ha-1100 has been researched along with Stroke* in 2 studies
2 other study(ies) available for ha-1100 and Stroke
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Amelioration of endothelial damage/dysfunction is a possible mechanism for the neuroprotective effects of Rho-kinase inhibitors against ischemic brain damage.
We investigated the neuroprotective effects of fasudil's active metabolite, hydroxyfasudil, a Rho-kinase inhibitor, in a rat stroke model in which endothelial damage and subsequent thrombotic occlusion were selectively induced in perforating arteries. By examining the effects on the endothelial damage/dysfunction, we thought to explore the mechanism of Rho-kinase inhibitors. Hydroxyfasudil (10mg/kg, i.p., once daily for 3 days) significantly improved neurological functions and reduced the size of the infarct area produced by internal carotid artery injection of sodium laurate in a rat cerebral microthrombosis model. Treatment with fasudil or hydroxyfasudil concentration-dependently inhibited tumor necrosis factor alpha-induced tissue factor expression on the surface of cultured human umbilical vein endothelial cells. They also inhibited thrombin-induced endothelial hyperpermeability. The present findings suggest that hydroxyfasudil is efficacious in preventing brain damage associated with cerebral ischemia, and is partially responsible for fasudil's cytoprotective potential. The results also suggest that the therapeutic benefits against ischemic injury of Rho-kinase inhibitors are attributed, at least in part, to activity upon endothelial damage/dysfunction. Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Brain; Brain Ischemia; Capillary Permeability; Cells, Cultured; Disease Models, Animal; Endothelium; Enzyme Inhibitors; Humans; In Vitro Techniques; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; rho-Associated Kinases; Stroke; Thromboplastin; Tumor Necrosis Factor-alpha; Umbilical Veins | 2010 |
Inhibition of Rho kinase (ROCK) leads to increased cerebral blood flow and stroke protection.
Endothelium-derived nitric oxide (NO) plays a pivotal role in vascular protection. The Rho kinase (ROCK) inhibitor, hydroxyfasudil, prevents the downregulation of endothelial NO synthase (eNOS) under hypoxic conditions. However, it is unknown whether inhibition of ROCK can attenuate ischemia-induced endothelial dysfunction and tissue damage in vivo.. Human vascular endothelial cells were treated with increasing concentrations of hydroxyfasudil (0.1 to 100 micromol/L) and eNOS expression and activity were measured. To determine the physiological relevance of eNOS regulation by ROCK, we administered fasudil, which is metabolized to hydroxyfasudil in vivo, to mice for 2 days before subjecting them to middle cerebral artery occlusion. Cerebral blood flow, cerebral infarct size, and neurologic deficit were measured.. In a concentration-dependent manner, hydroxyfasudil increased eNOS mRNA and protein expression, resulting in a 1.9- and 1.6-fold increase, respectively, at 10 micromol/L (P<0.05 for both). This correlated with a 1.5- and 2.3-fold increase in eNOS activity and NO production, respectively (P<0.05 for both). Fasudil increased cerebral blood flow to both ischemic and nonischemic brain areas, reduced cerebral infarct size by 33%, and improved neurologic deficit score by 37% (P<0.05). This correlated with inhibition of brain and vascular ROCK activity and increased eNOS expression and activity. Another ROCK inhibitor, Y-27632, also showed similar effects. The neuroprotective effects of fasudil were absent in eNOS-deficient mice.. These findings indicate that the neuroprotective effect of ROCK inhibition is mediated by endothelium-derived NO and suggest that ROCK may be an important therapeutic target for ischemic stroke. Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Amides; Analysis of Variance; Animals; Antihypertensive Agents; Aorta; Blotting, Northern; Blotting, Western; Brain Ischemia; Cattle; Cell Line; Cells, Cultured; Cerebrovascular Circulation; Dose-Response Relationship, Drug; Down-Regulation; Endothelium, Vascular; Enzyme Inhibitors; Humans; Hypoxia; Infarction, Middle Cerebral Artery; Intracellular Signaling Peptides and Proteins; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Protein Serine-Threonine Kinases; Pyridines; Regional Blood Flow; rho-Associated Kinases; RNA, Messenger; Stroke; Time Factors; Umbilical Veins; Up-Regulation | 2005 |