Protective action of NDP-MSH in experimental subarachnoid hemorrhage.
Subarachnoid hemorrhage (SAH) is still a major cause of morbidity and mortality. α-Melanocyte stimulating hormone (α-MSH) and other melanocortin peptides exert potent neuroprotective action and they might modulate key molecules involved in SAH-induced vasospasm. The aim of this research was to determine whether treatment with the α-MSH analog Nle4,DPhe7-α-MSH (NDP-MSH) exerts protective effects in experimental SAH in the rat. Initial experiments examined effects of NDP-MSH on the basilar artery phenotype in the absence of injury. In these tests intrathecal injection of small concentrations (10ng) of the peptide induced a tolerant phenotype similar to that observed after ischemic preconditioning. Then the effect of systemic treatment with NDP-MSH (100μg i.v.) on experimental SAH was evaluated. SAH was induced by a single-blood injection into the cisterna magna. The basilar artery phenotype was examined at 4h and the artery caliber at 5days following SAH. Expression of 96 genes was analyzed by real-time reverse transcription polymerase chain reaction (RT-PCR) using Custom Taqman Low-Density Arrays. Four hours after SAH, the transcriptional profile of the basilar artery was deeply disrupted. Transcript alteration included genes involved in inflammation, stress response, apoptosis, and vascular remodeling. Treatment with NDP-MSH prevented most of these transcription changes and decreased phosphorylation of extracellular-signal-regulated kinases (ERK1/2) and inhibitor protein IκBα. Vasospasm on day 5 was significantly reduced by NDP-MSH administration. These results combine with others on CNS inflammation to suggest that the melanocortins could be safe and effective therapeutic candidates to treat SAH-related complications.
Center for Surgical Research, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Stefano
S
Gatti
Caterina
C
Lonati
Francesco
F
Acerbi
Andrea
A
Sordi
Patrizia
P
Leonardi
Andrea
A
Carlin
Sergio M
SM
Gaini
Anna
A
Catania
D000704:Analysis of Variance; D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000188:drug therapy*; D020301:Vasospasm, Intracranial / Q000209:etiology / Q000517:prevention & control*; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000627:therapeutic use
D020672:I-kappa B Proteins; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D000521:alpha-MSH; C027756:MSH, 4-Nle-7-Phe-alpha-