title: Cortical hemorrhage-associated neurological deficits and tissue damage in mice are ameliorated by therapeutic treatment with nicotine.
abstract: Intracerebral hemorrhage (ICH) is associated with diverse sets of neurological symptoms and prognosis, depending on the site of bleeding. Relative rate of hemorrhage occurring in the cerebral cortex (lobar hemorrhage) has been increasing, but there is no report on effective pharmacotherapeutic approaches for cortical hemorrhage either in preclinical or clinical studies. The present study aimed to establish an experimental model of cortical hemorrhage in mice for evaluation of effects of therapeutic drug candidates. Type VII collagenase at 0.015 U, injected into the parietal cortex, induced hemorrhage expanding into the whole layer of the posterior parts of the sensorimotor cortex in male C57BL/6 mice. Mice with ICH under these conditions exhibited significant motor deficits as revealed by beam-walking test. Daily administration of nicotine (1 and 2 mg/kg), with the first injection given at 3 hr after induction of ICH, improved motor performance of mice in a dose-dependent manner, although nicotine did not alter the volume of hematoma. Immunohistochemical examinations revealed that the number of neurons was drastically decreased within the hematoma region. Nicotine at 2 mg/kg partially but significantly increased the number of remaining neurons within the hematoma at 3 days after induction of ICH. ICH also resulted in inflammatory activation of microglia/macrophages in the perihematoma region, and nicotine (1 and 2 mg/kg) significantly attenuated the increase of microglia. These results suggest that nicotine can provide a therapeutic effect on cortical hemorrhage, possibly via its neuroprotective and anti-inflammatory actions. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Junpei
authors.initials: J
authors.lastname: Anan
authors.affiliation: Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Hijioka
authors.affiliation: Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kurauchi
authors.affiliation: Priority Organization for Innovation and Excellence, Kumamoto University, Kumamoto, Japan.|Program for Leading Graduate Schools "HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program,", Kumamoto University, Kumamoto, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Hisatsune
authors.affiliation: Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Seki
authors.affiliation: Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Katsuki
mesh_terms: D000818:Animals; D002543:Cerebral Hemorrhage / Q000473:pathology*; D017364:Collagenases / Q000633:toxicity; D004195:Disease Models, Animal; D005731:Ganglionic Stimulants / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009538:Nicotine / Q000494:pharmacology*; D010296:Parietal Lobe / Q000187:drug effects*; D020127:Recovery of Function / Q000187:drug effects*
chemical_list: D005731:Ganglionic Stimulants; D018696:Neuroprotective Agents; D009538:Nicotine; D017364:Collagenases
keywords: RRID:AB_2298772; RRID:AB_2313606; RRID:AB_2336171; RRID:AB_2630384; RRID:AB_2631098; RRID:IMSR_JAX:000664; RRID:SCR_002526; RRID:SCR_002798; RRID:SCR_003070; RRID:SCR_013618; cerebral cortex; intracerebral hemorrhage; motor dysfunction; neuroinflammation; neuroprotection