Probenecid potentiates MPTP/MPP+ toxicity by interference with cellular energy metabolism.

摘要: The uricosuric agent probenecid is co-administered with the dopaminergic neurotoxin MPTP to produce a chronic mouse model of Parkinson's disease. It has been proposed that serves elevate concentrations in brain by reducing renal elimination toxin. However, this mechanism never formally demonstrated date and questioned our previous data showing intracerebral MPP(+), active metabolite MPTP, are not modified co-injection probenecid. In study, we investigated potentiating effects vivo vitro arguing against possibility altered metabolism or impaired MPTP. We find (i) toxic itself several neuronal populations apart from neurons, (ii) it also potentiates other mitochondrial complex I inhibitors such as rotenone. On mechanistic level, show able lower intracellular ATP its action on cells can be reversed extracellular ATP. Probenecid potentiate effect toxins due impact could therefore useful atypical parkinsonian syndromes.