A retinoic acid receptor agonist Am80 rescues neurons, attenuates inflammatory reactions, and improves behavioral recovery after intracerebral hemorrhage in mice.
Am80 (tamibarotene) is a retinoic acid receptor (RAR) agonist clinically available for treatment of acute promyelocytic leukemia. As intracerebral hemorrhage (ICH) accompanies inflammatory reactions in the brain and also because retinoids may suppress activation of microglia, we investigated the effect of Am80 on collagenase-induced experimental model of ICH in adult mice. Daily oral administration of Am80 (5 mg/kg) starting from 1 day before or from up to 6 hours after intrastriatal injection of collagenase significantly inhibited the decrease in the number of striatal neurons at 3 days after the insult. Am80 showed no significant effect on the hematoma size and the extent of edema associated with hemorrhage. Prominent expression of RARα was observed in activated microglia/macrophages, and the number of activated microglia/macrophages in the perihematoma region was lower in Am80-treated mice than in vehicle-treated mice. Am80 treatment also reduced areas affected by hemorrhage-associated oxidative stress as indicated by nitrotyrosine immunoreactivity, and attenuated heme oxygenase-1 expression in activated microglia/macrophages. Moreover, Am80-treated mice exhibited better recovery from hemorrhage-induced neurologic deficits than vehicle-treated mice. These results suggest that RAR is a promising target of neuroprotective therapy for ICH.
Matsushita
Hideaki
H
Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Hijioka
Masanori
M
Hisatsune
Akinori
A
Isohama
Yoichiro
Y
Shudo
Koichi
K
Katsuki
Hiroshi
H
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001565:Benzoates / Q000494:pharmacology*; D001834:Body Water / Q000378:metabolism; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry / Q000187:drug effects; D001929:Brain Edema / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000188:drug therapy* / Q000523:psychology*; D017364:Collagenases; D007150:Immunohistochemistry; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents; D004856:Postural Balance / Q000187:drug effects / Q000502:physiology; D018168:Receptors, Retinoic Acid / Q000819:agonists*; D020127:Recovery of Function; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001565:Benzoates; D018696:Neuroprotective Agents; D018168:Receptors, Retinoic Acid; D013764:Tetrahydronaphthalenes; C061133:tamibarotene; D017364:Collagenases