Excitotoxins their role in neurodegeneration


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excitotoxins and their role in neurodegeneration

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Excitotoxins their role in neurodegeneration

  1. 1. Excitotoxins ; their role inneurodegeneration : fact vs fictionTadvi NA*, Qureshi SA*Dept of Pharmacology, **Dept of Physiology,Kamineni Institute Of MedicalSciences,Narketpally
  2. 2. • Excitotoxins can be described as a class ofsubstances which lead to overexcitation of neuronscausing state of exhaustion & cell death.• The term excitotoxicity was coined by John Olneyin 1969 to describe the neuronal injury that resultsfrom presence of excess glutamate in the brain1.• The principle mechanism of action of almost allexcitotoxins is by means of increased cation influxesp. calcium2. Hence calcium is the primarymediator of excitotoxicityIntroduction
  3. 3. Introduction• Depending upon the source excitotoxins can beclassified as endogenous excitotoxins andexogenous excitotoxins• Endogenous excitotoxins occur naturally in thebody in the form of excitatory neurotransmitters &within the physiological range they perform myriadof important functions like learning, memory,perception of pain , immune function andfunctioning of various special senses.• But if their levels exceed then it can lead toexcitotoxic damage. Examples are glutamate ,aspartate etc.
  4. 4. • Exogenous excitotoxins are present in theenvironment & after entering the body either theydirectly cause excitotoxic damage or they increasethe sensitivity of receptors to endogenous excitatoryneurotransmitters which then become excitotoxiceven 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 allprocessed foodstuffs esp. instant food products &low calorie food supplementsIntroduction
  5. 5. Objective•• The purpose of this review is to evaluateextent of involvement of excitotoxins inneurodegeneration
  6. 6. • In presence of associated risk factors longterm exposure to excitotoxins has beenproved in etio pathogenesis ofneurodegenerative disorders like Alzheimer’sdisease3 ,Parkinson’s disease4 , amyotrophiclateral sclerosis5 , multiple sclerosis6 etc .• There is substantial evidence that shows thatexcitotoxic damage has a large share inneuronal death associated after statusepilepticus7, cerebral ishaemia , stroke8 andhead trauma.Results
  7. 7. Results• In fact, glutamate & aspartate toxicity are alsothought to be responsible for memory loss ,confusion , mild intellectual disorientation thatfrequently late middle age or old age9.• Domoic acid found in marine algae causesamnestic shell fish poisoning10 .• BOAA is found in chick peas & is a selectiveagonist AMPA receptors & causesNeurolathyrism11• BMAA is found in fruit of cycad plant & causesAmyotropic lateral sclerosis of Guam12.
  8. 8. • Following are the various mechanisms by whichthey are involved in neurodegeneration.1. Most of the excitotoxins after gettingmetabolized act on the various glutaminergicreceptors especially on ionotropic receptorslike NMDA , AMPA & kainate , increasingtheir sensitivity to local glutamate.2. They alter the capacity of mitochondria tohandle oxidative metabolism causingincreased production of free radicals orreactive oxygen species(ROS)1.Mechanism of action
  9. 9. Mechanism of action3. ROS alter the membrane potential , lift the magnesiumblock of NMDA receptors & cause sustained activation ofthese receptors which substantially increase calciuminflux activating various enzymes like phospholipase A2 ,nitric oxide synthase II , calpain , phosphatases ,proteases , endonucleases etc13.4. All these substances produced along with similarlyinduced platelet activating factor (PAF) set up a viciousauto stimulatory positive cycle.5. Free radicals along with endonucleases cause DNAfragmentation and induce apoptosis. If the damage issevere enough there is rupture of lysosomes andextracellular release of intact and enzymatically modifiedcellular organelles causing inflammation and necrosis14,15.
