Postischemic infusion of adrenomedullin protects against ischemic stroke by inhibiting apoptosis and promoting angiogenesis.
Adrenomedullin (AM) is a peptide hormone widely distributed in the central nervous system. Our previous study showed that AM gene delivery immediately after middle cerebral artery occlusion (MCAO) protected against cerebral ischemia/reperfusion (I/R) injury by promoting glial cell survival and migration. In the present study, we investigated the effect of delayed AM peptide infusion on ischemic brain injury at 24 h after MCAO. AM infusion significantly reduced neurological deficit scores at days 2, 4, and 8 after cerebral I/R. AM reduced cerebral infarct size at 8 and 15 days after surgery as determined by quantitative analysis. Double staining showed that AM infusion reduced TUNEL-positive apoptotic cells in both neurons and glial cells, as well as reduced caspase-3 activity in the ischemic area of the brain. In addition, AM treatment increased capillary density in the ischemic region at 15 days after I/R injury. Parallel studies revealed that AM treatment enhanced the proliferation of cultured endothelial cells as measured by both (3)H-thymidine incorporation and in situ BrdU labeling. Both in vitro and in vivo AM effects were blocked by calcitonin gene-related peptide (8-37), an AM receptor antagonist. Moreover, AM's effects were associated with increased cerebral nitric oxide (NO) levels, as well as decreased NAD(P)H oxidase activities and superoxide anion production. These results indicate that a continuous supply of exogenous AM peptide protects against I/R injury by improving the survival of neuronal and glial cells, and promoting angiogenesis through elevated NO formation and suppression of oxidative stress.
Xia
Chun-Fang
CF
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA.
Yin
Hang
H
Borlongan
Cesar V
CV
Chao
Julie
J
Chao
Lee
L
D053607:Adrenomedullin; D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects*; D020520:Brain Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D002545:Brain Ischemia / Q000503:physiopathology; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D042783:Endothelial Cells / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009460:Neurologic Examination; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000517:prevention & control*; D013997:Time Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005904:Glial Fibrillary Acidic Protein; D009566:Nitrates; D009573:Nitrites; D010455:Peptides; D053607:Adrenomedullin; D019255:NADPH Oxidases; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D015740:Calcitonin Gene-Related Peptide