title: Topiramate attenuates early brain injury following subarachnoid haemorrhage in rats via duplex protection against inflammation and neuronal cell death.
abstract: Early brain injury (EBI) following aneurysmal subarachnoid haemorrhage (SAH) insults contributes to the poor prognosis and high mortality observed in SAH patients. Topiramate (TPM) is a novel, broad-spectrum, antiepileptic drug with a reported protective effect against several brain injuries. The current study aimed to investigate the potential of TPM for neuroprotection against EBI after SAH and the possible dose-dependency of this effect. An endovascular perforation SAH model was established in rats, and TPM was administered by intraperitoneal injection after surgery at three different doses (20mg/kg, 40mg/kg, and 80mg/kg). The animals' neurological scores and brain water content were evaluated, and ELISA, Western blotting and immunostaining assays were conducted to assess the effect of TPM. The results revealed that TPM lowers the elevated levels of myeloperoxidase and proinflammatory mediators observed after SAH in a dose-related fashion, and the nuclear factor-kappa B (NF-κB) signalling pathway is the target of neuroinflammation regulation. In addition, TPM ameliorated SAH-induced cortical neuronal apoptosis by influencing Bax, Bcl-2 and cleaved caspase-3 protein expression, and the effect of TPM was enhanced in a dose-dependent manner. Various dosages of TPM also upregulated the protein expression of the γ-aminobutyric acid (GABA)-ergic signalling molecules, GABAA receptor (GABAAR) α1, GABAAR γ2, and K(+)-Cl(-) co-transporter 2 (KCC2) together and downregulated Na(+)-K(+)-Cl(-) co-transporter 1 (NKCC1) expression. Thus, TPM may be an effective neuroprotectant in EBI after SAH by regulating neuroinflammation and neuronal cell death.
authors.affiliation: Department of Neurosurgery, Second Affiliated Hospital, Zhejiang Chinese Medical University, 318 Chaowang Road, Hangzhou 310005, Zhejiang, China; Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou 310009, Zhejiang, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou 310009, Zhejiang, China; Department of Burns, Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou 310009, Zhejiang, China.
authors.forename: Song-Xue
authors.initials: SX
authors.lastname: Guo
authors.affiliation: Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou 310009, Zhejiang, China.
authors.forename: Jian-Ru
authors.initials: JR
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Second Affiliated Hospital, Zhejiang Chinese Medical University, 318 Chaowang Road, Hangzhou 310005, Zhejiang, China.
authors.forename: Hang-Gen
authors.initials: HG
authors.lastname: Du
authors.affiliation: Department of Neurosurgery, Ruian People's Hospital, 108 Wansong Road, Ruian 325200, Zhejiang, China.
authors.forename: Chao-Hui
authors.initials: CH
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou 310009, Zhejiang, China.
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou 310009, Zhejiang, China. Electronic address: wuqun30639@163.com.
authors.forename: Qun
authors.initials: Q
authors.lastname: Wu
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D001929:Brain Edema / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology; D007473:Ion Channels / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D000077236:Topiramate
chemical_list: D007473:Ion Channels; D016328:NF-kappa B; D018696:Neuroprotective Agents; D000077236:Topiramate; D005632:Fructose
keywords: Apoptosis; Early brain injury; GABA receptor; Haemorrhage; Ion co-transporter; Subarachnoid; Topiramate