Neurophysiology, Vol. 36, No.

4, 2004

Calcium Signaling in Diabetic Neuropathy

N. Voitenko1
Neirofiziologiya/Neurophysiology, Vol. 36, No. 4, pp. 348-353, July-August, 2004.

Received July 19, 2004.

Diabetic neuropathy is a frequent complication of diabetes mellitus, for which no adequate clinical treatment
is currently available. One of the main reasons for the absence of effective treatment of this disease is that in-
formation on how metabolic, vascular, and other abnormalities involved in the pathogenesis of diabetic neuro-
pathy lead to dysfunction of nerve cells and pathways remains insufficient. Recent studies demonstrated that
substantial abnormalities of calcium homeostasis in input neurons of the somatosensory nociceptive system
are associated with many symptoms of diabetic neuropathy. Although proof of the causal linkage between
calcium abnormalities and neuropathic complications is not conclusive, current research in neuroscience mo-
stly indicates that such a linkage exists. Practically all known modifications of synaptic transmission in both
central and peripheral nervous systems result from calcium-dependent modifications of the molecular players
involved in this transmission. This is why the main goal of our review is to analyze in detail the fundamental
cellular and molecular calcium-regulating mechanisms that are deteriorated in diabetes. As an important end-
point of the proposed review, the capability of a widely used calcium channel blocker, nimodipine, to correct
cytosolic and endoplasmic reticulum calcium abnormalities in neurons of the dorsal root ganglia and spinal
dorsal horn and possible curative value of this agent in diabetic neuropathy are discussed.

Keywords: diabetic neuropathy, dorsal root ganglia, spinal dorsal horn, neuron, endoplasmic reticul-
um, nimodipine.

Diabetic neuropathy is one of the most frequent
and troublesome complications of diabetes mellitus.
This disease is frequently manifested as distal
sensory polyneuropathy associated with complaints
of numbness, paresthesia, and tingling or prickling
feelings in the lower limbs of the patients. Severe
pain, which is also one of the most disturbing
symptoms of this disease, is obviously to a great
extent based on intensification of transmission of
nociceptive signals, which is indicative of significant
functional changes in primary and secondary neurons
of the somatosensory nociceptive systems. Although
various metabolic [1], vascular [2, 3], and other [4,
5] abnormalities were demonstrated as pathogenetic
factors in diabetic neuropathy, the immediate
mechanisms of neurological disorders in this disease
remain unclear. It has been suggested that disturbances
in neuronal calcium homeostasis can be a significant
1
Bogomolets Institute of Physiology, National Academy of Sciences of
Ukraine, Kyiv, Ukraine.
Correspondence should be addressed to N. Voitenko
(e-mail: nana@biph.kiev.ua)
reason for these disorders and can lead to changes in
synaptic plasticity, other functional modifications in
the neurons, and even to apoptosis of the latter [6, 7].
Calcium is a universal secondary messenger in
different cells, and changes in the intracellular
cytosolic Ca 2+ concentration ([Ca 2+] i) triggers a
wide range of various cellular responses, including
long-term modifications of synaptic transmission in
the nervous system [8, 9]. Thus, changes in some
aspects of regulation of cytosolic [Ca 2+] i may be a
reason for impaired nociceptive signaling in diabetic
neuropathy. As was shown in recent studies [10-16]
carried out in a number of laboratories (including
ours), experimental diabetes does induce significant
changes in cytosolic Ca 2+ homeostasis in dorsal root
ganglion (DRG) and in spinal dorsal horn (DH)
neurons, i.e., in primary and secondary input units
of the somatosensory nociceptive system providing
transmission of nociceptive signals. These changes
include a stable increase in the resting cytosolic Ca 2+
concentration, a decrease in the amplitude of calcium
signals related to KCl-induced depolarization or
application of neurotransmitters and prolongation of
the recovery time of [Ca 2+] i transients [17].