  10. 10. Figure1: Glutamate metabolism at synapse
  11. 11. Figure 2: Excitotoxicity induced apoptosis
  12. 12. Figure 3: Mechanism of action of excitoxins
  13. 13. • Specific excitotoxins like DMA , MOAA , BMAA ,3NPA are found in specific foodstuffs& can beeasily avoided by not eating marine shellfish, cycadfruit , chickpea , fungated sugarcane.Conclusion
  14. 14. Conclusion• However, the other exogenous excitotoxins likeMSG, aspartame are being consumed in largeamounts under the disguise of appetizing,processed food products and if co existent withgenetic predisposition or ageing or any other factorcausing oxidative metabolic stress inevitably, leadto an auto stimulatory glutaminergic vicious cyclecausing apoptosis & necrosis of specific neurons &development of neurodegenerative disorders.
  15. 15. Conclusion• It should also be appreciated that the effectsof excitotoxin food additives generally arenot dramatic and are subtle and developover a long period of time. But they certainlycan precipitate these disorders and worsentheir pathology. Likewise, foodborneexcitotoxins may be harmful to thosesuffering from strokes, head injury.
  16. 16. 1. Standerst D G, Young A B; Treatment of centralnervous system degenerative disorders In:Brunton J,Lazo S, Parker K L. Goodman & Gilman’s ThePharmacological basis of therapeutics.11th ed.NY:McGraw Hill;2006.p.528.2. Michaels RL and Rothman SM. Glutamate neurotoxicityinvitro: antagonist pharmacology and intracellularcalciumconcentrations. J Neurosci. 10: 283–292. 1990.3. Geerts H and Grossberg GT. Pharmacology ofacetylcholinesterase inhibitors and N-methyl-D-aspartate receptors for combination therapy in thetreatment of Alzheimer’s disease. J Clin Pharmacol2006;46(7)8-164. Beal MF. Excitotoxicity and nitric oxide in Parkinson’sdisease pathogenesis.References
  17. 17. References5. Ann Neurol.1998;44(3):110–114.6. Leigh PN and Meldrum BS. Excitotoxicity inamyotrophic lateral sclerosis. Neurology.1996; 47:221–227.7. Pitt D, Werner P, and Raine CS. Glutamateexcitotoxicity in a model of multiple sclerosis.Nature Med. 2000;6:67–70.8. Miller HP, Levey AI, Rothstein JD, Tzingounis AV,and Conn PJ. Alterations in glutamate transporterprotein levels in kindling-induced epilepsy. JNeurochem.1997;68: 1564–1570.
  18. 18. References9. Choi D W , Rothman S M. The role of neurotoxicity inhypoxic ischaemic neuronal celldeath.Annu.Rev.Neurosci,1990;13:171-182.10. Meldrum BS. Glutamate as a neurotransmitter in thebrain:review of physiology and pathology. J Nutr.130;2000: 1007–15.11. Giordano G, White CC, Mohar I, Kavanagh TJ, and CostaLG. Glutathione levels modulate domoic acid inducedapoptosis in mouse cerebellar granule cells. ToxicolSci.100;2007: 433–444.12. Spencer PS, Ludolph A, Dwivedi MP, Roy DN, HugonJ,and Schaumburg HH. Lathyrism: evidence for role of theneuroexcitatory aminoacid BOAA. Lancet. 2;1986: 1066–1067.
  19. 19. References13.Spencer PS, Ohta M, and Palmer VS. Cycad useand motor neuron disease in Kii peninsula of Japan.Lancet. 19;1987: 1462–3.14.Rousseaux C G.A review of glutamate receptorsII:Pathophysiology & Pathology. view of glutamatereceptors J Toxicol Pathol 2008; 21: 133–17315.Wallig MA. Morphological manifestations of toxiccell injury. In: Hand book of Toxicologic Pathology,2nd ed. WM Hascheck, CG Rousseaux, and MAWallig (eds). AcademicPress, San Diego.2002. 39–64.16.Conn PJ and Pin JP. Pharmacology and functionsof metabotrophic receptors. Ann Rev PharmacolToxicol. 37;1997:205–237