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By
V K C KIRAN PULLELA
Reg No. 133H1S0610
Dr. K.Ravishankar
M.Pharm,Ph.D
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
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