title: Berberine Preconditioning Protects Neurons Against Ischemia via Sphingosine-1-Phosphate and Hypoxia-Inducible Factor-1[Formula: see text].
abstract: Berberine exerts neuroprotective and modulates hypoxia inducible factor-1-alpha (HIF-1[Formula: see text]. Based on the role of HIF-1[Formula: see text] in hypoxia preconditioning and association between HIF-1[Formula: see text] and sphingosine-1-phosphate (S1P), we hypothesized that berberine preconditioning (BP) would ameliorate the cerebral injury induced by ischemia through activating the system of HIF-1[Formula: see text] and S1P. Adult male rats with middle cerebral artery occlusion (MCAO) and rat primary cortical neurons treated with oxygen and glucose deprivation (OGD) with BP at 24[Formula: see text]h (40[Formula: see text]mg/kg) and 2[Formula: see text]h (10[Formula: see text][Formula: see text]mol/L), respectively, were used to determine the neuroprotective effects. The HIF-1[Formula: see text] accumulation, and S1P metabolism were assayed in the berberine-preconditioned neurons, and the HIF-1[Formula: see text]-mediated transcriptional modulation of sphingosine kinases (Sphk) 1 and 2 was analyzed using chromatin immunoprecipitation and real-time polymerase chain reaction. BP significantly prevented cerebral ischemic injury in the MCAO rats at 24[Formula: see text]h and 72[Formula: see text]h following ischemia/reperfusion. In OGD-treated neurons, BP enhanced HIF-1[Formula: see text] accumulation with activation of PI3K/Akt, and induced S1P production by activating Sphk2 via the promotion of HIF-1[Formula: see text]-mediated Sphk2 transcription. In conclusion, BP activated endogenous neuroprotective mechanisms associated with the S1P/HIF-1 pathway and helped protect neuronal cells against hypoxia/ischemia.
authors.affiliation: * Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China.|† Jiangsu Botanical Medicine Refine Engineering Research Center, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China.|‡ Department of Clinic Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China.
authors.forename: Qichun
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: ‡ Department of Clinic Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China.
authors.forename: Huimin
authors.initials: H
authors.lastname: Bian
authors.affiliation: * Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China.|† Jiangsu Botanical Medicine Refine Engineering Research Center, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China.
authors.forename: Liwei
authors.initials: L
authors.lastname: Guo
authors.affiliation: * Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China.|† Jiangsu Botanical Medicine Refine Engineering Research Center, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China.
authors.forename: Huaxu
authors.initials: H
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001599:Berberine / Q000008:administration & dosage*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007511:Ischemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D001599:Berberine; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008246:Lysophospholipids; D018696:Neuroprotective Agents; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate
keywords: Berberine; Hypoxia-inducible Factor-1; Preconditioning; Sphingosine-1-phosphate