Excitotoxins ; their role in neurodegeneration : fact vs fiction

Tadvi NA*, Qureshi SA*Dept of Pharmacology, **Dept of Physiology,

Kamineni Institute Of Medical Sciences,Narketpally

• 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

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.

• 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

Objective

• • The purpose of this review is to evaluate

extent of involvement of excitotoxins in neurodegeneration

• 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

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.

• 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

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.

Figure1: Glutamate metabolism at synapse

Figure 2: Excitotoxicity induced apoptosis

Figure 3: Mechanism of action of excitoxins

• 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

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.

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.

1. Standerst D G, Young A B; Treatment of central nervous system degenerative disorders In:Brunton J, Lazo S, Parker K L. Goodman & Gilman’s The Pharmacological basis of therapeutics.11th ed.NY:Mc Graw Hill;2006.p.528.

2. Michaels RL and Rothman SM. Glutamate neurotoxicity invitro: antagonist pharmacology and intracellular calciumconcentrations. J Neurosci. 10: 283–292. 1990.

3. Geerts H and Grossberg GT. Pharmacology of acetylcholinesterase inhibitors and N-methyl-D-aspartate receptors for combination therapy in the treatment of Alzheimer’s disease. J Clin Pharmacol 2006;46(7)8-16

4. Beal MF. Excitotoxicity and nitric oxide in Parkinson’s disease pathogenesis.

References

References

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References

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12. Spencer PS, Ludolph A, Dwivedi MP, Roy DN, Hugon J,and Schaumburg HH. Lathyrism: evidence for role of the neuroexcitatory aminoacid BOAA. Lancet. 2;1986: 1066–1067.

References

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