Dopaminergic neuroprotective effects of inosine in MPTP-induced parkinsonian mice via brain-derived neurotrophic factor upregulation

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease. However, no curative or modifying therapy is known. Inosine is a purine nucleoside that increases brain-derived neurotrophic factor (BDNF) expression in the brain through adenosine receptors. Herein, we investigated the neuroprotective effects of inosine and elucidated the mechanisms underlying its pharmacological action. Inosine rescued SH-SY5Y neuroblastoma cells from MPP+ injury in a dose-dependent manner. Inosine protection correlated with BDNF expression and the activation of its downstream signaling cascade, as the TrkB receptor inhibitor, K252a and siRNA against the BDNF gene remarkably reduced the protective effects of inosine. Blocking the A1 or A2A adenosine receptors diminished BDNF induction and the rescuing effect of inosine, indicating a critical role of adenosine A1 and A2A receptors in inosine-related BDNF elevation. We assessed whether the compound could protect dopaminergic neurons from MPTP-induced neuronal injury. Beam-walking and challenge beam tests revealed that inosine pretreatment for 3 weeks reduced the MPTP-induced motor function impairment. Inosine ameliorated dopaminergic neuronal loss and MPTP-mediated astrocytic and microglial activation in the substantia nigra and striatum. Inosine ameliorated the depletion of striatal dopamine and its metabolite following MPTP injection. BDNF upregulation and the activation of its downstream signaling pathway seemingly correlate with the neuroprotective effects of inosine. To our knowledge, this is the first study to demonstrate the neuroprotective effects of inosine against MPTP neurotoxicity via BDNF upregulation. These findings highlight the therapeutic potential of inosine in dopaminergic neurodegeneration in PD brains.