Preclinical evidence of remote ischemic conditioning in ischemic stroke, a metanalysis update

Abstract

Remote ischemic conditioning (RIC) is a promising therapeutic approach for ischemic stroke patients. It has been proven that RIC reduces infarct size and improves functional outcomes. RIC can be applied either before ischemia (pre-conditioning; RIPreC), during ischemia (per-conditioning; RIPerC) or after ischemia (post-conditioning; RIPostC). Our aim was to systematically determine the efficacy of RIC in reducing infarct volumes and define the cellular pathways involved in preclinical animal models of ischemic stroke. A systematic search in three databases yielded 50 peer-review articles. Data were analyzed using random effects models and results expressed as percentage of reduction in infarct size (95% CI). A meta-regression was also performed to evaluate the effects of covariates on the pooled effect-size. 95.3% of analyzed experiments were carried out in rodents. Thirty-nine out of the 64 experiments studied RIPostC (61%), sixteen examined RIPreC (25%) and nine tested RIPerC (14%). In all studies, RIC was shown to reduce infarct volume (− 38.36%; CI − 42.09 to − 34.62%) when compared to controls. There was a significant interaction caused by species. Short cycles in mice significantly reduces infarct volume while in rats the opposite occurs. RIPreC was shown to be the most effective strategy in mice. The present meta-analysis suggests that RIC is more efficient in transient ischemia, using a smaller number of RIC cycles, applying larger length of limb occlusion, and employing barbiturates anesthetics. There is a preclinical evidence for RIC, it is safe and effective. However, the exact cellular pathways and underlying mechanisms are still not fully determined, and its definition will be crucial for the understanding of RIC mechanism of action.

Effects of ischemic postconditioning and long non-coding RNAs in ischemic stroke

“…The neuroprotective mechanisms of RIPostC are highly complex and have not been fully elucidated. In addition to attenuation of reperfusion injury [ 80 ], RIPostC has anti-inflammatory [ 81 ], anti-edema [ 69 , 73 , 82 ], angioneurogenic [ 83 ], anti-platelet, and vasodilatory (enhancement of collateral microvascular circulation) effects on ischemic stroke [ 84 , 85 ] that are mediated through numerous neurohumoral chemical messengers, including those released from endothelial-derived exosomes [ 86 ]. The neuronal isoform of NO synthase has also been shown to participate in the neuroprotective effect of RIPostC [ 87 ].…”

“…The neuronal isoform of NO synthase has also been shown to participate in the neuroprotective effect of RIPostC [ 87 ]. RIPostC protects the brain against cerebral ischemia-reperfusion injury by upregulating endothelial NO synthase through the PI3K/Akt pathway following focal cerebral ischemia in rats [ 85 , 88 ]. RIPostC effectively improved blood-brain barrier permeability by upregulating MMP-9 expression and downregulating claudin-5 expression in a rat model of hypoperfusion caused by severe carotid stenosis [ 80 , 89 ].…”

Editorial: Remote Ischemic Conditioning (Pre, Per, and Post) as an Emerging Strategy of Neuroprotection in Ischemic Stroke

“…Remote ischemic conditioning (RIC) represents a new paradigm in neuroprotective therapies (8)(9)(10), and it has the potential ability to protect the ischemic brain from injury until reperfusion and, later, to protect the brain from reperfusion injury (8,11). RIC consists of short and controlled cycles of ischemia-reperfusion applied to one limb during the establishment of cerebral ischemia (perconditioning), before (preconditioning), or after (postconditioning) (11).…”

“…RIC consists of short and controlled cycles of ischemia-reperfusion applied to one limb during the establishment of cerebral ischemia (perconditioning), before (preconditioning), or after (postconditioning) (11). Until now, the underlying mechanisms of RIC are not clear and there are limited data about the clinical translation of RIPerC in ischemic stroke patients (8,11). Recent trials have only demonstrated the feasibility and safety of this intervention in acute ischemic stroke patients (AIS) (12)(13)(14)(15)(16).…”

“…RIC reduces circulating biomarkers of myocardial necrosis, infarct size, and edema although these effects appear to have no effect in the outcomes of MI patients ( 18 ). In AIS, RIC is also effective in pre-clinical models ( 8 ) but has no significant clinical evidence in the few small studies completed to date ( 10 ). The lack of conclusive clinical evidence of RIC efficacy in MI and AIS may be due to heterogenous protocols and different RIC applications.…”