Clinical Effect of Fasudil Hydrochloride for Cerebral Vasospasm Following Subarachnoid Hemorrhage

Masaoka, Hiroyuki; Takasato, Yoshio; Nojiri, Takashi; Hayakawa, Takanori; Akimoto, Hideaki; Yatsushige, Hiroshi; Toumori, H.; Miyazaki, Yuji; Honma, Masato

doi:10.1007/978-3-7091-6232-3_44

Cited by 15 publications

(7 citation statements)

References 5 publications

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“…HA-1077 (Fasudil) is a ROCK inhibitor approved for clinical use in Japan. It is employed to suppress vasospasm in subarachnoid hemorrhage [9], [22], [23]. We have previously observed that HA-1077 is more effective than Y-27632 in suppressing phosphorylation of profilin at Ser-137.…”

Section: Resultsmentioning

confidence: 99%

Intravitreal Administration of HA-1077, a ROCK Inhibitor, Improves Retinal Function in a Mouse Model of Huntington Disease

Yasumura

et al. 2013

PLoS ONE

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Huntington disease (HD) is an inherited neurodegenerative disease that affects multiple brain regions. It is caused by an expanded polyglutamine tract in huntingtin (Htt). The development of therapies for HD and other neurodegenerative diseases has been hampered by multiple factors, including the lack of clear therapeutic targets, and the cost and complexity of testing lead compounds in vivo. The R6/2 HD mouse model is widely used for pre-clinical trials because of its progressive and robust neural dysfunction, which includes retinal degeneration. Profilin-1 is a Htt binding protein that inhibits Htt aggregation. Its binding to Htt is regulated by the rho-associated kinase (ROCK), which phosphorylates profilin at Ser-137. ROCK is thus a therapeutic target in HD. The ROCK inhibitor Y-27632 reduces Htt toxicity in fly and mouse models. Here we characterized the progressive retinopathy of R6/2 mice between 6–19 weeks of age to determine an optimal treatment window. We then tested a clinically approved ROCK inhibitor, HA-1077, administered intravitreally via liposome-mediated drug delivery. HA-1077 increased photopic and flicker ERG response amplitudes in R6/2 mice, but not in wild-type littermate controls. By targeting ROCK with a new inhibitor, and testing its effects in a novel in vivo model, these results validate the in vivo efficacy of a therapeutic candidate, and establish the feasibility of using the retina as a readout for CNS function in models of neurodegenerative disease.

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Section: Resultsmentioning

confidence: 99%

Intravitreal Administration of HA-1077, a ROCK Inhibitor, Improves Retinal Function in a Mouse Model of Huntington Disease

Yasumura

et al. 2013

PLoS ONE

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“…A previous study (Kitano et al, 2014 ) showed that Rho-kinase is activated during myocardial reperfusion, indicating that the inhibition of Rho-kinase activity is a potential target in suppressing the reperfusion injury salvage kinase (RISK) pathway and prevent myocardial I/R injury. Fasudil, a Rho-kinase inhibitor, has shown remarkable therapeutic effect against cerebral vasospasm after subarachnoid hemorrhage (SAH) in humans (Masaoka et al, 2001 ). Recent studies show that fasudil exerts its cardio-protective effects by relieving inflammation/oxidative stress (Shimokawa and Takeshita, 2005 ; Ma et al, 2011 ), inhibiting apoptosis (Tong and Zhang, 2007 ) and fibrosis (Xu et al, 2017 ), and improving coronary blood flow (Aizawa et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

Fasudil, a Rho-Kinase Inhibitor, Exerts Cardioprotective Function in Animal Models of Myocardial Ischemia/Reperfusion Injury: A Meta-Analysis and Review of Preclinical Evidence and Possible Mechanisms

Huang

et al. 2018

Front. Pharmacol.

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Fasudil, a Rho-kinase inhibitor, has shown outstanding therapeutic effects against cerebral vasospasm after subarachnoid hemorrhage (SAH) in humans. Studies show various biological effects of fasudil in the cardiovascular system. We conducted a preclinical systematic review to determine the efficacy and possible mechanisms of fasudil on animal models of myocardial ischemia/reperfusion (I/R) injury. Nineteen studies involving 400 animals were identified after searching 8 databases for articles published till June 2018. The methodological quality was assessed by the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES) 10-item checklist. The data were analyzed using Rev-Man 5.3 software, and the score of study quality ranged from 3 to 6 points. Compared to the control group, fasudil treated animals showed reduced myocardial infarct size (P < 0.05), lower levels of cardiac enzymes (P < 0.05) and cardiac troponin T (P < 0.05), improved systolic and diastolic functions (P < 0.05), and increased degree of decline in the ST-segment (P < 0.05). The possible mechanisms of fasudil action against myocardial I/R injury are improvement in coronary vasodilation, inhibition of apoptosis and oxidative stress, relieving inflammation, and reduction in endoplasmic reticulum stress and metabolism. In conclusion, fasudil exerts a cardio-protective function through multiple signaling pathways in animal models of myocardial I/R injury.

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“…Fasudil hydrochloride also inhibits Rho-associated protein kinase, which affects vascular smooth muscle contraction by inactivating myosin light chain phosphatase. 8,10) Fasudil hydrochloride is effective to prevent vasospasm following subarachnoid hemorrhage (SAH), 3,7,9) and is widely administered intravenously in Japan. However, no significant differences were found in activities of daily living improvement at discharge between patients treated before and after the widespread clinical introduction of fasudil hydrochloride, and no improvement in clinical outcome in patients with severe SAH.…”

Section: Introductionmentioning

confidence: 99%

Intro-arterial Administration of Fasudil Hydrochloride for Vasospasm Following Subarachnoid Hemorrhage-Analysis of Time-Density Curve With Digital Subtraction Angiography-

Iwabuchi

Yokouchi

Hayashi

et al. 2006

Neurol. Med. Chir.(Tokyo)

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The cerebral circulatory dynamics were evaluated before and after intra-arterial administration of fasudil hydrochloride in 20 patients with angiographic vasospasm after subarachnoid hemorrhage (SAH). The region of interest time-density curves obtained before and after intra-arterial administration of fasudil hydrochloride were compared in the proximal portion of the middle cerebral artery in the early arterial phase, the distal portion of the middle cerebral artery in the late arterial phase, and the transverse sinus in the venous phase. In the early arterial phase, the time to peak and the time to halfpeak were significantly reduced. In the late arterial phase and venous phase, the time to peak was significantly reduced. These results suggest that intra-arterial administration of fasudil hydrochloride induced dilation of the proximal arteries, and improved cerebral microcirculation. The present study suggests that intra-arterial administration of fasudil hydrochloride is effective as a treatment for vasospasm following SAH.

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Clinical Effect of Fasudil Hydrochloride for Cerebral Vasospasm Following Subarachnoid Hemorrhage

Cited by 15 publications

References 5 publications

Intravitreal Administration of HA-1077, a ROCK Inhibitor, Improves Retinal Function in a Mouse Model of Huntington Disease

Intravitreal Administration of HA-1077, a ROCK Inhibitor, Improves Retinal Function in a Mouse Model of Huntington Disease

Fasudil, a Rho-Kinase Inhibitor, Exerts Cardioprotective Function in Animal Models of Myocardial Ischemia/Reperfusion Injury: A Meta-Analysis and Review of Preclinical Evidence and Possible Mechanisms

Intro-arterial Administration of Fasudil Hydrochloride for Vasospasm Following Subarachnoid Hemorrhage-Analysis of Time-Density Curve With Digital Subtraction Angiography-

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