Role of cocaine- and amphetamine-regulated transcript in estradiol-mediated neuroprotection.
Estrogen reduces brain injury after experimental cerebral ischemia in part through a genomic mechanism of action. Using DNA microarrays, we analyzed the genomic response of the brain to estradiol, and we identified a transcript, cocaine- and amphetamine-regulated transcript (CART), that is highly induced in the cerebral cortex by estradiol under ischemic conditions. Using in vitro and in vivo models of neural injury, we confirmed and characterized CART mRNA and protein up-regulation by estradiol in surviving neurons, and we demonstrated that i.v. administration of a rat CART peptide is protective against ischemic brain injury in vivo. We further demonstrated binding of cAMP response element (CRE)-binding protein to a CART promoter CRE site in ischemic brain and rapid activation by CART of ERK in primary cultured cortical neurons. The findings suggest that CART is an important player in estrogen-mediated neuroprotection and a potential therapeutic agent for stroke and other neurodegenerative diseases.
Xu
Yun
Y
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Zhang
Wenri
W
Klaus
Judith
J
Young
Jennifer
J
Koerner
Ines
I
Sheldahl
Laird C
LC
Hurn
Patricia D
PD
Martínez-Murillo
Francisco
F
Alkayed
Nabil J
NJ
D000818:Animals; D002545:Brain Ischemia / Q000139:chemically induced; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology; D004958:Estradiol / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D020244:Infarction, Middle Cerebral Artery / Q000139:chemically induced; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation / Q000187:drug effects; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein; D004958:Estradiol