310
0090-2977/04/3604-0310 © 2004 Springer Science+Business Media, Inc.
Calcium Signaling in Diabetic Neuropathy
Intracellular calcium stores, in particular the
endoplasmic reticulum (ER), together with calcium-
regulating systems in the plasma membrane play
a key role in the formation of calcium signals. It
was recently shown [18, 19] that Ca 2+ can play a
signaling role not only in the cytoplasm but also in
the ER where it regulates synthesis of proteins, their
chaperoning, and activation of calcium influx via a
capacitative calcium entry. A conclusion based on
recently obtained experimental data seems to be even
more important: The ER, being a calcium store, plays
an exclusively important role with respect to fast
processes occurring during synaptic transmission [9,
20-22]. This statement is, probably, correct also with
respect to slower phenomena, e.g., the plasticity of
synaptic transmission in the CNS [7, 9, 23]. Thus, it is
becoming apparent that impaired calcium homeostasis
in both the cytosol and lumen of the ER can be a
common factor significantly responsible for a variety
of neurodegenerative disorders, including diabetic
neuropathy [6, 7, 24].
Results of several recent studies proved that
diabetes leads to a dramatic weakening of Ca 2+
release from intracellular stores in both DRG and
DH neurons [12, 14, 15, 17]. This suggests that Ca 2+
handling in the ER has been modified, and the amount
of releasable Ca 2+ stored within the ER lumen has
been decreased. However, the fundamental molecular
mechanisms underlying these abnormalities have not
been elucidated.
The ability of Ca 2+ to successfully function as a
messenger is due to the existence of an effective
metabolically dependent system that keeps a very low
[Ca 2+] i level in the cytosol and a relatively high level
of this parameter in the ER lumen [25, 26]. Increases
in the cytosolic [Ca 2+] i in response to various signals
are based on Ca 2+ influx through the channels of
the plasma membrane [27] and/or channels of the
membranes of intracellular Ca 2+-storing organelles.
Among the latter, the ER and mitochondria are the
most important [8, 28]. Transient calcium signals are
also effectively regulated by the system of different
calcium-binding proteins located in both the cytosol
and ER [18, 25, 29].
In most units of the CNS and peripheral nervous
system (PNS), calcium signaling is initiated by the
activation of plasma membrane calcium channels
or calcium-releasing channels in the ER membrane
(channels of inositol trisphosphate and ryanodine
receptors, IP 3R and RyR, respectively) [26, 30]. An
abnormally enhanced activity of the plasma membrane
calcium channels has been described in primary [10,
311
12, 14] and secondary [14-16] sensory neurons; this
phenomenon has been already implicated in the list
of pathogenetic factors responsible for diabetes
mellitus-related neuropathic complications [7, 31].
On the other hand, some researchers suggest that
the activity of Ca 2+ ATPase could be suppressed in
such situations. This, together with intensified Ca 2+
influx, can result in abnormal net Ca 2+ overloading
of the cell [32]. Recent studies of myocardial cells
demonstrated that the expression of ER calcium
pumps is reduced in diabetes [33]. The transgenic
overexpression of these proteins (ATPases)
normalizes calcium handling in the ER [34, 35]. It is
also very important to note that a significant decrease
in the level of Ca 2+ ATPase activity is observed not
only in diabetic animal models but also in diabetic
patients with sensory neuropathy [36]. Thus, a
decrease in Ca 2+ release from the ER observed in
several recent studies carried out on sensory neurons
can result from reduced Ca 2+ uptake by the ER via
thapsigargin-sensitive sarco(endo)plasmic reticulum
Ca 2+ ATPase (SERCA) pumps. The inability of
the ER to properly regulate Ca 2+ fluxes can also
be considered one of the reasons for impaired
clearance of cytosolic Ca 2+ following membrane
depolarization, while alterations in the functioning
of plasma membrane Ca 2+ ATPases (PMCA) can
also be involved in this process. Both SERCA and
PMCA are extremely important for proper calcium
regulation, as they are the only metabolically active
systems determining the levels of [Ca 2+] in both the
ER and cytosol. Together with some still unknown
systems, which are responsible for calcium leakage
from the ER, Ca 2+ ATPases also determine the filling
status of the ER [37]. Other important players in
a calcium regulating game are calcium-binding
(buffering) proteins, which are present abundantly in
neurons and determine the calcium-binding capacity
of the cytosol and ER [38, 39]. The calcium-binding
capacity influences the shape, amplitude, and
duration of [Ca 2+] i transients, which, in turn, affect
a number of significant neuronal calcium-dependent
processes, including synaptic transmission, its plastic
rearrangements, excitotoxicity, protein synthesis and
folding, etc. [18, 29].
Diabetes-induced abnormalities in neuronal
calcium homeostasis, which resemble those leading
to the impairment of nociceptive neurotransmission
in other pain models [40-43], were well documented
in both DRG and DH neurons. It is also important
to emphasize that calcium abnormalities correlate
with many symptoms of diabetic neuropathy, such
312
as thermal hypoalgesia, modified pain sensitivity,
etc. [43-47], indicating possible causal relationship
between these phenomena. It should, however,
be noted that there is no single theory that can
explain the development of allodynia and hyper-
or hypoalgesia in diabetes mellitus, as well as
