title: Topiramate attenuates cerebral ischemia/reperfusion injury in gerbils via activating GABAergic signaling and inhibiting astrogliosis.
abstract: Impaired GABAergic inhibitory synaptic transmission plays an essential role in the pathogenesis of selective neuronal cell death following transient global ischemia. GABA(A) receptor (GABA(A)R), K⁺-Cl⁻ co-transporter 2 (KCC2), Na⁺-K⁺-Cl⁻ co-transporter 1 (NKCC1) and astrocytes are of particular importance to GABAergic transmission. The present study was designed to explore whether the neuroprotective effect of topiramate (TPM) was linked with the alterations of GABAergic signaling and astrocytes. The bilateral carotid arteries were occluded, and TPM (80 mg/kg/day (divided twice daily), i.p.) was injected into gerbils. At day 1, 3 and 7 post-ischemia, neurological deficit was scored and changes in hippocampal neuronal cell death were evaluated by Nissl staining. The apoptosis-related regulatory proteins (procaspase-3, caspase-3, Bax and Bcl-2) and GABAergic signal molecules (GABA(A)R α1, GABA(A)R γ2, KCC2 and NKCC1) were also detected using western blot assay. In addition, the fluorescent intensity and protein level of glial fibrillary acidic protein (GFAP), a major component of astrocyte, were examined by confocal and immunoblot analysis. Our results showed that TPM treatment significantly decreased neurological deficit scores, attenuated the ischemia-induced neuronal loss and remarkably decreased the expression levels of procaspase-3, caspase-3 as well as the ratio of Bax/Bcl-2. Besides, treatment with TPM also resulted in the increased protein expressions of GABA(A)R α1, GABA(A)R γ2 and KCC2 together with the decreased protein level of NKCC1 in gerbils hippocampus. Furthermore, fluorescent intensity and protein level of GFAP were evidently reduced in TPM-treated gerbils. These findings suggest that the therapeutic effect of TPM on global ischemia/reperfusion injury appears to be associated with the enhancement of GABAergic signaling and the inhibition of astrogliosis in gerbils.
authors.affiliation: Department of Pharmaceutical Toxicology, School of Pharmaceutical Science, China Medical University, Shenyang 110001, China.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Mao
authors.forename: Changwei
authors.initials: C
authors.lastname: Ji
authors.forename: Chunyan
authors.initials: C
authors.lastname: Sun
authors.forename: Danfeng
authors.initials: D
authors.lastname: Cao
authors.forename: Ping
authors.initials: P
authors.lastname: Ma
authors.forename: Zhong
authors.initials: Z
authors.lastname: Ji
authors.forename: Fangyuan
authors.initials: F
authors.lastname: Cao
authors.forename: Dongyu
authors.initials: D
authors.lastname: Min
authors.forename: Shuzhi
authors.initials: S
authors.lastname: Li
authors.forename: Jiqun
authors.initials: J
authors.lastname: Cai
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Cao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005849:Gerbillinae; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000378:metabolism* / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077236:Topiramate; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D005904:Glial Fibrillary Acidic Protein; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D011963:Receptors, GABA-A; D051028:bcl-2-Associated X Protein; D000077236:Topiramate; D005632:Fructose