Mechanisms and Prevention of Neurodegeneration via Microglial Activation in the Nigro-Striatal System

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This study addressed the mechanisms of microglia-mediated dopaminergic neurodegeneration as well as the effects of neuroprotective drugs expected to have novel pharmacodynamic actions. (1) Am80, a retinoid RAR agonist, inhibited dopaminergic neuron death induced by IFN- γ/LPS. Am80 increased the expression of BDNF mRNA in cultured midbrain tissues, and the protective effect of Am80 was reversed by a TrkB inhibitor and anti-BDNF neutralizing antibodies. BDNF, whose production is enhanced by RAR stimulation, is suggested to protect dopaminergic neurons in an autocrine / paracrine manner. (2) Resveratrol, an activator of sirtuin family of histone deacetylases, prevented dopaminergic neuron death induced by MPP+ and thrombin. However, the inhibitor of histone deacetylases did not affect the protective action of resveratrol. Resveratrol prevented the increase in the production of reactive oxygen species and the depletion of glutathione induced by MPP+, suggesting that antioxidative properties are involved in the protective effect of resveratrol. On the other hand, dopaminergic neuron death and enhanced p53 acetylation induced by DNA alkylating agents were inhibited by resveratrol and NAD, indicating that sirtuin-activating properties may be involved in neuroprotection under several circumstances. (3) IFN- γ/LPS, NO donors and a cyclic GMP analog all induced HO-1 expression in cultured midbrain tissues. HO-1 induction in dopaminergic neurons in response to IFN- γ/LPS was suppressed by a soluble guanylate cyclase (sGC) inhibitor. An HO-1 inhibitor and a sGC inhibitor exacerbated, whereas an HO-1 activator and a cyclic GMP analog prevented, dopaminergic neuron death induced by IFN-γ/LPS. The results suggest that induction of HO-1 expression via NO-cyclic GMP signaling pathway functions as an endogenous protective mechanism of dopaminergic neurons.