Role of salt-induced kinase 1 in androgen neuroprotection against cerebral ischemia |
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Authors: | Jian Cheng Masayoshi Uchida Wenri Zhang Marjorie R Grafe Paco S Herson Patricia D Hurn |
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Institution: | 1.Department of Anesthesiology and Peri-Operative Medicine, Portland, Oregon, USA;2.Department of Pathology, Oregon Health and Science University, Portland, Oregon, USA;3.Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon, USA;4.Department of Neurology, Oregon Health and Science University, Portland, Oregon, USA |
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Abstract: | Androgens within physiological ranges protect castrated male mice from cerebral ischemic injury. Yet, underlying mechanisms are unclear. Here, we report that, after middle cerebral artery occlusion (MCAO), salt-induced kinase 1 (SIK1) was induced by a potent androgen—dihydrotestosterone (DHT) at protective doses. To investigate whether SIK1 contributes to DHT neuroprotection after cerebral ischemia, we constructed lentivirus-expressing small interference RNA (siRNA) against SIK1. The SIK1 knockdown by siRNA exacerbated oxygen–glucose deprivation (OGD)-induced cell death in primary cortical neurons, suggesting that SIK1 is an endogenous neuroprotective gene against cerebral ischemia. Furthermore, lentivirus-mediated SIK1 knockdown increased both cortical and striatal infarct sizes in castrated mice treated with a protective dose of DHT. Earlier studies show that SIK1 inhibits histone deacetylase (HDAC) activities by acting as a class IIa HDAC kinase. We observed that SIK1 knockdown decreased histone H3 acetylation in primary neurons. The SIK1 siRNA also exacerbated OGD-induced neuronal death in the presence of trichostatin A (TSA), an HDAC inhibitor, and decreased histone H3 acetylation at 4 hours reoxygenation in TSA-treated neurons. Finally, we showed that DHT at protective doses prevented ischemia-induced histone deacetylation after MCAO. Our finding suggests that SIK1 contributes to neuroprotection by androgens within physiological ranges by inhibiting histone deacetylation. |
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Keywords: | androgen cerebral ischemia dihydrotestosterone neuroprotection salt-induced kinase 1 |
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