Attenuation of cerebral vasospasm following experimental subarachnoid hemorrhage by the bronchodilator KMUP-3.
Delayed cerebral vasospasm is a main cause of morbidity and mortality as well as poor outcome in patients following aneurysmal subarachnoid hemorrhage (SAH). In this study, the effect of the bronchodilator KMUP-3 (7-[2-[4-(4-nitrobenzene)piperazinyl]ethyl]-1,3-dimethylxanthine) on basilar artery narrowing, neurological outcome, and expression of rhoA/rho kinase II (ROCKII), rhoA, and protein kinase C (PKC) γ proteins were evaluated in a rat model of SAH. SAH was induced by double injection of autologous blood into the cistern magna on days 0 and 3. KMUP-3 was administered (0.3 mg/kg/day) by osmotic minipumps implanted subcutaneously (beginning day -3 in pretreatment group and at 1 h after the initiation of the first autologous blood injection in the treatment group). Neurological outcome was assessed by ambulation and placing/stepping reflex responses at 48 h after the second injection of autologous blood. Tissue morphology and protein expression were conducted on day 7 post-day 0 injection. Both KMUP-3 treatment regimens significantly improved neurological outcome and completely attenuated basilar artery narrowing as well as reduced the enhancement of ROCKII, rhoA, and PKCγ protein expression in rats subjected to SAH, compared with normal and untreated SAH rats. These results suggest that KMUP-3 may be a novel agent for the treatment of cerebral vasospasm following SAH.
Poznan University of Medical Sciences, Poznan, Poland.
William
W
Winardi
Chih-Jen
CJ
Wang
Chih-Lung
CL
Lin
Shu-Chuan
SC
Wu
Hung-Pei
HP
Tsai
Yen-Hsin
YH
Kuo
Ming-Yen
MY
Lee
Ing-Jun
IJ
Chen
Aij-Lie
AL
Kwan
D000818:Animals; D001993:Bronchodilator Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D008124:Locomotion / Q000187:drug effects; D008297:Male; D009460:Neurologic Examination; D010880:Piperidines / Q000627:therapeutic use*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012018:Reflex / Q000187:drug effects; D013345:Subarachnoid Hemorrhage / Q000150:complications*; D020301:Vasospasm, Intracranial / Q000188:drug therapy* / Q000209:etiology*; D014970:Xanthines / Q000627:therapeutic use*; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
C508169:7-(2-(4-(4-nitrobenzene)piperazinyl)ethyl)-1,3-dimethylxanthine; D001993:Bronchodilator Agents; D010880:Piperidines; D014970:Xanthines; D054460:rho-Associated Kinases; D011493:Protein Kinase C; D020742:rhoA GTP-Binding Protein