Systematic review and stratified meta-analysis of the efficacy of RhoA and Rho kinase inhibitors in animal models of ischaemic stroke

Abstract

BackgroundThere is currently only one clinically approved drug, tissue plasminogen activator (tPA), for the treatment of acute ischaemic stroke. The RhoA pathway, including RhoA and its downstream effector Rho kinase (ROCK), has been identified as a possible therapeutic target. Our aim was to assess the impact of study design characteristics and study quality on reported measures of efficacy and to assess for the presence and impact of publication bias.MethodsWe conducted a systematic review and meta-analysis on publications describing the efficacy of RhoA and ROCK inhibitors in animal models of focal cerebral ischaemia where outcome was assessed as a change in lesion size or neurobehavioural score, or both.ResultsWe identified 25 published papers which met our inclusion criteria. RhoA and ROCK inhibitors reduced lesion size by 37.3% in models of focal cerebral ischaemia (95% CI, 28.6% to 46.0%, 41 comparisons), and reduced neurobehavioural data by 40.5% (33.4% to 47.7%, 30 comparisons). Overall study quality was low (median=4, interquartile range 3–5) and measures to reduce bias were seldom reported. Publication bias was prevalent and associated with a substantial overstatement of efficacy for lesion size.ConclusionsRhoA and ROCK inhibitors appear to be effective in animal models of stroke. However the low quality score, publication bias and limited number of studies are areas which need attention prior to conducting clinical trials.

Rho Kinases in Health and Disease: From Basic Science to Translational Research

“…In addition to these vascular effects, inhibition of ROCK also preserves cerebral tissue from damage by decreasing neuronal apoptosis via stimulation of Akt signaling (Wu et al, 2012). This experimental evidence thus points to a promising protecting effect of fasudil against acute ischemic stroke-induced neuronal loss in humans (Satoh et al, 2001;Vesterinen et al, 2013). This hypothesis has been addressed in a phase 3 clinical studies in 160 patients with acute ischemic stroke.…”

In vivo roles for myosin phosphatase targeting subunit‐1 phosphorylation sites T694 and T852 in bladder smooth muscle contraction

“…C, gross appearance of mutant embryos (E18.5). to its ability to inhibit force maintenance in different smooth muscle tissues (Fernandes et al 2007;Fonseca et al 2009;Satoh et al 2011;Zhou et al 2011;Fukumoto & Shimokawa, 2013;Vesterinen et al 2013), it is important to understand its mechanistic importance relative to MYPT1 T853 phosphorylation. Previous investigations show ileal and urinary bladder smooth muscles contract and relax in MYPT1-depleted tissues although RLC phosphorylation and force maintenance may be enhanced Tsai et al 2014).…”

“…; Vesterinen et al . ). Thus, force maintenance is a basic physiological property of smooth muscle that is important for diverse functions of different hollow organs.…”

“…vascular blood vessels for maintaining blood pressure, various sphincters for prolonged closure of an orifice and emptying of the urinary bladder. Abnormal contractile performance of smooth muscles contributes to different diseases, such as urinary incontinence, incomplete bladder emptying or retention of urine, hypertension, hypotension, asthma, gut dysmotility and various reproductive disorders (Uehata et al 1997;Fernandes et al 2007;Ohama et al 2007;He et al 2008;Fonseca et al 2009;Meng et al 2010;Satoh et al 2011;Zhou et al 2011;Zderic & Chacko, 2012;Fukumoto & Shimokawa, 2013;He et al 2013;Hypolite et al 2013;Stav et al 2013;Vesterinen et al 2013). Thus, force maintenance is a basic physiological property of smooth muscle that is important for diverse functions of different hollow organs.…”

Infralimbic cortex Rho-kinase inhibition causes antidepressant-like activity in rats

“…The RhoA pathway and its downstream effector Rho-kinase (ROCK) are associated with a wide variety of intracellular signalling pathways, and have been considered as possible therapeutic targets for diverse disease models (Vesterinen et al, 2013), including spinal cord injury (Chan et al, 2005;Dergham et al, 2002;Wu et al, 2013), Parkinson's disease (Rodriguez-Perez et al, 2013;Tatenhorst et al, 2014;Tonges et al, 2012), global cerebral ischemia (Castro-Alvarez et al, 2011), Huntington disease (Li et al, 2009), traumatic brain injury (Dubreuil et al, 2006), epilepsy (Inan and Buyukafsar, 2008) and amyotrophic lateral sclerosis (Günther et al, 2014). Likewise, ROCK pathway has been revealed to be involved in a wide range of fundamental cellular functions, such as contraction, adhesion, migration, proliferation, and apoptosis (Shi and Wei, 2013).…”