title: Pretreatment of rats with increased bioavailable berberine attenuates cerebral ischemia-reperfusion injury via down regulation of adenosine-5'monophosphate kinase activity.
abstract: Berberine (BBR) exhibits multiple beneficial biological effects. However, poor bioavailability of BBR has limited its clinical application. We previously demonstrated that solid dispersion of BBR with sodium caprate (HGSD) remarkably improves its bioavailability. We examined whether this increased bioavailability of BBR could protect the brain from ischemia-reperfusion (IR) induced injury. Rats treated with HGSD, SC and saline for 7 days then subjected to cerebral ischemia reperfusion by middle cerebral artery occlusion for 2h followed 12h reperfusion. Neurological deficit scores, infarct size, SOD, MDA and NO levels were examined. P-AMPK, Bax, cleaved-Caspase-3 in brain was determined. To further probe for the mechanism of beneficial effect of HGSD, PC12 cells were incubated with serum from control or HGSD pretreated animals, incubated with 300μM H2O2 to induce apoptosis. Caspase-3 activity and cell apoptosis was evaluated. HGSD pretreatment significantly attenuated neurological deficit scores, reduced infarct size, increased SOD and decreased MDA and NO after cerebral IR injury compared to controls. Meanwhile, HGSD pretreatment significantly reduced expression of p-AMPK, Bax, cleaved-Caspase-3 after cerebral IR injury. Sodium caprate (100mg/kg/d) pretreatment alone did not exhibit any of these beneficial effects. PC12 cell apoptosis was attenuated when cells were cultured with HGSD serum compared to control. The presence of AMPK activator (AICAR) attenuated whereas AMPK inhibitor (Compound C) augmented the protective effect of HGSD serum on PC12 cell apoptosis.The results indicate that HGSD-pretreatment of rats protects the brain from ischemia-reperfusion injury and the mechanism is due to its anti-apoptotic effect mediated by decreased activation of AMPK.
authors.affiliation: Department of Pharmacology, College of Basic Medical Sciences, School of Nursing, Jilin University, Changchun Jilin, China; Department of Pharmacology, College of Pharmacy, Jilin University, Changchun, Jilin, China.
authors.forename: Weijia
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, College of Basic Medical Sciences, School of Nursing, Jilin University, Changchun Jilin, China.
authors.forename: Shengnan
authors.initials: S
authors.lastname: Wei
authors.affiliation: Department of Pharmacology, College of Basic Medical Sciences, School of Nursing, Jilin University, Changchun Jilin, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, College of Basic Medical Sciences, School of Nursing, Jilin University, Changchun Jilin, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Xue
authors.affiliation: Department of Pharmacology, College of Basic Medical Sciences, School of Nursing, Jilin University, Changchun Jilin, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yao
authors.affiliation: Department of Pharmacology, College of Basic Medical Sciences, School of Nursing, Jilin University, Changchun Jilin, China. Electronic address: zhangming_00@126.com.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, the Second Hospital of Jilin University, Changchun, Jilin, China. Electronic address: surgeonxiao@sohu.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Department of Pharmacology & Therapeutics, University of Manitoba, Manitoba Institute of Child Health, Winnipeg, Manitoba, Canada.
authors.forename: Grant M
authors.initials: GM
authors.lastname: Hatch
authors.affiliation: Department of Pharmacology, College of Basic Medical Sciences, School of Nursing, Jilin University, Changchun Jilin, China.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001599:Berberine / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D001682:Biological Availability; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003652:Decanoic Acids / Q000737:chemistry; D015536:Down-Regulation / Q000187:drug effects*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats
chemical_list: D003652:Decanoic Acids; D001599:Berberine; D009569:Nitric Oxide; C031071:decanoic acid; D008315:Malondialdehyde; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: AMPK; Apoptosis; HGSD; Ischemia-reperfusion brain injury