Related Experiment Videos
Creatine and cyclocreatine attenuate MPTP neurotoxicity
R T Matthews1, R J Ferrante, P Klivenyi
1Neurology Service, Massachusetts General Hospital, Boston, Massachusetts, USA.
Abstract:
Systemic administration of 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) produces parkinsonism in experimental animals by a mechanism involving impaired energy production. MPTP is converted by monoamine oxidase B to 1-methyl-4-phenylpyridinium (MPP+), which blocks complex I of the electron transport chain. Oral supplementation with creatine or cyclocreatine, which are substrates for creatine kinase, may increase phosphocreatine (PCr) or cyclophosphocreatine (PCCr) and buffer against ATP depletion and thereby exert neuroprotective effects. In the present study we found that oral supplementation with either creatine or cyclocreatine produced significant protection against MPTP-induced dopamine depletions in mice. Creatine protected against MPTP-induced loss of Nissl and tyrosine hydroxylase immunostained neurons in the substantia nigra. Creatine and cyclocreatine had no effects on the conversion of MPTP to MPP+ in vivo. These results further implicate metabolic dysfunction in MPTP neurotoxicity and suggest a novel therapeutic approach, which may have applicability for Parkinson's disease.
Insights
Oral creatine supplementation protected mice against 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-induced neurotoxicity. This suggests creatine may offer a novel therapeutic approach for Parkinson's disease by supporting energy production.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) induces parkinsonism by impairing cellular energy production.
- MPTP is metabolized to MPP+, which inhibits Complex I of the mitochondrial electron transport chain.
- Creatine and cyclocreatine may enhance cellular energy buffering via phosphocreatine (PCr) or cyclophosphocreatine (PCCr).
Purpose of the Study:
- To investigate the neuroprotective effects of oral creatine and cyclocreatine supplementation against MPTP-induced neurotoxicity in mice.
- To determine if creatine or cyclocreatine supplementation influences MPTP metabolism to MPP+.
Main Methods:
- Mice were administered oral creatine or cyclocreatine.
- MPTP was administered systemically to induce parkinsonism.
- Dopamine levels, neuronal counts (Nissl and tyrosine hydroxylase staining) in the substantia nigra were assessed.
- MPTP to MPP+ conversion was measured in vivo.
Main Results:
- Oral creatine and cyclocreatine supplementation significantly protected against MPTP-induced dopamine depletions.
- Creatine administration prevented MPTP-induced loss of dopaminergic neurons in the substantia nigra.
- Neither creatine nor cyclocreatine affected the in vivo conversion of MPTP to MPP+.
Conclusions:
- Metabolic dysfunction is implicated in MPTP neurotoxicity.
- Oral creatine and cyclocreatine supplementation demonstrate neuroprotective effects against MPTP toxicity.
- These findings suggest a potential therapeutic strategy for Parkinson's disease involving creatine supplementation.