no generally accepted viewpoint concerning the
influence of altered calcium homeostasis on neuronal
mechanisms immediately responsible for impaired
nociceptive synaptic transmission. The possibilities
for studies of calcium-regulating systems in diabetic
distal sensory polyneuropathy at the spinal cord level
remain extremely limited. It also remains unclear how
changes in intracellular calcium homeostasis observed
in sensory neuropathy depend on the duration and
severity of the disease, and to what extent different
levels of the nervous system (CNS and PNS) are
involved in such pathological process within different
stages of the disease. Taking into account that many
sensory pathways are relayed via spinal DH neurons,
coordinated studies of calcium homeostasis studies in
both DRG and DH neurons can be rather promising.
Adequate understanding of basic molecular
mechanisms underlying calcium abnormalities in diabetes
mellitus is especially important with respect to the DH
neurons, since mechanisms of central sensitization of the
respective nociceptive neuronal chains are most probably
calcium-dependent [41, 42, 48, 49].
Attempts to correct metabolic abnormalities
derived from diabetes are a new issue in the treatment
of diabetic complications. In a few studies, calcium
channel blockers were considered “first choice”
drugs to correct a number of diabetic disorders [7,
50, 51]. The comparatively low level of side effects
of these agents and the absence of detrimental effects
on the serum lipid level and glucose tolerance are
also very important [52]. Calcium channel blockers
may be of additional potential benefit for diabetic
patients due to the ability of these drugs to slow
down the development of arteriosclerosis, to reverse
intracellular calcium defects that may contribute to
the pathogenesis of diabetic cardiomyopathy, and
to protect against the progression of chronic renal
insufficiency [53]. They seem to have beneficial
effects on the body weight, the level of glycosylated
hemoglobin, and concentration of glucose in the
blood of experimental diabetic animals [54]. Some
results suggest that dihydropyridines (members of
one of the families of calcium channel blockers) can
improve cardiac dysfunction in diabetic rats; these
drugs decrease the Na +-Ca 2+ imbalance and normalize
the water content [55].
N. Voitenko
Nimodipine is a widely used L-type calcium
channel blocker. It relatively easily penetrates
the blood-brain barrier [56], and, therefore, this
member of the dihydropyridine family is most often
used in studies of the effect of calcium channel
blockers on neuronal Ca 2+ homeostasis and neuronal
functions. Treatment with nimodipine restores
adrenergic synaptic responses in diabetic rats [57].
Nimodipine was reported to ameliorate symptoms
of experimental diabetic neuropathy related
to streptozotocin-induced and BB-determined
diabetes (in both young and adult rats) [57]. It was
shown that, in addition to direct neuroprotective
effects, nimodipine exerts beneficial influences on
the disturbed blood flow in the nerves [57] and on
thermal hyperalgesia [47, 50, 58] in experimental
diabetic neuropathy. Recent results also indicated
that nimodipine, due to its action on vascular
mechanisms (probably, in combination with direct
effects on neurons), can be a rather effective tool in
experimental peripheral neuropathy [7]. It should
also be mentioned that nimodipine also normalizes
Ca 2+ -dependent forms of the synaptic plasticity in
the hippocampus of diabetic rats [7].
It has recently been reported that prolonged
treatment of diabetic animals with nimodipine leads
to an increase in the amplitude of depolarization-
induced cytosolic [Ca 2+] transients in DRG neurons
of diabetic animals [14]. It was also shown that
nimodipine can not only act as a calcium channel
blocker but also enhances the intensity of calcium
release from the ER, which is reduced in diabetes
[47]. Thus, at least in DRG and DH nociceptive
neurons, nimodipine is capable of correcting all
(or nearly all) known diabetes-induced disorders in
calcium homeostasis. Moreover, some recent studies
demonstrated that prolonged nimodipine treatment
effectively normalizes impaired calcium homeostasis
in DRG and DH neurons of diabetic animals, reduces
diabetes-induced thermal hypoalgesia [46], and
ameliorates other symptoms of diabetic neuropathy
[58].
Taking into account the published results of
experimental studies and clinical observations by
Gispen and colleagues [57, 59], detailed studies of
cellular and molecular mechanisms of the effects
of nimodipine in diabetic neuropathy are becoming
more and more important. If we also take into account
the ability of nimodipine to positively influence
Ca 2+-dependent forms of synaptic plasticity [7], to
easily penetrate the blood-brain barrier [56], and to
correct some abnormalities in calcium homeostasis
Calcium Signaling in Diabetic Neuropathy
in primary and secondary nociceptive neurons [47],
this drug should be considered a perfect candidate
for pharmacological treatment of diabetic neuropathy
due to its ability to correct calcium homeostasis in
nociceptive neurons. At the same time, the molecular
mechanisms underlying the action of nimodipine on
calcium homeostasis and the relation of the respective
effects to relief of nociceptive neuropathic symptoms
have not been established yet and surely require
further investigations.
Acknowledgments. This work was supported by the Juvenile
Diabetes Research Foundation grant 1-2004-30 to N.V.
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