lipoxygenases; DAG:1,2-diacylglycerol;
DHA: Docosahexenoic acid; FFA: Free fatty acid; N-SMase: Neutral sphingomyelinase; PA: Phosphatidic acid; PLA: Phospholipase A;
PLD: Phospholipase D; ROS: Reactive oxygen species; SM: Sphingomyelin.

Box 1. CDP-choline and stroke: an issue to be revisited.

The therapeutic action of CDP-choline is thought to be due to stimulation of phosphatidylcholine (PC) synthesis in the brain after
stroke. However, to the best of our knowledge there were no reports in stroke models demonstrating that loss of PC occurs, and
CDP-choline treatment restores PC levels. CDP-choline has also been termed a membrane stabilizer, free radical scavenger and
antioxidant without any experimental evidence. Recent research on this drug revealed some interesting findings [68,101].
PC is a major membrane phospholipid and its loss threatens cell viability. PC homeostasis is regulated by the balance between
hydrolysis and synthesis [67]. PC is hydrolyzed by phospholipase A2 (PLA2) [4], PC-phospholipase C (PC-PLC) and phospholipase D
(PLD). PC synthesis is rate-limited by CTP: phosphocholine cytidylyltransferase (CCT) which produces CDP-choline.
Proinflammatory cytokines TNF- and IL-1 are upregulated following stroke and activate phospholipases and sphingomyelinases
(SMases), generating arachidonic acid (ArAc) and pro-apoptotic ceramide, and also down-regulate CCT and sphingomyelin (SM)
synthase (Figure 3).
In rat stroke model, the upregulation of phospholipases and downregulation of CCT collectively resulted in the loss of PC [68].
CDP-choline treatment significantly attenuated phospholipase induction, loss of CCT and PC, and infarction volume. CDP-choline
also attenuated cytokine expression (TNF- and IL-1) after stroke [102], suggesting that CDP-choline may affect PC synthesis and
hydrolysis through proinflammatory pathways.
CDP-choline in stroke clinical trials
Clinical trials in Japan and Europe used intravenous administration in contrast to oral route in US trials, which gave ambiguous results
[67,101]. It was unclear why the oral route was chosen in US trials (to the best of our knowledge, this is the only drug given orally to
stroke patients; if the patient was incapable of swallowing, the drug was administered nasally). Animal studies have shown brain
uptake of CDP-choline increased to 2% when administered intravenously, compared with 0.5% by oral route. The following points
are worth considering in future CDP-choline clinical trials:
CDP-choline efficacy may depend on the formulation and route of delivery [103]. Liposome encapsulation of CDP-choline
provided more efficient delivery of the drug to the brain and significantly decreased infarction (by 62%) compared with the
equivalent dose of free CDP-choline (26% reduction) after stroke [101]. Bloodbrain barrier permeability following stroke allows
passage of liposomes less than 100 nm directly through the compromised vasculature [101]. Advantages of CDP-choline
liposomes in stroke include:
Effectiveness at low doses (18 mg/kg in CDP-choline liposomes vs 500 mg/kg free CDP-choline);
The presence of GM1 ganglioside confers long-circulating properties by suppressing phagocytosis;
Brain uptake of the drug is increased to approximately 23% of the injected dose;
Exogenous CDP-choline is rapidly hydrolyzed and absorbed as cytidine and choline and needs to be re-synthesized by CCT [101].
However, it should be noted that CCT expression is significantly reduced following stroke [68]. CDP-choline liposomes deliver the
agent intact to the brain, circumventing the rate-limiting CCT step (Figure 4) [101].
Conclusions
CDP-choline beneficial effects could be attributed to interactions at TNF-/IL-1-mediated events, differentially affecting
phospholipases and CCT [102]. This limits phospholipid hydrolysis and increases synthesis, thereby restoring PC and SM levels
(Figure 3). Our recent studies also showed that PC loss is a cause rather than a result of cell death [32]. Since all cells (neurons,
astrocytes and endothelial cells etc., called the neurovascular unit) contain PC as a membrane building block, CDP-choline
protection may arise from stabilizing the neurovascular unit. These studies provide an integration of CDP-choline effects with
cytokine biology and lipid metabolism in stroke [67,74,102].
IVAX Corporation, a Florida based company, has entered into a licensing agreement with Grupo Ferrer, Barcelona, Spain, for the
final development of CDP-choline in oral neuroprotective therapy for the treatment of stroke.
Traumatic brain injury occur subsequent to the initial trauma present

Traumatic brain injury (TBI) is usually associ- targets for therapeutic intervention. Corticoster-
ated with significant neuropsychological deficits, oids have been proposed as therapies to reduce
primarily in the domains of attention, executive the secondary injuries following TBI. Corticos-
functioning and memory. In TBI, the initial teroids inhibit the PLA2/COX/LOX pathways,
traumatic event is shearing, laceration and/or thus limiting ArAc release and metabolism,
contusion of brain tissue resulting from a physi- downregulating proinflammatory cytokines and
cal impact. Secondary injury after the initial attenuating the inflammatory response. How-
trauma results from ischemia, alterations in ion ever, large scale clinical trials of corticosteroids
and neuromodular levels, oxidative stress caused and lazaroids (21-aminosteroids) for treatment
by ROS, edema and axonal swelling [81]. Similar of TBI have either failed to demonstrate efficacy
to stroke, pathways of secondary injury that or found increased risk of mortality [81].

Figure 2. Time course of changes related to cytokines, lipid metabolism and oxidative
stress after transient brain ischemia.
sPLA2
PLD2
sPLA2 ArAc
PLD2 sPLA2 OH
MDA PLD2 HNE
PC-PLC TNF- TNF- TNF- sPLA2
ArAc IL-1 IL-1 IL-1 PLD2
1h 13 h 6h 1 day 3 day 7 day
CCT
Ischemia Reperfusion CCT
Phospholipids
Future Lipidology
PLA2 enzyme activity, sPLA2 mRNA and protein expression, PC-PLC activity and PLD2 protein expression were
increased after stroke. CCT catalyzes the rate-limiting step in the biosynthesis of PC. CCT activity and protein
expression decreased following stroke. Activation of phospholipases and loss of CCT collectively resulted in
loss of PC.
: Increase; : Decrease, compared to control; ArAc: Arachidonic acid; CCT: Cytidine
triphosphate:phosphocholine cytidylyltransferase; HNE: 4-hydroxynonenal; MDA: malondialdehyde;
OH: hydroxyl radical; PLA : Phospholipase A ; PC: Phosphatidylcholine; PC-PLC: Phosphatidylcholine-specific
2 2
phospholipase C; PLD2: Phospholipase D2; sPLA2: Secretory PLA2.
TBI & ApoE not find an association of APOE 4 allele with

