DNA damage in brain mitochondria caused by aging and MPTP treatment

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyrine (MPTP) treatment leads to marked depletion of dopamine (DA) levels in the nigrostriatal pathway and dopamin ergic neuronal degeneration in caudate-putamen and substantia nigra. MPTP i s believed to inhibit complex I of the electron transport system leading to the generation of reactive oxygen species. We sought to test the hypothese s that MPTP treatment: (1) leads to dopamine depletion; (2) causes extensiv e mitochondrial DNA damage, and (3) that these effects would be age depende nt. The levels of dopamine and its metabolites, DOPAC and HVA were analyzed by HPLC equipped with electrochemical detection. DNA damage was measured b y quantitative PCR in both mitochondrial and nuclear (beta -polymerase) tar gets from the caudate-putamen, substantia nigra and cerebellum regions of c ontrol and MPTP-treated mice. The age groups studied were 22 days and 12 mo nths. MPTP produced no significant effect on the levels of dopamine and its metabolites in young mice whereas in old, there was a significant decrease in this neurotransmitter system after MPTP administration. These 12-month- old mice, when compared to the young mice, showed a significant increase in mitochondrial DNA damage in the caudate-putamen and cerebellum. The latter region also displayed a significant increase in DNA damage in a nuclear ge ne. After treatment with MPTP, there was an age-dependent increase in DNA d amage in mitochondria of the caudate-putamen while there was no significant DNA damage in the nuclear target. MPTP treatment led to damage in both mit ochondrial and nuclear DNA of the substantia nigra, while there was no dama ge in either mitochondria or nucleus in cerebellum which was used as a nega tive control. (C) 2000 Elsevier Science B.V. All rights reserved.