Studies in the rat have shown that loss of striatal DA innervatio

Studies in the rat have shown that loss of striatal DA innervation is followed by a compensatory increase in serotonergic innervation.46 This may also be the situation at some stage of Parkinson’s disease; however, in the advanced Parkinsonian brain, the serotonergic midbrain raphe nucleus, from which the striatal fibers originate,

also degenerates and is lost. We are currently studying where BMS-907351 clinical trial L-dopa is deaminated following loss of both dopaminergic and serotonergic axonal Inhibitors,research,lifescience,medical varicosities. Our preliminary data show that following both dopaminergic denervation by 6-hydroxydopamine, and 5-HT depletion by 5,6-dihydroxytryptamine, rasagiline treatment causes a greater increase in DA produced from L-dopa

than following single lesion with 6-hydroxydopamine alone.47 It is conceivable that a greater proportion of Inhibitors,research,lifescience,medical administered L-dopa is decarboxylated to DA in glial cells (which express MAO-B) in the Parkinsonian brain. Rasagiline and other MAO-B inhibitors may therefore produce some of their clinical L-dopa potentiating effect by inhibition of glial MAO-B. In the early-stage Parkinsonian brain, where a substantial number of DA neurons are still present, the β-phenylethylamine mechanism may participate in the anti-Parkinsonian effect of rasagiline. RASAGILINE AND NEUROPROTECTION NEUROPROTECTION IN ANIMAL MODELS AND CELLS As described above, Inhibitors,research,lifescience,medical selegiline was found to possess neuroprotective effect in isolated neuronal Inhibitors,research,lifescience,medical preparations. Neuroprotection was observed at concentrations below those required for MAO inhibition, and other MAO inhibitors did not consistently produce neuroprotection. We observed neuroprotection by rasagiline both in dopaminergic and non-dopaminergic rat embryonic mesencephalic neurons.48 The neuroprotective effect of rasagiline was greater than that of selegiline at equimolar concentrations, although this action was seen at a relatively

high concentration of rasagiline (1 μM). Later, we described the anti-apoptotic Inhibitors,research,lifescience,medical action of rasagiline in primary cultures of rat cerebellar neurons, which are non-catecholaminergic.49 The neuroprotective effect in cerebellar granule cells was seen at concentrations (1 X 10–10 M) below those required for MAO inhibition (1 X 10–8M). The intracellular Journal of Clinical Oncology mechanism of action of rasagiline’s anti-apoptotic effect has been extensively investigated by Youdim and co-workers.50–53 The proposed mechanisms of action include up-regulation of Bcl2 family proteins, reduced expression of pro-apoptotic Bax family proteins, up-regulation of protein kinase C ε, up-regulation of superoxide dismutase, and antagonism of nuclear translocation of glyceraldehyde phosphate dehydrogenase (GAPDH). Most, but not all of these effects have been described at therapeutically relevant concentrations (nanomolar).

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