While the APOE 4 allele was first implicated as poorer outcome after TBI, these differences could
a significant risk factor for AD, a number of be due to the severity of the TBI (no association
clinical studies have indicated that performance in some studies with predominantly mild TBI),
on neuropsychological tasks is worse in TBI the neurological evaluation methods that assess
patients with the APOE 4 allele than those the involvement of different brain regions, and
without it [82]. While other clinical studies did the evaluation time post injury (up to 25 years
after TBI). Fluid percussion brain injury upregu-
Figure 3. CDP-choline: integration of cytokine response and lated both ApoE mRNA and protein expression
lipid metabolism after stroke. in rats [83]. Both human postmortem and experi-
mental studies have shown A deposition and tau
pathology following TBI [84]. The development
Stroke of AD-like neuropathological and biochemical
changes after severe TBI suggested that TBI may
CDP-choline
be a risk factor for subsequent development of
dementia [85]. Epidemiological studies have pro-
SMases TNF- PLA2 , PC-PLC
vided discrepant findings and the relationship
SM synthase IL-1 PLD and CCT
between TBI and dementia remains a topic for
further investigation. It has been suggested that
TBI may lower the threshold for dementia
PC , ArAc among predisposed individuals. In other studies,
SM and ceramide the presence of the APOE 4 allele has been asso-
Future Lipidology
ciated with poorer outcome after cardiopulmo-
Upregulation of TNF- and IL-1 differentially affects phospholipases, SMases, nary resuscitation and intracerebral hemorrhage,
CCT and SM synthase in collectively causing loss of PC and SM and release of but not after ischemic stroke [86]. Statins have
ArAc and ceramide. CDP-choline partially prevents loss of these phospholipids shown benefit in experimental TBI [87], but it is
by attenuating the inflammatory response. unknown if statin treatment affected A levels.
ArAc: Arachidonic acid; CCT: Cytidine triphosphate:phosphocholine ApoE is an important mediator of cholesterol
cytidylyltransferase; CDP-choline: Cytidine-5'-diphosphocholine; and lipid transport in the brain and is encoded
PC: Phosphatidylcholine; SM: Sphingomyelin.
by the polymorphic gene APOE. ApoE has been
Taken from [74].
shown to reduce glial activation and CNS

Figure 4. CDP-choline and PC synthesis.
Cytidine Cytidine triphosphate 1,2-diacylgycerol

Hydrolysis
CDP-choline
Choline Phosphocholine CCT CDP-choline CPT PC
CDP-choline
liposomes
Control Stroke
42 kDa CCT
-actin
Future Lipidology
CCT is downregulated after stroke, impeding PC synthesis [68]. CDP-choline liposomes deliver the drug intact
to the brain, bypassing the CCT step [101]. The Western blot shows loss of CCT protein after stroke.
CCT: Cytidine triphosphate:phosphocholine cytidylyltransferase; CDP-choline: Cytidine-5-diphosphocholine;
PC: Phosphatidylcholine.
Data taken from [68,101].
inflammatory response. While it may be reasona- oxide synthase (NOS) and PLA2. PLA2 releases
ble to relate effects of ApoE to cholesterol ArAc into the COX/LOX pathways to generate
transport, the mechanism whereby ApoE elicits eicosanoids. One consequence of mitochondrial
these effects has not been elucidated. This action dysfunction, activation of NOS and COX/LOX
is isoform-specific with the ApoE4 isoform being activity is generation of free radicals (comprised of
less effective at downregulating inflammatory different species including reactive nitrogen spe-
cytokines [88]. These studies suggest that ApoE cies [RNS], ROS and other radicals) and subse-
could be a therapeutic target for treatment of TBI, quent lipid peroxidation, believed to be a major
although administration of the full protein would pathway of secondary injury in SCI [89].
be impractical due to its large size and inability to The glucocorticoid steroids dexamethasone
cross the bloodbrain barrier. A small peptide and methylprednisolone have been extensively
apoE(133149) was created from the receptor used in clinical treatment of SCI. The initial
binding region that retains the ability of the native rationale was that, since these compounds
protein in downregulating inflammatory reduced brain edema in brain tumor patients,
responses. Administration of apoE(133149) was they would also reduce edema in SCI. With the
shown to significantly improve histological and knowledge of the lipid peroxidation mechanism,
functional outcome after experimental TBI [88]. later attention focused on the potential of gluco-
corticoid steroids to inhibit post-SCI lipid per-
Spinal cord injury oxidation, based on their ability to intercalate
Similar to TBI, spinal cord injury (SCI) is the into artificial membranes and limit propagation
result of an initial physical trauma followed by a of lipid peroxidation chain reactions [89]. In
secondary degenerative process. The majority of animal studies, it was demonstrated that a high
SCI do not involve physical transection of the spi- dose of methylprednisolone did inhibit post-trau-
nal cord; instead, the cord is injured as a result of matic lipid peroxidation in spinal cord tissue.
contusive, compressive or stretch injury. Residual Beneficial effects secondary to inhibition of lipid
white matter containing portions of sensory and peroxidation included preservation of ion home-
motor tracts remain intact, suggesting that phar- ostasis, mitochondrial energy metabolism and
macological interventions aimed at the secondary attenuation of delayed glutamate release [89]. It is
injury cascade could promote neurological recov- believed that inhibition of lipid peroxidation is
ery and preserve function [89]. The initial event the principle neuroprotective mechanism of
after SCI is depolarization and opening of voltage- high-dose methylprednisolone and that gluco-
dependent ion channels, and consequent massive corticoid receptor-mediated anti-inflammatory
release of neurotransmitters, including glutamate. effects have only a minor role [89]. In clinical
This leads to accumulation of intracellular cal- trials, high-dose methylprednisolone was shown
cium, initiating a number of damaging events: to improve outcome in SCI if treatment was
mitochondrial dysfunction, activation of nitric initiated within 8 h of the initial trauma.

