EXCITOTOXICITY

By

V K C KIRAN PULLELA

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

• Metabotropic

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

• Huntington’s 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

• Alzheimer’s disease– Progressive cognitive and memory loss– Cholinergic neurons are degenerated– β-Amyloid Peptides (Aβ) 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

• Parkinson’s Disease– Degeneration of nigral dopaminergic

neurons and massive drop of dopamine content in striatum

– α-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 Dale’s 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): 379–387