Oxytocin Anti-Apoptotic Potential Mediates Neuroprotection Against 3-Nitropropionic Acid-Induced Huntington’s Disease-Like Pathophysiology in Rats: Involvement of Calpain-2/p25 Cdk5/MEF-2 Signaling Pathway

Abstract

The increasing interest in the pro-apoptotic function of calpain-2 in the course of Huntington’s disease (HD) is attributed to the involvement of its substrate, cyclin-dependent kinase 5 (Cdk5), in neuronal death during neurodegeneration. Oxytocin has been demonstrated to suppress apoptosis in many neurodegenerative disorders. This research aimed to investigate the effect of oxytocin on several calpain 2-induced apoptogenic factors in 3-nitropropionic acid (3-NP) animal model of HD in rats. For 14 days, rats received 3-NP (10 mg/kg, i.p.), and oxytocin (160 µg/kg, i.p.) 1 h before 3-NP administration. Oxytocin reversed the detrimental effects of 3-NP on the striatum, which was evidenced by improvement of motor behavior, as well as histological picture and neurochemical balance. Oxytocin markedly reduced striatal calpain-2 and p25 Cdk5 protein expressions and increased the endogenous calpain inhibitor, calpastatin expression along with the pro-survival factor, myocyte-enhancer factor 2 (MEF-2) contents. Moreover, it suppressed striatal content of the pro-apoptotic biomarkers (BCl-2-associated X protein (Bax), tumor suppressor protein (p53), and caspase-3) and elevated striatal anti-apoptotic B-cell lymphoma/leukemia 2 (BCl-2) content. It repressed the release of mitochondrial cytochrome c and apoptosis-inducing factor (AIF) to hinder caspase-dependent and caspase-independent apoptotic neuronal death. Oxytocin could be a promising candidate for HD management by hampering both mitochondrial and non-mitochondrial apoptosis through inhibition of calpain-2/p25 Cdk5/MEF-2 pathway.