Another agent that has undergone Phase III Future trends: lipidomics & RNA silencing
clinical trials for SCI is GM1 ganglioside. Since The emerging field of lipidomics tries to define
high-dose methylprednisolone had become the crucial role of lipids in the cell; the research is
widely accepted for treatment of SCI, GM1 was aimed at mapping the entire lipid population in a
administered after the completion of the 24-h biological system, describing the composition and
methylprednisolone dosing protocol. The biological function [1,96,97]. The main progress
results indicated that GM1 did not provide that has spurred recent advances in lipid analysis
greater functional improvement compared with was the development of new mass spectroscopic
methylprednisolone alone [89]. techniques, particularly the soft ionization tech-
niques of electrospray ionization (ESI) and
DHA generates anti-inflammatory matrix-assisted laser desorption/ionization
resolvins & protectins including (MALDI). Lipidomics seeks to provide a molecu-
neuroprotectin D1 lar signature to a certain pathway or a disease con-
Release of lipid second messengers following dition. The role of lipids in formation of cell
neuronal injury can either promote further neu- membranes makes them both ligand and substrate
ronal injury or neuroprotection. Cerebral for proteins, suggesting that advances in lipid-
ischemia results in rapid accumulation of free omics could have far-reaching implications in
fatty acids, including ArAc (20:4) and DHA genomic, proteomic and metabolomic fields.
(22:6). Through the COX/LOX pathways, ArAc Impressive achievements and advancements have
is metabolized to proinflammatory and vaso- surfaced during the last few years [91]. Lipidomics
active eicosanoids (prostaglandins, leukotrienes holds the promise of characterizing complex mix-
and thromboxanes). ArAc is also metabolized to tures of lipids, identifying previously unknown
anti-inflammatory lipoxins through the LOX changes in lipid metabolism [67].
pathway (Figure 1A). RNA interference (RNAi) [98100] takes advan-
DHA is the most abundant polyunsaturated tage of a naturally occurring process to degrade
fatty acid in the brain, and is concentrated in ami- RNA. RNAi selectively and temporarily switches
nophospholipids of cell membranes. Although off specific genes, providing a powerful tool to
the underlying mechanisms of its essential func- analyze protein function and biochemical path-
tion are not clear, emerging evidence suggests that ways. Lipidomic analyses together with RNAi
unique metabolism of DHA plays an important may provide a powerful tool to elucidate the spe-
role [90]. Studies on the role of PLA2 and PLA2 cific roles of lipid intermediates in cell signaling.
hydrolysis products have identified the DHA These approaches have provided crucial informa-
metabolites resolvins and protectins, including tion that was previously unachievable [95]. A
10,17S-docosatriene (neuroprotectin D1), fol- deeper knowledge of the complexity of lipid sign-
lowing cerebral ischemia/reperfusion in mouse aling will elevate our understanding of the role of
models (Figure 1A) [91]. Neuroprotectin D1 was lipid metabolism in various CNS disorders, open-
found to serve an endogenous neuroprotective ing new opportunities for drug development and
role by inhibiting apoptotic DNA damage, therapies for neurological diseases.
upregulating anti-apoptotic proteins Bcl-2 and
BclxL, and downregulating pro-apoptotic Bax Acknowledgements & financial disclosure
and Bad expression [92]. Neuroprotectin D1 also This work was supported by grants from NIH/NINDS
inhibited oxidative stress-induced caspase-3 (NS42008), American Heart Association Greater Midwest
activation and IL-1-stimulated COX-2 expres- Affiliate Grant-in-Aid (0655757Z), UW-School of Medicine
sion [93]. Administration of albumin causes and Public Health and UW-Graduate school (to RMA), and
systemic mobilization of n-3 PUFAs including laboratory resources provided by William S. Middleton VA
DHA, and provides substantial neuroprotection Hospital. We would like to thank Ms. Shah for help with
in models of brain ischemia and trauma. preparation of Table 1. Owing to space limitations, we sin-
DHA-albumin administration increased neuro- cerely apologize for those important contributions that could
protectin D1 in the ipsilateral brain following not be included. We would like to express our sincere thanks to
transient cerebral ischemia in rat [94]. Recent the anonymous reviewers for their excellent suggestions that
studies also showed that neuroprotectin D1 pro- have improved the quality of this review article.
moted neuronal survival by the induction of The authors have no relevant financial interests including
neuroprotective gene expression and anti-apop- employment, consultancies, honoraria, stock ownership or
totic pathways that attenuated A42-induced options, expert testimony, grants or patents received or pending,
neurotoxicity [95]. or royalties related to this manuscript.

