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.
Highlights
There is currently only one clinically approved drug, tissue plasminogen activator, for the treatment of acute ischaemic stroke
Rho-associated kinase (ROCK) is a major downstream effector of the GTP-bound form of RhoA [7] and is associated with a range of intracellular signalling pathways including a reduction in endothelial nitric oxide synthase expression
Our aim was to assess the impact of study design characteristics and study quality on the reported measures of efficacy in a systematic review and meta-analysis of RhoA and ROCK inhibitors tested in animal models of focal cerebral ischaemia to inform both the design of clinical trials and, if required, further preclinical experiments
Summary
There 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. Tissue plasminogen activator (tPA) is the only biological intervention used in routine clinical practice in the treatment of acute ischaemic stroke, albeit in a select cohort of patients. The Rho kinase pathway is closely related to the pathogenesis of several CNS disorders and has been proposed as an attractive target in the treatment of ischaemic stroke [5]. Rho-associated kinase (ROCK) is a major downstream effector of the GTP-bound form of RhoA [7] and is associated with a range of intracellular signalling pathways including a reduction in endothelial nitric oxide synthase (eNOS) expression. Putative ROCK inhibition mediated neuroprotection is hypothesised to occur, in part at least, due to increased eNOS expression that increases the production of the potent vasodilator nitric oxide and increases cerebral blood flow, including collateral flow to the ischaemic area [8]
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