3-Hydroxymorphinan protects against hypoxia-induced cell death in primary astrocyte by regulating Ca2+ influx and the glutamate homeostasis

Abstract

Background Hypoxia is a pathological phenomenon of the central nervous system that occurs during ischemia and stroke, leading to brain cell damage. Astrocytes play an important role in maintaining homeostasis in the brain microenvironment under normal as well as in pathological conditions. 3-hydroxymorphinan (3-HM) is an active metabolite of dextromethorphan (DM) that is widely used in anti-cough remedies and is more potent and safer than DM in the treatment of neurological disorders. However, previous research has not examined whether 3-HM has a protective effect in ischemic condition. Objective In this study, we aimed to confirm the effect of 3-HM on hypoxia-induced astrocyte death. We also investigated the protective mechanism of 3-HM and its potential applicability in ischemia brain injury. Result For the in vitro hypoxic conditions, CoCl2, a hypoxia-mimetic agent, was added to mouse primary astrocytes. 200 mu M of CoCl2 showed cytotoxicity, whereas pre-incubation with 3-HM attenuated cell death by CoCl2. Moreover, pre-treatment with 3-HM dramatically reduced oxidative stress and mitochondrial damage by CoCl2. Further, 3-HM significantly reduced intracellular calcium influx induced by extracellular glutamate and finally modulated the glutamate released from the astrocytes. Conclusion Taken together, these results suggest that 3-HM has a potential to regulate glutamate release from the astrocytic cell death in hypoxic condition and could be used as a promising preventive or therapeutic agent for ischemic brain injury.