In this study we have demonstrated that, similarly to DDC, the CYP 2E1 inhibitors, such as DAS and PIC, markedly enhance MPTP toxicity, as measured by the dramatic fall in striatal DA content. This finding cannot be considered a fortuitous event, since for many years a great number of compounds have been tested as 'enhancers' but none of them have proved to increase MPTP toxicity, except for ethanol and acetaldehyde.
In order to provide direct evidence of toxicity, we have also performed the usual procedure of tyrosine-hydroxylase immuno-reactivity in midbrain coronal slices of our treated mice (not reported here). Our results clearly indicate that while MPTP, at the dose we used, produced a minimal loss of DA perikaria in the SNpc (about 10%), the combined treatments induced at least 50% damage of the DA neurons, as previously observed with DDC (Vaglini et al., 2004). All these data confirm that DAS and PIC also strongly potentiate MPTP toxicity in this animal species, suggesting a specific role of CYP 2E1 in this toxic event.
In order to provide direct evidence for CYP 2E1 involvement, CYP 2E1 knockout mice (GONZ) and their respective wild type animals (SVI) were challanged with MPTP or the combined DDC + MPTP treatment. GONZ mice revealed a sensitivity to MPTP neuro-toxicity similar to that one of SVI animals, but significantly lower than C57/bl strain. This suggests that it is likely that transgenic mice compensate the lack of CYP 2E1 with other isozyme. A similar compensation among
C. Viaggi et al.: Cytochrome P45G and Parkinson's disease different P450 enzymes in this strain was observed for acetominophene toxicity (Lee et al., 1996). However in these knockout mice, DDC completely failed to enhance MPTP toxicity; this effect was instead regularly observed in the wild type animals. This further confirms the direct role of CYP 2E1 in DDC-induced enhancement of MPTP toxicity.
This study adds new insight into the role of CYP isozymes in MPTP-induced lesions of the nigro-striatal DA pathway, drawing attention more towards the metabolism in the brain than in the liver.
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