Neuroprotective properties of a protein kinase inhibitor against ischaemia‐induced neuronal damage in rats and gerbils

Abstract

1 The neuroprotective properties of fasudil (HA1077), a novel protein kinase inhibitor, were evaluated in two animal models of cerebral ischaemia: transient bilateral carotid artery occlusion in Mongolian gerbils and cerebral microembolization in rats. 2 The cytoprotective effect of fasudil on delayed neuronal death in gerbils was compared with the effects of nimodipine, a calcium channel antagonist and ozagrel, a thromboxane A2 synthetase inhibitor.The average of the neuronal cell density in the ischaemic control group was 17.8+2.1 cells mm-', whereas fasudil (30 mg kg-') significantly diminished the loss of CAl neurones with the average of the neuronal cell density of 101.0+22.0 cells mm-'; nimodipine (10 mg kg-') and ozagrel (30 mg kg-1) did not significantly protect against the ischaemia-induced neuronal loss. 3 In the rat model, the effects of fasudil on the histological and neurological consequences of cerebral microembolization produced via the injection of microspheres were examined. Twenty-four hours after the injection of microspheres into the internal carotid artery, all animals in the control group showed typical symptoms of stroke. Neurological function was significantly improved in the fasudil-treated animals. In the controls, the infarcted area in a cortical slice selected to include the hippocampal area was 0.25 + 0.01 cm2 (mean+s.e.mean) (43.9+2.4% of cortical section of the half hemisphere); the difference was significant compared to the mean area of 32.7+2.8 and 21.5+4.8% observed in rats treated with fasudil (3, 10 mg kg-'), respectively. Fasudil (10 mg kg-') significantly suppressed the increased water content in ischaemic brain tissues (saline-treated rats, 82.4+0.2% vs fasudil-treated rats, 81.0 + 0.4%). 4 These results suggest that: (i) various protein kinases are involved in the pathogenesis of ischaemic injury; and (ii) the inhibition of protein kinases may be efficacious in preventing neuronal death, thus improving neurological function in the brain damage associated with ischaemic stroke.

Rho-Kinase Mediates Hypoxia-Induced Downregulation of Endothelial Nitric Oxide Synthase

“…14,22 The phosphorylation of MLC is required for its interaction with actin filaments, forming actin stress fibers and focal adhesion complexes. Indeed, inhibition of Rho-kinase by hydroxyfasudil enhances cerebral blood flow 23 and prevents cerebral vasospasm after subarachnoid hemorrhage. 24 Our finding with cytochalasin D, however, suggests that Rho-kinase-induced actin cytoskeletal reorganization mediates hypoxia-induced downregulation of eNOS expression.…”

Serum-borne bioactivity caused by pulmonary multiwalled carbon nanotubes induces neuroinflammation via blood–brain barrier impairment

“…To mechanistically delineate whether neuroinflammation was the result of BBB disruption, mice were administered vehicle or the rho kinase inhibitor fasudil, which has been shown to improve BBB function by relaxing cytoskeletal interactions in endothelial cells, thereby improving outcomes in stroke-related models (26,27). Mice received fasudil either 2 h after MWCNT aspiration but before injection of the BBB tracer sodium fluorescein or just before MWCNT aspiration and again 2 h later (Fig.…”

Rho-Kinase Inhibition Acutely Augments Blood Flow in Focal Cerebral Ischemia via Endothelial Mechanisms

“…Neuroprotection in cerebral ischemia was previously reported for fasudil (Hitomi et al, 2000;Satoh et al, 1999), hydroxyfasudil (Satoh et al, 2001), and Y-27632 Satoh et al, 1996). For example, hydroxyfasudil (10 mg/kg) reduced infarct size and neurological deficits in rat microembolic ischemia when administered 5 mins after ischemia onset; however, intraischemic CBF reduction was not studied, and neuroprotection was in part attributed to the anti-inflammatory effects of hydroxyfasudil leading to a significant reduction in neutrophil infiltration (Satoh et al, 2001).…”