title: Natural and synthetic retinoids afford therapeutic effects on intracerebral hemorrhage in mice.
abstract: We have recently proposed that retinoic acid receptor (NR1B) is a promising target of neuroprotective therapy for intracerebral hemorrhage, since pretreatment of mice with an NR1B1/NR1B2 agonist Am80 attenuated various pathological and neurological abnormalities associated with the disease. In the present study we further addressed the effects of retinoids as potential therapeutic drugs, using a collagenase-induced model of intracerebral hemorrhage. Daily oral administration of all-trans retinoic acid (ATRA; 5 and 15 mg/kg), a naturally occurring NR1B agonist, from 1 day before collagenase injection significantly inhibited loss of neurons within the hematoma. ATRA in the same treatment regimen also decreased the number of activated microglia/macrophages around the hematoma but did not affect the hematoma volume. ATRA (15 mg/kg) as well as Am80 (5mg/kg) rescued neurons in the central region of hematoma, even when drug administration was started from 6h after induction of intracerebral hemorrhage. However, in this post-treatment regimen, only Am80 significantly decreased the number of activated microglia/macrophages. With regard to neurological deficits, both ATRA (15 mg/kg) and Am80 (5mg/kg) given in the post-treatment regimen improved performance of mice in the beam-walking test and the modified limb-placing test. ATRA and Am80 also significantly attenuated damage of axon tracts as revealed by amyloid precursor protein immunohistochemistry. These results underscore potential therapeutic values of NR1B agonists for intracerebral hemorrhage.
authors.affiliation: Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Matsushita
authors.forename: Masanori
authors.initials: M
authors.lastname: Hijioka
authors.forename: Akinori
authors.initials: A
authors.lastname: Hisatsune
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Isohama
authors.forename: Koichi
authors.initials: K
authors.lastname: Shudo
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Katsuki
mesh_terms: D000818:Animals; D001426:Bacterial Proteins; D001565:Benzoates / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D002452:Cell Count; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D017364:Collagenases; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D003012:Microbial Collagenase; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D011596:Psychomotor Disorders / Q000209:etiology / Q000517:prevention & control; D018168:Receptors, Retinoic Acid / Q000819:agonists*; D012176:Retinoids / Q000008:administration & dosage / Q000627:therapeutic use*; D013764:Tetrahydronaphthalenes / Q000627:therapeutic use; D013997:Time Factors; D014212:Tretinoin / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D001426:Bacterial Proteins; D001565:Benzoates; D018696:Neuroprotective Agents; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D013764:Tetrahydronaphthalenes; C082925:retinoic acid receptor beta; C061133:tamibarotene; D014212:Tretinoin; D017364:Collagenases; C533954:collagenase VII-S, Clostridium histolyticum; D003012:Microbial Collagenase