Executive summary
Importance of lipids
Lipids are important components of all mammalian cells and have a variety of biological functions, including forming the
phospholipid bilayer that provides structural integrity for the cellular membrane, serving as an energy reservoir (e.g., triglycerides)
and as precursors for various second messengers such as arachidonic acid (ArAc), 1,2-diacylglycerol (DAG), ceramide and
phosphatidic acid, and so on.
Lipid involvement in neurological disorders
Alzheimers disease (AD) is characterized by formation of amyloid (A)-peptide plaques and tau protein tangles. Apolipoprotein
(Apo)E is the principal cholesterol carrier protein in the brain, and the gene encoding the variant ApoE4 is a significant risk factor
for AD. Cholesterol-lowering statins reduced A levels. Proinflammatory secretory phospholipase A2 IIA (sPLA2 IIA) is upregulated
in AD brains.
Parkinsons disease (PD) is characterized by selective degeneration of dopaminergic neurons of the substantia nigra. Free radical
generation and lipid peroxidation due to phospholipases activation are believed to play a significant role in PD pathogenesis.
Niemann-Pick (NP) diseases types A and B are due to defects in acidic sphingomyelinase (A-SMase), resulting in accumulation of
sphingomyelin (SM), while NPC is caused by accumulation of cholesterol due to a defect in transport. Tricyclodecan-9-yl
potassium xanthate (D609) inhibits SM synthase and may help prevent accumulation of SM in NPB, a possibility not yet explored.
Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the CNS. Inhibiting cytosolic PLA2 or sPLA2
attenuated the onset and progression of experimental autoimmune encephalomyelitis (EAE), an animal model for MS. MS
patients were shown to have elevated sPLA2 activity.
Huntingtons disease (HD) is an inherited neurological disorder caused by a trinucleotide repeat expansion in the Huntingtin (Htt)
gene. The endocannabinoid system is hypoactive in HD, and may be the cause of the clinical manifestations of the disease. On
the other hand clinical trials with ethyl-eicosapetaenoate (Ethyl-EPA) and the combination of minocycline and coenzyme Q10
(CoQ10) in a transgenic model showed great promise.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of spinal cord and cortical
motorneurons. Inflammatory markers such as cyclooxygenase 2 (COX-2) and TNF- are increased in spinal cord tissue in
transgenic models of ALS. Inhibition of COX-2 reduced spinal neurodegeneration and prolonged the survival of ALS
transgenic mice.
Schizophrenia is associated with alterations in lipid transport proteins and membrane phospholipid composition. Dietary
supplementation with eicosapentaenoic acid (EPA) provided improvement in schizophrenia patients. The combination of EPA and
docosahexaenoic acid also provided benefit in bipolar disorder. The ketogenic diet, in which over 90% of calories are derived
from fat, is an established and effective nonpharmacological symptomatic treatment for epilepsy.
CNS injuries
Focal cerebral ischemia (stroke), caused by obstruction of blood flow to the brain, leads to paralysis.
Tissue plasminogen activator (tPA) is the only US FDA approved drug (since 1996) for the treatment of ischemic stroke. tPA poses
hemorrhagic risk if given beyond 3 h, and only 0.5% of all the stroke patients benefit from tPA. Recent failure of NXY-059 stroke
clinical trials once again renewed the challenges for discovery of new neuroprotectants.
CDP-choline has undergone several stroke clinical trials in USA and was slated as safe but ineffective, a conclusion that needs to
be re-examined. CDP-choline liposomes provided more efficient delivery of the drug to the brain and better neuroprotection at a
lower dose compared with the free drug (see Box 1). This once again reiterates the fact that effective treatment for stroke requires
not only the discovery of protective agents, but also an effective system to deliver them to the stroke-stricken brain.
In traumatic brain injury (TBI), data suggest that presence of the APOE 4 allele is associated with poorer recovery. Human and
experimental studies have shown A deposition and tau pathology after TBI. Statin treatment after experimental TBI showed
better outcome but it is unknown whether statins have any effect on A levels. Large clinical trials with lazaroids
(21-aminosteroids) in TBI did not yield fruitful results. In spinal cord injury, high-dose methylprednisolone showed benefit,
which was attributed to attenuating the lipid peroxidation.
Neurotoxic & neurotrophic actions of PLA2
PLA2 releases arachidonic acid (ArAc), which is metabolized to eicosanoids through cyclooxygenases/lipoxygenase (COX/LOX)
pathways with the production of free radicals. Carbon-centered radicals formed on ArAc during metabolism by COX can cause
lipid peroxidation, a pathway of neuronal injury common to many CNS disorders and neurodegenerative diseases. COX-2 is not a
major source of ROS.
PLA2 also releases docosahexaenoic acid (DHA), which is metabolized to resolvins and protectins, including neuroprotectin D1, an
endogenous neuroprotectant.
What we can look for in the future?
The emerging field of lipidomics together with RNA interference will provide powerful tools to elucidate the specific roles of
lipid intermediates in cell signaling. This will lead to better understanding of the CNS disease process and provide new
treatment paradigms.

