title: Role of salt-induced kinase 1 in androgen neuroprotection against cerebral ischemia.
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.
authors.affiliation: Department of Anesthesiology and Peri-Operative Medicine, Portland, Oregon 97239-3098, USA. chengj@ohsu.edu
authors.forename: Jian
authors.initials: J
authors.lastname: Cheng
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Uchida
authors.forename: Wenri
authors.initials: W
authors.lastname: Zhang
authors.forename: Marjorie R
authors.initials: MR
authors.lastname: Grafe
authors.forename: Paco S
authors.initials: PS
authors.lastname: Herson
authors.forename: Patricia D
authors.initials: PD
authors.lastname: Hurn
mesh_terms: D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002545:Brain Ischemia / Q000235:genetics* / Q000517:prevention & control*; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000502:physiology; D013196:Dihydrotestosterone / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D005947:Glucose / Q000172:deficiency; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D016086:Lentivirus / Q000235:genetics; D008297:Male; D008845:Microinjections; D018696:Neuroprotective Agents; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000502:physiology*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020521:Stroke / Q000209:etiology / Q000473:pathology
chemical_list: D000728:Androgens; D056572:Histone Deacetylase Inhibitors; D018696:Neuroprotective Agents; D034741:RNA, Small Interfering; D013196:Dihydrotestosterone; D017346:Protein Serine-Threonine Kinases; C120299:Sik1 protein, rat; D005947:Glucose