EXCITOTOXICITY

By

V K C KIRAN PULLELA
Reg No. 133H1S0610

Under the guidance of ,

Dr. K.Ravishankar
M.Pharm,Ph.D

Professor, And Principal,

Contents

Introduction to excitotoxicity
Neurons that contain
excitatory amino acids
play crucial roles in
psychological functions
such as learning and
memory.
On the other hand,
over-activity of the
excitatory amino acid
system is also harmful.

Introduction to excitotoxicity
Excitotoxicity is defined as cell
death resulting from the toxic
actions of excitatory amino acids.
This process was originally
discovered by two
ophthalmologists, Lucas and
Newhouse in 1957 and given the
name excitotoxicity by Dr John
Olney in 1969.

Introduction to excitotoxicity
The causative amino acids include
cysteine, cysteine sulfinic acid, cysteic
acid, and homocysteine, as well as the
neurotransmitters glutamate and
aspartate.
In fact, glutamate is the most abundant
neurotransmitter in the CNS and is
responsible for attention, alertness, and
learning. It is also the most neurotoxic.

Implications of excitotoxicity

Glutamate receptors
Ionotropic
NMDA
AMPA
Kainate

Metabotropi
c

Glutamate receptors
NMDA
Calcium favoring
Effective in mediating excitotoxic injury

AMPA
Highly permeable to calcium
Contribute to delayed neuronal cell death

Glutamate receptors
Metabotropic Glutamate Receptors
mGluR1, mGluR5
Coupled to IP3
Trigger delayed cell death

mGluR2
Helps to mediate survival of neurons
Activation leads to increased phosphorylation of Tau
and reduces oxidative stress mediated cytotoxicity

Increase in glutamate receptor activity

induces proapoptotic proteins such as p53.

Excitotoxicity and ions

Acute excitotoxicity is mediated by the
excessive depolarization of the post synaptic
membrane causes.
This excessive depolarization, when coupled
by influx of Na+, Cl- and water leads to
eventual rupture of cell membrane
Na-K-Cl Cotransporter type 1 (NKCC1) is
involved in initial stages of cell damage that
depends upon extracellular Na+ and Cl-

Excitotoxicity and ions

Excitotoxicity and Oxidative

stress
Oxidative stress damages nucleic
acids, proteins and lipids
It potentially opens the mitochondrial
permeability transition pore, which
can stimulate further ROS production
It can release proapoptotic factors
such as cytochrome c into the
cytoplasm.

Excitotoxicity and Oxidative

stress
Nitric Oxide production is activated in
cerebrovascular disease by the release of
glutamate, which leads to NMDA receptor
overactivation and excess Ca2+ influx.
Toxic effects of NO are due to ONOO- ion
NO induces metalloproteinases, which
triggers the extracellular proteolytic
cascades, which leads to cell detachment
and anoikis

Excitotoxicity and mitochondria

mediated apoptosis and
autophagy

Mitochondria are centers for Oxidative

phosphorylation and cellular respiration
They also play an important role in
maintaining a low concentration of calcium
in the cytosol
Excessive uptake of Ca2+ or generation of
ROS induce activation of mitochondrial
permeability transition and subsequent
release of Ca2+ and proapoptotic factors into
the cytosol.

Excitotoxicity and mitochondria

mediated apoptosis and
autophagy

Low intensity stress causes

depolarization of mitochondria
during the permeability transition,
leading to induction of autophagy,
which removes damaged
mitochondria as a cytoprotective
mechanism
Overburdened autophagic apparatus
may release lysosomal enzymes and
other factors to promote cell death.

Excitotoxicity and
neurodegenerative diseases
Huntingtons disease
Affects cognition, motor
function, mood
GABAergic neurons are
effected
Huntingtin (htt) protein forms
insoluble nuclear aggregates
(plays a key role in apoptosis)
htt is thought to enhance
NMDA mediated calcium influx

Excitotoxicity and
neurodegenerative diseases
Alzheimers disease
Progressive cognitive and memory
loss
Cholinergic neurons are
degenerated
-Amyloid Peptides (A) and
Neurofibrillatory Tangles are seen
(initiate multiple neurotoxic
pathways)
NMDA receptor overactivation is
implicated (Hence the use of NMDA
receptor antagonists such as
Memantine)

Excitotoxicity and
neurodegenerative diseases
Parkinsons Disease
Degeneration of nigral dopaminergic
neurons and massive drop of
dopamine content in striatum

-Synuclein is an abundant
protein in Lewy bodies (it may
enhance ROS production and
microglial enhanced
dopaminergic
neurodegeneration
Parkin dampens excitatory
amino acid transmission

References
H.P.Rang, M.M.Dale, J.M.Ritter,
R.J.Flower. Rang and Dales
Pharmacology. 6th ed.. Churchill
Livingstone Elsevier; 2009
Xiao-xia DONG et al. Molecular
mechanisms of excitotoxicity and
their relevance to pathogenesis
of neurodegenerative diseases.
Acta Pharmacol Sin 2009 Apr; 30 (4):
379387