Bibliography 10. Mandavilli A: The amyloid code. Nat. Med. 20. Moses GS, Jensen MD, Lue LF et al.:
Papers of special note have been highlighted as 12(7), 747751 (2006). Secretory PLA2-IIA: A new inflammatory
either of interest () or of considerable interest () Provocative commentary on the factor for Alzheimers disease.
to readers. current amyloid theories in Alzheimers J. Neuroinflammation. 3(1),
1. Wenk MR: The emerging field of disease (AD). doi:10.1186/1742209411831128
lipidomics. Nat. Rev. Drug Discov. 4(7), 11. Herrup K, Neve R, Ackerman SL, Copani (2006).
594610 (2005). A: Divide and die: Cell cycle events as First report showing the expression of
Excellent comprehensive review on various triggers of nerve cell death. J. Neurosci. sPLA2 IIA (inflammatory PLA2) in
aspects of lipidomics and bioinformatics. 24(42), 92329239 (2004). AD brains.
2. Fahy E, Subramaniam S, Brown HA et al.: Critical review on neuronal cell cycle and 21. Williams TI, Lynn BC, Markesbery WR,
A comprehensive classification system for death and transgenic models in AD. Lovell MA: Increased levels of 4-
lipids. J. Lipid Res. 46(5), 839862 (2005). 12. Schwab C, Hosokawa M, McGeer PL: hydroxynonenal and acrolein, neurotoxic
Comprehensive classification of lipids with Transgenic mice over-expressing amyloid markers of lipid peroxidation, in the brain in
a common platform that is compatible beta protein are an incomplete model of mild cognitive impairment and early
with informatics requirements for the Alzheimer disease. Exp. Neurol. 188(1), Alzheimers disease. Neurobiol. Aging 27(8),
hard-core lipid community. 5264 (2004). 10941099 (2006).
3. Adibhatla RM, Hatcher JF, Dempsey RJ: Transgenic models over-expressing A 22. Liu X, Lovell MA, Lynn BC: Development
Lipids and lipidomics in brain injury and alone are incomplete models for AD and of a method for quantification of acrolein-
diseases. AAPS J. 8(2), E314E321 (2006). have limited use. deoxyguanosine adducts in DNA using
4. Adibhatla RM, Hatcher JF: Phospholipase 13. Gotz J, Streffer JR, David D et al.: isotope dilution-capillary LC/MS/MS and
A2, reactive oxygen species, and lipid Transgenic animal models of Alzheimers its application to human brain tissue. Anal.
peroxidation in cerebral ischemia. Free disease and related disorders: histopathology, Chem. 77(18), 59825989 (2005).
Radic. Biol. Med. 40(3), 376387 (2006). behavior and therapy. Mol. Psychiatry 9(7), 23. Mariani E, Polidori MC, Cherubini A,
5. Jiang J, Borisenko GG, Osipov A et al.: 664683 (2004). Mecocci P: Oxidative stress in brain aging,
Arachidonic acid-induced carbon-centered 14. Puglielli L: Aging of the brain, neurotrophin neurodegenerative and vascular diseases: an
radicals and phospholipid peroxidation in signaling, and Alzheimers disease: Is IGF1- overview. J. Chromatog. B. 827(1), 6575
cyclo-oxygenase-2-transfected PC12 cells. R the common culprit? Neurobiol. Aging (2005).
J. Neurochem. 90(5), 10361049 (2004). doi:10.1016/j.neurobiolaging.2007.01.010 24. Oddo S, Billings L, Kesslak JP, Cribbs DH,
6. Simmons DL, Botting RM, Hla T: (2007). LaFerla FM: A immunotherapy leads to
Cyclooxygenase isozymes: The biology of 15. Puglielli L, Tanzi RE, Kovacs DM: clearance of early, but not late,
prostaglandin synthesis and inhibition. Alzheimers disease: the cholesterol hyperphosphorylated tau aggregates via the
Pharmacol Rev. 56(3), 387437 (2004). connection. Nature Neurosci. 6(4), 345351 proteasome. Neuron 43(3), 321332 (2004).
Comprehensive review on (2003). 25. Farooqui AA, Ong W-Y, Horrocks LA:
cyclooxygenease (COX) enzymes Presents the connection between Inhibitors of brain phospholipase A2
and prostaglandin synthesis. cholesterol and A and how statins lower activity: their neuropharmacological effects
7. Kunz A, Anrather J, Zhou P, Orio M, A in experimental models by inhibiting and therapeutic importance for the
Iadecola C: Cyclooxygenase-2 does not cholesterol synthesis. treatment of neurologic disorders.
contribute to postischemic production of 16. Whitfield JF: Can statins put the brakes on Pharmacol Rev. 58(3), 591620 (2006).
reactive oxygen species. J. Cereb. Blood Flow Alzheimers disease? Expert Opin. Investig. 26. Hauser RA, Zesiewicz TA: Advances in the
Metab. 27(3), 545551 (2007). Drugs. 15(12), 14791485 (2006). pharmacologic management of early
First report showing that COX-2 does Review suggests more clinical trials are Parkinson disease. Neurologist 13(3),
not contribute to reactive oxygen species needed to specifically assess the statin 126132 (2007).
(ROS) production. effects on sporadic AD. 27. Welch K, Yuan J: -Synuclein
8. Delacourte A, Sergeant N, Champain D 17. Grimm MOW, Grimm HS, Patzold AJ oligomerization: a role for lipids? Trends
et al.: Nonoverlapping but synergetic tau et al.: Regulation of cholesterol and Neurosci. 26(10), 517519 (2003).
and APP pathologies in sporadic sphingomyelin metabolism by amyloid- Discusses the relationship between
Alzheimers disease. Neurology. 59(3), and presenilin. Nat. Cell Biol. 7(11), polyunsaturated fatty acid (PUFA) and
398407 (2002). 11181123 (2005). -synuclein multimerization in PD.
Highlights the missing link between Model suggesting the combined effects of 28. Sharon R, Bar-Joseph I, Frosch MP,
synergetic tau and A pathologies. cellular cholesterol and sphingomyelin Walsh DM, Hamilton JA, Selkoe DJ: The
9. Ehehalt R, Keller P, Haass C, Thiele C, levels regulate -secretase activity in formation of highly soluble oligomers of -
Simons K: Amyloidogenic processing of the APP cleavage. synuclein is regulated by fatty acids and
Alzheimer -amyloid precursor protein 18. Mattson MP, Cutler RG, Jo DG: enhanced in Parkinsons disease. Neuron.
depends on lipid rafts. J. Cell Biol. 160(1), Alzheimer peptides perturb lipid-regulating 37(4), 583595 (2003).
113123 (2003). enzymes. Nat. Cell Biol. 7(11), 10451047 29. Samadi P, Grgoire L, Rouillard C et al.:
Suggests that cleavage of the different (2005). Docosahexaenoic acid reduces levodopa-
amyloid precursor protein (APP) pools by 19. Caballero J, Nahata M: Do statins slow induced dyskinesias in 1-methyl-4-phenyl-
- versus -secretases depends on down Alzheimers disease? A review. J. Clin. 1,2,3,6-tetrahydropyridine monkeys. Ann.
distribution of APP to lipid rafts. Pharm. Ther. 29(3), 209213 (2004). Neurol. 59(2), 282288 (2006).

