Neuroanatomical mapping of DNA repair and antioxidative responses in mouse brain: Effects of a single dose of MPTP

Abstract

The primary objective of this study was to map the normal distribution of the base excision enzyme oxyguanosine glycosylase (OGG1) across mouse-brain regions as a prelude to assessing the effects of various neurotoxicants, ranging from highly selective molecules like MPTP to more global toxic agents. This research is based on the hypothesis that regional brain vulnerability to a toxicant is determined, in part, by variation in the intrinsic capacity of cellular populations to successfully repair oxidative DNA damage. After mapping the normal distributions of OGG1 and superoxide dismutase (SOD) across 44 loci dissected from mouse brain, MPTP, a mitochondrial toxicant with selective dopamine (DA) neuron cytotoxicity was used to elicit focal oxidative stress and DNA repair responses. A single dose of MPTP (20mg/kg, i.p.) elicited time- and region-dependent changes in both SOD and OGG1, with early increases in DNA repair and anti-oxidant activities throughout all regions of brain. In some sampled loci, notably the substantia nigra (SN) and hippocampus, the heightened DNA repair and antioxidant responses were not maintained beyond 48h. Other loci from cerebellum, cerebral cortex and pons maintained high levels of activity up to 72h. Levels of dopamine (DA) were decreased significantly at all time points and remained below control levels in nigro-striatal and mesolimbic systems (ventral tegmental area and nucleus accumbens). Assessment of apoptosis by TUNEL staining revealed a significant increase in number of apoptotic nuclei in the substantia nigra at 72h and not in other loci. The marked degree of apoptosis that became evident in SN at 72h was associated with large decreases in SOD and DNA repair activity at that locus. In conclusion, MPTP elicited global effects on DNA repair and antioxidant activity in all regions of brain, but the most vulnerable loci were unable to maintain elevated DNA repair and antioxidant responses.