Creatine and cyclocreatine attenuate MPTP neurotoxicity

Systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MP TP) produces parkinsonism in experimental animals by a mechanism involving impaired energy production. MPTP is converted by monoamine oxidase B to 1-m ethyl-4-phenylpyridinium (MPPS), which blocks complex I of the electron tra nsport chain. Oral supplementation with creatine or cyclocreatine, which ar e substrates for creatine kinase, may increase phosphocreatine (PCr) or cyc lophosphocreatine (PCCr) and buffer against ATP depletion and thereby exert neuroprotective effects. In the present study we found that oral supplemen tation with either creatine or cyclocreatine produced significant protectio n against MPTP-induced dopamine depletions in mice. Creatine protected agai nst MPTP-induced loss of Nissl and tyrosine hydroxylase immunostained neuro ns in the substantia nigra. Creatine and cyclocreatine had no effects on th e conversion of MPTP to MPP + in vivo. These results further implicate meta bolic dysfunction in MPTP neurotoxicity and suggest a novel therapeutic app roach, which may have applicability for Parkinson's disease. (C) 1999 Acade mic Press.