Agonist Types

More recently, nigrostriatal degene ration has been related to an imp airm entofmito chondri alresp ira tory activity dence has also suggested an invo lv em entofexcito tox icity. In lightof these cons ide rations, the following discussion conce rn ing the roleof excito tox icity in P a rk in son sdisease will emphasizethere lationsh ips be tween EAA induced dam ageandotherbiochem Pyridoxine icaland pha rmaco log ic alter ations. Indeed, dop aminetu rnover involves its ox idation via mono am ineoxidase. Dop am inemay also unde rgo au tox id ation with the fo rmationof tox ic quinoncsas well as H. Ithas therefore become a widely used model for research conce rn ing the nigrostriatal system,prov id ing the initialhintth atan imp airm entofmitochondrialrespi ra tory ch a in activity cou ld play a role in the pa thogenes isof cell loss in P a rk in son sdisease.MPTP is converted by MAO B to its me thyl pheny lpyrid in ium, which represen ts theultima te media torofits neu ro tox icity. MPP is actively taken up by dopam ine rg ic neu rons and it is also accumulated in to mi to chondria where it acts as an inh ibitorofcomp lex I. MPTP MPP toxicity has been directly linked to a failureof energy supplies in a numberof in litro modelsystems cently, the dep letionof dop aminecaused by MPTP in the mou sestri a tum has been found to be preceded by a selective decrease in ATP levels. Thethirdpro to type model for striatal damage is th atofme th amphet am inetoxicity.When adm inis te red in re am inecausesdr am aticdamage to nigrostriatalneu rons bo th in rodents and nonhum an pr ima tes, as ev idenced by longlasting dep ictionof striatal dop am ine, decreases in ty pam ineuptakesites, andhis tochem icalobse rvationof nervete rm in aldegene ration in thestri a tum. Tox icity mode ls shou ld he lp us to unravelthe precise na tureof even ts underly ing a pa tho log ic condit ion. Using in have found an increase in striatal glutamate release after repeated administrationofmeth amphet am ineto rats.Glu tama te release and, more in general, excitationof the NMDA receptor may result in the productionof oxygen radicals, suggesting one possible link between excitotoxicity and oxidative stress.This link is further supported by the fact thatme thamphe tam ine neu ence and releaseof striatal dopam ine which, as previously discussed, may Furosemide itself lead to oxidative stress.Indeed, meth amphe tam ine causes an increase in extracellular dopam ine levels, as assessed by in vivo microdialysis, and its toxic effects can be prevented by blocking dopam ine synthesis with amethyltyrosine. Recent work has also revealed thata failureof energy sup. A significant and ra ther selective decrease in ATP was found in the stria tumof mice injected with meth amphe tam ine. This decrease seemed to be correlated with dopam ine depletion, since pre trea tmentofmice with de oxyglucose, an inhibitorof glucose uptake and utilization, potentiated both ATP and dopam ine loss caused by meth amphe tam ine. Taken together, these findings suggest that different toxic events, including excitotoxicity, oxygen rad ical production, and energy failure, may all play a role in nigrostriatal damage.ap pears therefore to be supported by experimental evidence, making the me thamphe tam ine model particularly valuable notonly for studies on the roleof excitotoxicity in nigrostri atal degeneration, butalso for evaluating the interactions between excitotoxicity andothertoxic mechanisms.

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