30. Horinouchi K, Erlich S, Perl DP et al.: Acid 42. Aktas O, Waiczies S, Zipp F: This articles discusses clinical trials in ALS.
sphingomyelinase deficient mice - a model Neurodegeneration in autoimmune Despite intense research, riluzole, an anti-
of types A and B Niemann-Pick disease. demyelination: Recent mechanistic insights glutamate agent, still remains the only
Nature Genetics 10(3), 288293 (1995). reveal novel therapeutic targets. treatment for ALS.
An animal model for Niemann-Pick types J. Neuroimmunol. 184(12), 1726 (2007). 54. Minghetti L: Cyclooxygenase-2 (COX-2) in
A and B diseases was developed. 43. Maccarrone M, Battista N, Centonze D: inflammatory and degenerative brain
31. Futerman AH, van Meer G: The cell biology The endocannabinoid pathway in diseases. J. Neuropath. Exp. Neurol. 63(9),
of lysosomal storage disorders. Nat. Rev. Huntingtons disease: A comparison with 901910 (2004).
Mol. Cell Biol. 5(7), 554565 (2004). other neurodegenerative diseases. Prog. 55. Agar J, Durham H: Relevance of oxidative
32. Larsen EC, Hatcher JF, Adibhatla RM: Neurobiol. 81(56), 349379 (2007). injury in the pathogenesis of motor neuron
Effect of tricyclodecan-9-yl potassium Review discusses the endocannabinoid diseases. Amyotroph. Lateral Scler. Other
xanthate (D609) on phospholipid pathway in AD, parkinsons disease (PD), Motor Neuron Disord. 4(4), 232242
metabolism and cell death during oxygen- Huntington disease (HD) and MS. (2003).
glucose deprivation in PC12 cells. Agonists/antagonists of endocannabinoid 56. Simpson EP, Henry YK, Henkel JS, Smith
Neuroscience 146(3), 946961 (2007). receptors and inhibitors of endocannabinoid RG, Appel SH: Increased lipid peroxidation
Report showing that the loss of metabolism are discussed in detail. in sera of ALS patients: A potential
phosphatidylcholine (PC) is a cause rather 44. Pacher P, Batkai S, Kunos G: The biomarker of disease burden. Neurology
than a result of cell death. endocannabinoid system as an emerging 62(10), 17581765 (2004).
33. Vance JE: Lipid imbalance in the target of pharmacotherapy. Pharmacol. Rev. 57. Horrobin D: The lipid hypothesis of
neurological disorder, Niemann-Pick C 58(3), 389462 (2006). schizophrenia. In: Brain Lipids and Disorders
disease. FEBS Lett. 580(23), 55185524 45. Degroot A, Nomikos GG: In vivo in Biological Psychiatry. Skinner ER (Ed.),
(2006). neurochemical effects induced by changes Elsevier Science, Amsterdam, The
34. Maxfield FR, Tabas I: Role of cholesterol in endocannabinoid neurotransmission. Netherlands 3952 (2002).
and lipid organization in disease. Nature Curr. Opin. Pharmacol. 7(1), 6268 Role of lipids in schizophrenia is elegantly
438(7068), 612621 (2005). (2007). presented in this book chapter.
This review is more biophysical in nature 46. Battista N, Fezza F, Finazzi-Agro A, 58. Berger GE, Smesny S, Amminger GP:
and discusses the importance of cholesterol Maccarrone M: The endocannabinoid Bioactive lipids in schizophrenia. Int. Rev.
in membrane phospholipid organization. system in neurodegeneration. Ital. Psychiatry. 18(2), 8598 (2006).
35. Aarli JA: Role of cytokines in neurological J. Biochem. 55(34), 283289 (2006). 59. Hakak Y, Walker JR, Li C et al.:
disorders. Curr. Med. Chem. 10, 19311937 47. Clifford JJ, Drago J, Natoli AL et al.: Genome-wide expression analysis reveals
(2003). Essential fatty acids given from conception dysregulation of myelination-related
36. Carlson NG, Rose JW: Antioxidants in prevent topographies of motor deficit in a genes in chronic schizophrenia. Proc.
multiple sclerosis: do they have a role in transgenic model of Huntingtons disease. Natl. Acad. Sci. USA 98(8), 47464751
therapy? CNS Drugs 20(6), 433441 Neuroscience 109(1), 8188 (2002). (2001).
(2006). 48. Puri BK, Leavitt BR, Hayden MR et al.: 60. Papandreou D, Pavlou E, Kalimeri E,
37. Kalyvas A, David S: Cytosolic phospholipase Ethyl-EPA in Huntington disease: a Mavromichalis I: The ketogenic diet in
A2 plays a key role in the pathogenesis of double-blind, randomized, placebo- children with epilepsy. Br. J. Nutr. 95(1),
multiple sclerosis-like disease. Neuron. controlled trial. Neurology 65(2), 513 (2006).
41(3), 323335 (2004). 286292 (2005). 61. LaRoche SM: A new look at the second-
First report showing the cytosolic 49. Muma NA: Transglutaminase is linked to generation antiepileptic drugs: a decade of
phospholipase A2 (cPLA2) role in multiple neurodegenerative diseases. J. Neuropathol. experience. Neurologist. 13(3), 133139
sclerosis (MS). Exp. Neurol. 66(4), 258263 (2007). (2007).
38. Marusic S, Leach MW, Pelker JW et al.: 50. Stack EC, Smith KM, Ryu H et al.: 62. Bialer M, Johannessen SI, Kupferberg HJ,
Cytosolic phospholipase A2a-deficient mice Combination therapy using minocycline Levy RH, Perucca E, Tomson T: Progress
are resistant to experimental autoimmune and coenzyme Q10 in R6/2 transgenic report on new antiepileptic drugs: a
encephalomyelitis. J. Exp. Med. 202(6), Huntingtons disease mice. Biochim. Biophys. summary of the Eigth Eilat Conference
841851 (2005). Acta. 1762(3), 373380 (2006). (EILAT VIII). Epilepsy Research 73(1), 152
39. Heller RA, Kronke M: TNF receptor- 51. Kunst CB: Complex genetics of (2007).
mediated signaling pathways. J. Cell Biol. amyotrophic lateral sclerosis. Am. J. Hum. Review of the new generation
126, 59 (1994). Genet. 75(6), 933947 (2004). anti-epileptic drugs.
40. Kronke M, Adam-Klages S: Role of caspases Thorough review of amyotrophic lateral 63. Klotz U: The role of pharmacogenetics in
in TNF-mediated regulation of cPLA2. sclerosis (ALS) genetics. the metabolism of antiepileptic drugs:
FEBS Lett. 531(1), 1822 (2002). 52. Bruijn LI, Miller TM, Cleveland DW: pharmacokinetic and therapeutic
41. Cunningham TJ, Yao L, Oetinger M, Cort Unraveling the mechanisms involved in implications. Clin. Pharmacokinet. 46(4),
L, Blankenhorn EP, Greensteinm JI: motor neuron degeneration in ALS. Ann. 271279 (2007).
Secreted phospholipase A2 activity in Rev. Neurosci. 27(1), 723749 (2004). 64. Gasior M, Rogawski MA, Hartman AL:
experimental autoimmune 53. Nirmalananthan N, Greensmith L: Neuroprotective and disease-modifying
encephalomyelitis and multiple sclerosis. Amyotrophic lateral sclerosis: recent effects of the ketogenic diet. Behav.
J. Neuroinflammation 3 doi: advances and future therapies. Curr. Opin. Pharmacol. 17(56), 431439
10.1186/174220943-26, (2006). Neurol. 18(6), 712719 (2005). (2006).

