excitotoxins and their role in neurodegeneration

1. Excitotoxins ; their role in
neurodegeneration : fact vs fiction
Tadvi NA*, Qureshi SA
*Dept of Pharmacology, **Dept of Physiology,
Kamineni Institute Of Medical
Sciences,Narketpally

2. • Excitotoxins can be described as a class of
substances which lead to overexcitation of neurons
causing state of exhaustion & cell death.
• The term excitotoxicity was coined by John Olney
in 1969 to describe the neuronal injury that results
from presence of excess glutamate in the brain1.
• The principle mechanism of action of almost all
excitotoxins is by means of increased cation influx
esp. calcium2. Hence calcium is the primary
mediator of excitotoxicity
Introduction

3. Introduction
• Depending upon the source excitotoxins can be
classified as endogenous excitotoxins and
exogenous excitotoxins
• Endogenous excitotoxins occur naturally in the
body in the form of excitatory neurotransmitters &
within the physiological range they perform myriad
of important functions like learning, memory,
perception of pain , immune function and
functioning of various special senses.
• But if their levels exceed then it can lead to
excitotoxic damage. Examples are glutamate ,
aspartate etc.

4. • Exogenous excitotoxins are present in the
environment & after entering the body either they
directly cause excitotoxic damage or they increase
the sensitivity of receptors to endogenous excitatory
neurotransmitters which then become excitotoxic
even at low levels.
• Examples include monosodium glutamate (MSG)
, aspartame , domoic acid , β –N-oxalylamino l-
alanine (BOAA) , β –methyl l-alanine(BMAA) ,3-
nitropropionic acid etc.
• MSG & Aspartame are found almost inevitably in all
processed foodstuffs esp. instant food products &
low calorie food supplements
Introduction

5. Objective
•
• The purpose of this review is to evaluate
extent of involvement of excitotoxins in
neurodegeneration

6. • In presence of associated risk factors long
term exposure to excitotoxins has been
proved in etio pathogenesis of
neurodegenerative disorders like Alzheimer’s
disease3 ,Parkinson’s disease4 , amyotrophic
lateral sclerosis5 , multiple sclerosis6 etc .
• There is substantial evidence that shows that
excitotoxic damage has a large share in
neuronal death associated after status
epilepticus7, cerebral ishaemia , stroke8 and
head trauma.
Results

7. Results
• In fact, glutamate & aspartate toxicity are also
thought to be responsible for memory loss ,
confusion , mild intellectual disorientation that
frequently late middle age or old age9.
• Domoic acid found in marine algae causes
amnestic shell fish poisoning10 .
• BOAA is found in chick peas & is a selective
agonist AMPA receptors & causes
Neurolathyrism11
• BMAA is found in fruit of cycad plant & causes
Amyotropic lateral sclerosis of Guam12.

8. • Following are the various mechanisms by which
they are involved in neurodegeneration.
1. Most of the excitotoxins after getting
metabolized act on the various glutaminergic
receptors especially on ionotropic receptors
like NMDA , AMPA & kainate , increasing
their sensitivity to local glutamate.
2. They alter the capacity of mitochondria to
handle oxidative metabolism causing
increased production of free radicals or
reactive oxygen species(ROS)1.
Mechanism of action

9. Mechanism of action
3. ROS alter the membrane potential , lift the magnesium
block of NMDA receptors & cause sustained activation of
these receptors which substantially increase calcium
influx activating various enzymes like phospholipase A2 ,
nitric oxide synthase II , calpain , phosphatases ,
proteases , endonucleases etc13.
4. All these substances produced along with similarly
induced platelet activating factor (PAF) set up a vicious
auto stimulatory positive cycle.
5. Free radicals along with endonucleases cause DNA
fragmentation and induce apoptosis. If the damage is
severe enough there is rupture of lysosomes and
extracellular release of intact and enzymatically modified
cellular organelles causing inflammation and necrosis14,15.

10. Figure1: Glutamate metabolism at synapse

11. Figure 2: Excitotoxicity induced apoptosis

12. Figure 3: Mechanism of action of excitoxins

13. • Specific excitotoxins like DMA , MOAA , BMAA ,
3NPA are found in specific foodstuffs& can be
easily avoided by not eating marine shellfish, cycad
fruit , chickpea , fungated sugarcane.
Conclusion

14. Conclusion
• However, the other exogenous excitotoxins like
MSG, aspartame are being consumed in large
amounts under the disguise of appetizing,
processed food products and if co existent with
genetic predisposition or ageing or any other factor
causing oxidative metabolic stress inevitably, lead
to an auto stimulatory glutaminergic vicious cycle
causing apoptosis & necrosis of specific neurons &
development of neurodegenerative disorders.

15. Conclusion
• It should also be appreciated that the effects
of excitotoxin food additives generally are
not dramatic and are subtle and develop
over a long period of time. But they certainly
can precipitate these disorders and worsen
their pathology. Likewise, foodborne
excitotoxins may be harmful to those
suffering from strokes, head injury.

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