title: Valproic acid ameliorates ischemic brain injury in hyperglycemic rats with permanent middle cerebral occlusion.
abstract: Valproic acid (VPA) is widely used for the clinical treatment of epilepsy. Previous studies have demonstrated that VPA ameliorates brain injury following experimental stroke. However, the effect of VPA in stroke models featuring comorbid conditions has not been fully explored. In this study, we investigate the effects of VPA on permanent ischemic stroke with hyperglycemia. Hyperglycemia was induced by streptozotocin (STZ) injection 3 days before. Test animals received a single injection of VPA immediately after induction of ischemia. Control animals received occlusion and physiological saline injection, or STZ, occlusion, and saline. Magnetic resonance imaging of cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) was performed 60 min after ischemia. Infarct volume, neurological deficits, rotarod test performance, and immunohistological markers were assessed 3 days after ischemia. Hyperglycemia significantly expanded the area of decreased of CBF and ADC, and increased the number of myeloperoxidase-positive cells, ionized calcium binding adapter molecule 1-positive cells, inducible nitric oxide synthase-positive cells, von Willebrand factor-positive cells, and Fluoro-Jade C-positive cells in the ischemic boundary zone, which was accompanied by increased infarct volume and deteriorated neurological deficit and rotarod test compared with normoglycemia (P < 0.05). VPA significantly alleviated the aggravation of functional outcome accompanied by suppressing these inflammation, endothelial injury, and neuronal degeneration compared with saline-treated group (P < 0.05). A single injection of VPA following permanent ischemia in STZ-induced hyperglycemic rats ameliorates neurological deficits and reduces neuronal degeneration by inhibiting inflammation and endovascular injury. VPA may be promising as a candidate therapy for human stroke.
authors.affiliation: Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan. Electronic address: suda-sa@nms.ac.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Suda
authors.affiliation: Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ueda
authors.affiliation: Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan.
authors.forename: Chikako
authors.initials: C
authors.lastname: Nito
authors.affiliation: Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nishiyama
authors.affiliation: Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Okubo
authors.affiliation: Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan.
authors.forename: Arata
authors.initials: A
authors.lastname: Abe
authors.affiliation: Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Aoki
authors.affiliation: Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Sakamoto
authors.affiliation: Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Kimura
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy*; D006943:Hyperglycemia / Q000150:complications* / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D045442:Rotarod Performance Test; D013311:Streptozocin; D020521:Stroke / Q000150:complications / Q000188:drug therapy*; D014635:Valproic Acid / Q000627:therapeutic use*
chemical_list: D001786:Blood Glucose; D013311:Streptozocin; D014635:Valproic Acid
keywords: Diabetes mellitus; Hyperglycemia; Ischemic stroke; Neuroprotection; Valproic acid