65. Bough KJ, Rho JM: Anticonvulsant mRNAs follows early response gene Fluid percussion injury showed A
mechanisms of the ketogenic diet. Epilepsia. expression in transient focal ischemia. Mol. accumulation and increased ApoE mRNA
48(1), 4358 (2007). Chem. Neuropath. 23(23), 103114 (1994). expression in rats.
Presents a view of how the ketogenic diet 74. Adibhatla RM, Dempsey RJ, Hatcher JF: 84. Jellinger KA: Head injury and dementia.
exerts anticonvulsant effects, summarizing Integration of cytokine biology and lipid Curr Opin Neurol. 17(6), 719723 (2004).
key insights from experimental and clinical metabolism in stroke. Front Neurosurg. Res. 85. Starkstein SE, Jorge R: Dementia after
studies. PUFAs are generated after (under the aegis of Front Biosci). (2007) traumatic brain injury. Int. Psychogeriatr.
ketogenic diet that up-regulate various (In Press). 17(Suppl. 1), S93S107 (2005).
energy metabolism genes and 75. Secades JJ, Lorenzo JL: Citicoline: 86. Smith C, Graham DI, Murray LS, Stewart J,
mitochondrial biogenesis that reduces ROS Pharmacological and clinical review, 2006 Nicoll JAR: Association of APOE e4 and
generation and increase energy production. update. Methods Find. Exp. Clin. Pharmacol. cerebrovascular pathology in traumatic brain
66. Savitz SI: A critical appraisal of the NXY- 28, 156 (2006). injury. J. Neurol. Neurosurg. Psychiatry 77(3),
059 neuroprotection studies for acute 76. Savitz SI, Fisher M: Future of 363366 (2006).
stroke: A need for more rigorous testing of neuroprotection for acute stroke: In the 87. Mahmood A, Lu D, Qu C, Goussev A,
neuroprotective agents in animal models of aftermath of the SAINT trials. Ann. Neurol. Chopp M: Treatment of traumatic brain
stroke. Exp. Neurol. 205(1), 2025 (2007). 61(5), 396402 (2007). injury with a combination therapy of
A critical appraisal of failed Stroke Acute Critical issues and Stroke Therapy marrow stromal cells and atorvastatin in
Ischemic NXY-059 Treatment (SAINT) II Academic Industrial Roundtable (STAIR) rats. Neurosurgery 60(3), 546554 (2007).
Phase III stroke clinical trial. guidelines for future stroke clinical trials 88. Lynch JR, Wang H, Mace B et al.: A novel
67. Adibhatla RM, Hatcher JF: Cytidine 5- are discussed in the aftermath of failed therapeutic derived from apolipoprotein E
diphosphocholine (CDP-choline) in stroke SAINT-II NXY-059 stroke trails. reduces brain inflammation and improves
and other CNS disorders. Neurochem. Res. 77. Crack PJ, Taylor JM: Reactive oxygen species outcome after closed head injury. Exp.
30(1), 1523 (2005). and the modulation of stroke. Free Radic. Neurol. 192(1), 109116 (2005).
Review on CDP-choline actions in Biol. Med. 38(11), 14331444 (2005). 89. Hall ED, Springer JE: Neuroprotection and
stroke and its possible effect in regulating 78. Liu KJ, Rosenberg GA: Matrix acute spinal cord injury: a reappraisal.
proinflammatory cytokines such as TNF- metalloproteinases and free radicals in NeuroRx 1(1), 80100 (2004).
and IL-1. cerebral ischemia. Free Radic. Biol. Med. 90. Kim H-Y: Novel metabolism of
68. Adibhatla RM, Hatcher JF, Larsen EC, 39(1), 7180 (2005). docosahexaenoic acid in neural cells.
Chen X, Sun D, Tsao F: CDP-choline 79. Margaill I, Plotkine M, Lerouet D: J. Biol. Chem. 282(26), 1886118665
significantly restores the Antioxidant strategies in the treatment of (2007).
phosphatidylcholine levels by differentially stroke. Free Radic. Biol. Med. 39(4), 91. Marcheselli VL, Hong S, Lukiw WJ et al.:
affecting phospholipase A2 and CTP- 429443 (2005). Novel docosanoids inhibit brain ischemia-
phosphocholine cytidylyltransferase after 80. Tomitori H, Usui T, Saeki N et al.: reperfusion-mediated leukocyte infiltration
stroke. J. Biol. Chem. 281(10), 67186725 Polyamine oxidase and acrolein as novel and pro-inflammatory gene expression.
(2006). biochemical markers for diagnosis of J. Biol. Chem. 278(44), 4380743817
First report showing the loss of PC due to cerebral stroke. Stroke 36(12), 26092613 (2003).
activation of sPLA2 and loss of CCT; CDP- (2005). 92. Bazan N: The onset of brain injury and
choline restored PC levels by opposing First report showing acrolein, a highly toxic neurodegeneration triggers the synthesis of
these actions in stroke model. aldehyde (100-times more potent than docosanoid neuroprotective signaling. Cell.
69. Mehta SL, Manhas N, Raghubir R: HNE), in plasma of stroke patients. So far Mol. Neurobiol. 26(46), 901913 (2006).
Molecular targets in cerebral ischemia for accumulation of acrolein in stroke brains 93. Ariel A, Serhan CN: Resolvins and
developing novel therapeutics. Brain Res. had not been demonstrated. protectins in the termination program of
Rev. 54(1) 3466, (2007). 81. Rigg JL, Zafonte RD: Corticosteroids in acute inflammation. Trends Immunol. 28(4),
Comprehensive review of molecular TBI: is the story closed? J. Head Trauma 176183 (2007).
mechanisms in cerebral ischemia. Rehab. 21(3), 285288 (2006). 94. Belayev L, Marcheselli VL, Khoutorova L
70. Liu T, Clark RK, McDonnell PC et al.: 82. Ariza M, Pueyo R, Matarin MdM et al.: et al.: Docosahexaenoic acid complexed to
TNF- expression in ischemic neurons. Influence of APOE polymorphism on albumin elicits high-grade ischemic
Stroke 25(7), 14811488 (1994). cognitive and behavioral outcome in neuroprotection. Stroke 36(1), 118123
71. Wang CX, Shuaib A: Involvement of moderate and severe traumatic brain injury. (2005).
inflammatory cytokines in central nervous J. Neurol. Neurosurg. Psychiatry. 77(10), 95. Lukiw WJ, Cui J-G, Marcheselli VL et al.:
system injury. Prog. Neurobiol. 67(2), 11911193 (2006). A role for docosahexaenoic acid-derived
161172 (2002). Interesting clinical study demonstrating neuroprotectin D1 in neural cell survival
72. Loddick SA, Rothwell NJ: Neuroprotective that performance of neuropsychological and Alzheimer disease. J. Clin. Invest.
effects of human recombinant interleukin-1 tasks is worse in patients with APOE 4 115(10), 27742783 (2005).
receptor antagonist in focal cerebral allele after TBI. 96. Balazy M: Eicosanomics: targeted lipidomics
ischaemia in the rat. J. Cereb. Blood Flow 83. Iwata A, Browne KD, Chen X-H, Yuguchi of eicosanoids in biological systems.
Metab. 16(5), 932940 (1996). T, Smith DH: Traumatic brain injury Prostaglandins Other Lipid Mediat. 73(34),
73. Wang X, Yue TL, Barone FC, White RF, induces biphasic upregulation of ApoE and 173180 (2004).
Gagnon RC, Feuerstein GZ: Concomitant ApoJ protein in rats. J. Neurosci. Res. 82(1), 97. Hillard CJ: Lipids and drugs of abuse. Life
cortical expression of TNF- and IL-1 103114 (2005). Sci. 77(14), 15311542 (2005).

