title: Baclofen mediates neuroprotection on hippocampal CA1 pyramidal cells through the regulation of autophagy under chronic cerebral hypoperfusion.
abstract: GABA receptors play an important role in ischemic brain injury. Studies have indicated that autophagy is closely related to neurodegenerative diseases. However, during chronic cerebral hypoperfusion, the changes of autophagy in the hippocampal CA1 area, the correlation between GABA receptors and autophagy, and their influences on hippocampal neuronal apoptosis have not been well established. Here, we found that chronic cerebral hypoperfusion resulted in rat hippocampal atrophy, neuronal apoptosis, enhancement and redistribution of autophagy, down-regulation of Bcl-2/Bax ratio, elevation of cleaved caspase-3 levels, reduction of surface expression of GABAA receptor α1 subunit and an increase in surface and mitochondrial expression of connexin 43 (CX43) and CX36. Chronic administration of GABAB receptors agonist baclofen significantly alleviated neuronal damage. Meanwhile, baclofen could up-regulate the ratio of Bcl-2/Bax and increase the activation of Akt, GSK-3β and ERK which suppressed cytodestructive autophagy. The study also provided evidence that baclofen could attenuate the decrease in surface expression of GABAA receptor α1 subunit, and down-regulate surface and mitochondrial expression of CX43 and CX36, which might enhance protective autophagy. The current findings suggested that, under chronic cerebral hypoperfusion, the effects of GABAB receptors activation on autophagy regulation could reverse neuronal damage.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China.|Neurology Department, Huanggang central hospital, Hubei Province, Huanggang, 438000, PR China.
authors.forename: Chang-jun
authors.initials: CJ
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Center for Integrated Protein Science (CIPSM) and Zentrum für Pharmaforschung, Department Pharmazie, Ludwig-Maximilians-Universität München, 80539 Munich, Germany.
authors.forename: Xian-gang
authors.initials: XG
authors.lastname: Zong
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China.
authors.forename: Chao
authors.initials: C
authors.lastname: Luo
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China.|Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Hubei Province, Wuhan 430030, China.
authors.forename: Lian-jun
authors.initials: LJ
authors.lastname: Guo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D001418:Baclofen / Q000494:pharmacology*; D015415:Biomarkers; D002545:Brain Ischemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D056547:CA1 Region, Hippocampal / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D017630:Connexins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D000066829:Neuroprotection / Q000187:drug effects*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism; D000097004:Gap Junction delta-2 Protein
chemical_list: D001418:Baclofen; D015415:Biomarkers; D053148:Caspase 3; D018031:Connexin 43; D017630:Connexins; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D051057:Proto-Oncogene Proteins c-akt; D011963:Receptors, GABA-A; D000097004:Gap Junction delta-2 Protein; C000605508:Gsk3b protein, rat