9-Cis-retinoic acid reduces ischemic brain injury in rodents via bone morphogenetic protein.
Retinoic acid (RA), a biologically active derivative of vitamin A, has protective effects against damage caused by H(2)O(2) or oxygen-glucose deprivation in mesangial and PC12 cells. In cultured human osteosarcoma cells, RA enhances the expression of bone morphogenetic protein-7 (BMP7), a trophic factor that reduces ischemia- or neurotoxin-mediated neurodegeneration in vivo. The purpose of this study is to examine whether RA reduces ischemic brain injury through a BMP7 mechanism. We found that intracerebroventricular administration of 9-cis-retinoic acid (9cRA) enhanced BMP7 mRNA expression, detected by RT-PCR, in rat cerebral cortex at 24 hr after injection. Rats were also subjected to transient focal ischemia induced by ligation of the middle cerebral artery (MCA) at 1 day after 9cRA injection. Pretreatment with 9cRA increased locomotor activity and attenuated neurological deficits 2 days after MCA ligation. 9cRA also reduced cerebral infarction and TUNEL labeling. These protective responses were antagonized by the BMP antagonist noggin given 1 day after 9cRA injection. Taken together, our data suggest that 9cRA has protective effects against ischemia-induced injury, and these effects involve BMPs.
Shen
Hui
H
National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland 21224, USA.
Luo
Yu
Y
Kuo
Chi-Chung
CC
Deng
Xiaolin
X
Chang
Chen-Fu
CF
Harvey
Brandon K
BK
Hoffer
Barry J
BJ
Wang
Yun
Y
D000077556:Alitretinoin; D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000096:biosynthesis / Q000187:drug effects*; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D002352:Carrier Proteins / Q000494:pharmacology; D015870:Gene Expression; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D007276:Injections, Intraventricular; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014212:Tretinoin / Q000008:administration & dosage*; D000099176:Noggin Protein
D000077556:Alitretinoin; D055419:Bone Morphogenetic Protein 7; D002352:Carrier Proteins; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D014212:Tretinoin; D000099176:Noggin Protein