98. Senn C, Hangartner C, Moes S, Guerini D, 105. Lane RM, Farlow MR: Lipid homeostasis 113. Narayan RK, Michel ME, Ansell B et al.:
Hofbauer KG: Central administration of and apolipoprotein E in the development Clinical trials in head injury. J. Neurotrauma
small interfering RNAs in rats: a comparison and progression of Alzheimers disease. 19(5), 503557 (2002).
with antisense oligonucleotides. Eur. J. J. Lipid Res. 46(5), 949968 (2005). Despite promising preclinical data, most of
Pharmacol. 522(13), 3037 (2005). 106. Farooqui AA, Horrocks LA, Farooqui T: the clinical TBI trials that have been
99. Cejka D, Losert D, Wacheck V: Short Modulation of inflammation in brain: a performed in recent years have failed to
interfering RNA (siRNA): tool or matter of fat. J. Neurochem. 101(3), demonstrate any significant improvement
therapeutic? Clin. Sci. (Lond). 110(1), 577599 (2007). in outcomes. This report summarizes the
4758 (2006). 107. Mukherjee S, Maxfield FR: Lipid and key points of a workshop sponsored by
This review and the following one by cholesterol trafficking in NPC. Biochim. NIH/National Institute of Neurological
Dykxhoorn et al. discuss the technology of Biophys. Acta. 1685(13), 2837 (2004). Disorders and Stroke (NINDS) to evaluate
RNA silencing, potential obstacles and 108. Miranda SRP, He X, Simonaro CM et al.: problems of past trials and insights into
possibilities for clinical applications. Infusion of recombinant human acid proper planning of future clinical trials.
100. Dykxhoorn DM, Palliser D, Lieberman J: sphingomyelinase into Niemann-Pick
The silent treatment: siRNAs as small disease mice leads to visceral, but not Affiliations
molecule drugs. Gene Ther. 13, 541552 neurological, correction of the Rao Muralikrishna Adibhatla
(2006). pathophysiology. FASEB J. 14(13), Department of Neurological Surgery,

101. Adibhatla RM, Hatcher JF, Tureyen K: 19881995 (2000). H4330 Clinical Science Center,
CDP-choline liposomes provide significant 109. Kanter JL, Narayana S, Ho PP et al.: Lipid 600 Highland Avenue, University of Wisconsin
reduction in infarction over free CDP- microarrays identify key mediators of School of Medicine and Pulic Health-Madison,
choline in stroke. Brain Res. 1058(12), autoimmune brain inflammation. Nat. Med. Madison, WI 537923232, USA,
193197 (2005). 12(1), 138143 (2006). and,
Efficient delivery of CDP-choline to the 110. Centonze D, Finazzi-Agro A, Bernardi G, Cardiovascular Research Center, University of
brain using liposome encapsulation Maccarrone M: The endocannabinoid Wisconsin School of Medicine and Public
substantially improves the outcome after system in targeting inflammatory Health-Madison,
stroke. The route of administration is very neurodegenerative diseases. Trends and,
important in clinical trials, which has been Pharmacol. Sci. 28(4), 180187 (2007). Neuroscience Training Program, University of
ignored in US trials. 111. Lin T-N, Wang Q, Simonyi A et al.: Wisconsin School of Medicine and Public
102. Adibhatla RM: Mechanistic aspects of Induction of secretory phospholipase A2 in Health -Madison,
CDP-choline (Citicoline) action in stroke. reactive astrocytes in response to transient and,
In: 4th Asia Pacific Conference Against Stroke focal cerebral ischemia in the rat brain. William Middleton Veterans Affairs Hospital,
(APCAS March 30-April 1, 2007). J. Neurochem. 90(3), 637645 Madison, WI 53705
Conference Secretariat, APCAS New Delhi, (2004). Tel.: +1 608 263 1791;
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mechanisms and clinical efficacy in cerebral Chem. 12(25), 30113026 (2005). James F Hatcher
ischemia. J. Neurosci. Res. 70(2), 133139 Presents the structurally diverse array of Department of Neurological Surgery, University
(2002). available sPLA2 group IIA inhibitors, their of Wisconsin School of Medicine and Public
104. Wolozin B: Cholesterol, statins and associated biological activity in animal Health, F4-359; Clinical Science Center, 600
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Role of Lipids in Brain Injury and Diseases

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Role of Lipids in Brain Injury and Diseases

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Future Lipidology

ISSN: 1746-0875 (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/tlip19

Role Of Lipids In Brain Injury And Diseases

Rao Muralikrishna Adibhatla & James F Hatcher

To link to this article: http://dx.doi.org/10.2217/17460875.2.4.403

Copyright 2007 Future Medicine Ltd

Published online: 18 Jan 2017.

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Role of lipids in brain injury and diseases

Table 1. Major lipid classes and representative subtypes.

A comprehensive listing of lipids is provided in [2].

404 Future Lipidol. (2007) 2(4) future science group

allele affects clinical outcome.

future science group www.futuremedicine.com 405

Future Lipidol. (2007) 2(4)

future science group

future science group

Treatment of PD Niemann-Pick diseases

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vent accumulation of SM in NPB, a therapeutic be elevated in CSF of MS patients, and HNE

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Huntingtons disease R6/2 transgenic HD mouse models also pro-

cannabinoid receptors comprised of amides, malondialdehyde in HD [23].

410 Future Lipidol. (2007) 2(4) future science group

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hyper-excitability caused by excessive stimula- subsequent production of eicosanoids, ceramide

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Figure 1. Lipid metabolism in ischemic neuronal death.

Glutamate release Ischemia

Ca++ [Ca++]i IP3 PIP2

PC-PLC 1,2-diacylglycerol (DAG)

COX/LOX Prostaglandins, leukotrienes

Free radicals including ROS, lipid

future science group www.futuremedicine.com 413

Box 1. CDP-choline and stroke: an issue to be revisited.

hydrolysis through proinflammatory pathways.

CDP-choline in stroke clinical trials

Traumatic brain injury occur subsequent to the initial trauma present

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1h 13 h 6h 1 day 3 day 7 day

TBI & ApoE not find an association of APOE 4 allele with

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Figure 4. CDP-choline and PC synthesis.

Cytidine Cytidine triphosphate 1,2-diacylgycerol

Choline Phosphocholine CCT CDP-choline CPT PC

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(2006). pathophysiology. FASEB J. 14(13), Department of Neurological Surgery,

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