title: Transient receptor potential canonical 3 inhibitor Pyr3 improves outcomes and attenuates astrogliosis after intracerebral hemorrhage in mice.
abstract: OBJECTIVE
  Intracerebral hemorrhage (ICH) stems from the rupture of blood vessels in the brain, with the subsequent accumulation of blood in the parenchyma. Increasing evidence suggests that blood-derived factors induce excessive inflammatory responses that are involved in the progression of ICH-induced brain injury. Thrombin, a major blood-derived factor, leaks into the brain parenchyma on blood-brain barrier disruption and induces brain injury and astrogliosis. Furthermore, thrombin dynamically upregulates transient receptor potential canonical 3 channel, which contributes to pathological astrogliosis through a feed-forward upregulation of its own expression. The present study investigated whether Ethyl-1-(4-(2,3,3-trichloroacrylamide)phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Pyr3), a specific transient receptor potential canonical 3 inhibitor, can improve functional outcomes and attenuate astrogliosis after ICH in mice.
  
  
  METHODS
  Male C57BL6 mice received an intracerebral infusion of collagenase or autologous blood to induce ICH. Pyr3 was given both intracerebroventricularly and intraperitoneally after ICH induction. ICH-induced brain injury was evaluated by quantitative assessment of neurological deficits, brain swelling, and injury volume after ICH. Astrocyte activation was evaluated by immunohistochemical assessment of changes in S100 protein expression.
  
  
  RESULTS
  Neurological deficits, neuronal injury, brain edema, and astrocyte activation were all significantly improved by administration of Pyr3. Moreover, delayed administration of Pyr3 at 6 hours or 1 day after blood or collagenase infusion, respectively, also improved the symptoms.
  
  
  CONCLUSIONS
  Pyr3, a specific inhibitor of transient receptor potential canonical 3, reduced the perihematomal accumulation of astrocytes and ameliorated ICH-induced brain injury. Therefore, transient receptor potential canonical 3 provides a new therapeutic target for the treatment of hemorrhagic brain injury.
authors.affiliation: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Munakata
authors.forename: Hisashi
authors.initials: H
authors.lastname: Shirakawa
authors.forename: Kazuki
authors.initials: K
authors.lastname: Nagayasu
authors.forename: Jun
authors.initials: J
authors.lastname: Miyanohara
authors.forename: Takahito
authors.initials: T
authors.lastname: Miyake
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Katsuki
authors.forename: Shuji
authors.initials: S
authors.lastname: Kaneko
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D004195:Disease Models, Animal; D005911:Gliosis / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009483:Neuropsychological Tests; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D011720:Pyrazoles; C559943:ethyl-1-(4-(2*3*3-trichloroacrylamide)phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate
keywords: Pyr3; TRPC channel; TRPC3; astrocyte; inflammation; intracerebral hemorrhage