The present study examined whether ethyl pyruvate (EP) promotes the survival of nigrostriatal dopaminergic (DA) neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease. MPTP induced degeneration of nigrostriatal DA neurons and glial activation as visualized by tyrosine hydroxylase, macrophage antigen complex-1, and/or glial fibrillary acidic protein immunoreactivity. Western blotting and immunohistochemistry showed activation of microglial NADPH oxidase and astroglial myeloperoxidase (MPO), and subsequent reactive oxygen species (ROS)/reactive nitrogen species (RNS) production and oxidative DNA damage in the MPTP-treated substantia nigra. Additional immunohistochemical staining also showed that MPTP induced glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) in the substantia nigra (SN). Interestingly, treatment with EP prevented degeneration of nigrostriatal DA neurons, increased striatal dopamine levels, and improved motor function. This neuroprotection afforded by EP was associated with the suppression of astroglial MPO expression, NADPH oxidase- and/or inducible nitric oxide synthase-derived ROS/RNS production by activated microglia. In parallel, treatment of EP significantly increased GDNF and CNTF in the MPTP-treated SN. Also, EP was found to protect DA neurons from 1-methyl-4-phenyl-pyridinium (MPP+) neurotoxicity in co-cultures of mesencephalic neurons and glia, but not in neuron-enriched mesencephalic cultures devoid of glia. The present findings show that EP may inhibit oxidative stress and increase levels of neurotrophic factors in glia, suggesting that EP may have therapeutic value in the treatment of aspects of Parkinson’s disease related to glia activation.
