Abstract
Secondary injuries mediated by oxidative stress lead to deterioration of neurological functions after intracerebral hemorrhage (ICH). Cortical astrocytes are among the most important cells in the central nervous system (CNS), and play key roles in maintaining redox homeostasis by providing oxidative stress defense. Hemin is a product of hemoglobin degradation, which has strong toxicity and can induce reactive oxygen species (ROS). Melatonin (Mel) and its metabolites are well tolerated without toxicity, prevent tissue damage as well as effectively assist in scavenging free radicals. We evaluated the hemin neurotoxicity to astrocytes and the resistance of Mel-treated astrocytes to hemin neurotoxicity. And we found Mel induced PKCα phosphorylation (p-PKC), nuclear translocation of Nrf2 in astrocytes, and upregulation of HO-1, which contributed to the reduction of ROS accumulation and cell apoptosis. Nrf2 and HO1 protein expression upregulated by Mel were decreased after administration of PKC inhibitor, Ro 31-8220 (Ro 31). Luzindole (Luz), a melatonin receptor inhibitor, suppressed p-PKCα, HO-1, and Nrf2 expression upregulated by Mel and increased cell apoptosis rate. The upregulation of HO-1 induced by Mel was depressed by knocking down Nrf2 expression by siRNA, which also decreased the resistance of astrocytes to toxicity of hemin. Mel activates astrocytes through PKCα/Nrf2/HO-1 signaling pathway to acquire resistance to toxicity of hemin and resist from oxidative stress and apoptosis. The positive effect of Mel on PKCα/Nrf2/HO-1 signaling pathway may become a new target for neuroprotection after intracerebral hemorrhage.
Highlights
intracerebral hemorrhage (ICH) is a destructive form of stroke with high mortality and morbidity, and survivors typically have severe nervous harm (Qureshi et al, 2009; Keep et al, 2012)
The major findings of this study are as below: (1) the cell viability of astrocytes was decreased after hemin exposure, in a dosedependent manner; (2) astrocytes are extensively damaged by neurotoxicity induced by hemin without Mel treatment, but after treated with Mel, Mel helped astrocytes resist the neurotoxicity and reduce the degree of damage; (3) Mel administration induced PKCα phosphorylation, Nrf2 upregulation and nuclear translocation in astrocytes, and led to phase II enzyme hydroxyl radical (HO)-1 upregulation; (4) Nrf2 and HO1 protein expression upregulated by Mel were blocked after administration of PKC inhibitor, Ro 31-8220 (Ro 31); (5) Mel-induced activation of PKCα/Nrf2/HO1 pathway could be partly abolished by Mel receptor inhibitor, Luz; (6) the in vitro protective effect of Mel on astrocytes was PKCα/Nrf2 dependent
Mel has been reported to play an active role in several neurological disease, such as epilepsy (Brigo et al, 2016), Parkinson’s disease (Mendivil-Perez et al, 2017), cerebral ischemia (Yang et al, 2015), intracerebral Hemorrhage (Wang Z. et al, 2018), and subarachnoid hemorrhage (SAH) (Dong et al, 2016; Zhao et al, 2017)
Summary
ICH is a destructive form of stroke with high mortality and morbidity, and survivors typically have severe nervous harm (Qureshi et al, 2009; Keep et al, 2012). Mel Protects Astrocytes From Hemin (Hb) and its catabolite such as iron, bilirubin and hemin is a major cause of brain injury induced by ICH (Zhao et al, 2011; Keep et al, 2012; Xi et al, 2014). These molecules increase the secretion of inflammatory cytokines including IL-1β and TNF-α, which play a key role in inflammation and enlarge the inflammatory cascade (Wang J. et al, 2018).
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