Limb remote ischemic conditioning increases Notch signaling activity and promotes arteriogenesis in the ischemic rat brain

Ren, Chang­hong; Li, Sijie; Wang, Brian; Han, Rongrong; Li, Ning; Gao, Jinhuan; Li, Xiaohua; Jin, Kunlin; Ji, Xunming

doi:10.1016/j.bbr.2016.10.036

Cited by 38 publications

(67 citation statements)

References 33 publications

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“…Not only in light of its potential therapeutic relevance but also due to its practicability has ischemic rPostC been thoroughly studied in a variety of experimental models. The latter implies experimental studies on the kidney, the liver, the lung, the heart, and the brain, to name but a few ( Ren et al, 2011 ; Hasseldam et al, 2013 ; Khan et al, 2015 ; Leung et al, 2015 ; Li P. et al, 2015 ; Gao et al, 2016 , 2017 ; Ramagiri and Taliyan, 2017a , b ; Sandweiss et al, 2017 ; Kitagawa et al, 2018 ; Ren et al, 2018 ). The mechanisms being involved are as diverse as the models that have been applied.…”

Section: Discussionmentioning

confidence: 99%

“…Whereas immediate ischemic post-conditioning of the brain itself is impractical in clinical settings for obvious reasons, the concept of remote ischemic post-conditioning (rPostC) has gained a substantial amount of attraction. Indeed, rPostC in general and hind limb rPostC in particular has been shown to be neuroprotective, albeit survival periods of these studies did not extend 2 weeks, giving insights in some underlying cellular signaling pathways only ( Hasseldam et al, 2013 ; Li S. et al, 2015 ; Ren et al, 2015 , 2018 ; Ramagiri and Taliyan, 2017a , b ). Although first clinical trials with regard to rPostC in stroke-like settings are underway with indication of both a putative beneficial effect and safety ( Hou et al, 2016 ; England et al, 2017 ; Wang et al, 2017 ; Zhao et al, 2017 ), further pre-clinical studies are urgently needed in order to address fundamental issues.…”

Section: Introductionmentioning

confidence: 99%

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Very Delayed Remote Ischemic Post-conditioning Induces Sustained Neurological Recovery by Mechanisms Involving Enhanced Angioneurogenesis and Peripheral Immunosuppression Reversal

Doeppner

Zechmeister

Kaltwasser

et al. 2018

Front. Cell. Neurosci.

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Ischemic conditioning is defined as a transient and subcritical period of ischemia integrated in an experimental paradigm that involves a stimulus of injurious ischemia, activating endogenous tissue repair mechanisms that lead to cellular protection under pathological conditions like stroke. Whereas ischemic pre-conditioning is irrelevant for stroke treatment, ischemic post-conditioning, and especially non-invasive remote ischemic post-conditioning (rPostC) is an innovative and potential strategy for stroke treatment. Although rPostC has been shown to induce neuroprotection in stroke models before, resulting in some clinical trials on the way, fundamental questions with regard to its therapeutic time frame and its underlying mechanisms remain elusive. Hence, we herein used a model of non-invasive rPostC of hind limbs after cerebral ischemia in male C57BL6 mice, studying the optimal timing for the application of rPostC and its underlying mechanisms for up to 3 months. Mice undergoing rPostC underwent three different paradigms, starting with the first cycle of rPostC 12 h, 24 h, or 5 days after stroke induction, which is a very delayed time point of rPostC that has not been studied elsewhere. rPostC as applied within 24 h post-stroke induces reduction of infarct volume on day three. On the contrary, very delayed rPostC does not yield reduction of infarct volume on day seven when first applied on day five, albeit long-term brain injury is significantly reduced. Likewise, very delayed rPostC yields sustained neurological recovery, whereas early rPostC (i.e., <24 h) results in transient neuroprotection only. The latter is mediated via heat shock protein 70 that is a well-known signaling protein involved in the pathophysiological cellular cascade of cerebral ischemia, leading to decreased proteasomal activity and decreased post-stroke inflammation. Very delayed rPostC on day five, however, induces a pleiotropic effect, among which a stimulation of angioneurogenesis, a modulation of the ischemic extracellular milieu, and a reversal of the stroke-induced immunosuppression occur. As such, very delayed rPostC appears to be an attractive tool for future adjuvant stroke treatment that deserves further preclinical attention before large clinical trials are in order, which so far have predominantly focused on early rPostC only.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Very Delayed Remote Ischemic Post-conditioning Induces Sustained Neurological Recovery by Mechanisms Involving Enhanced Angioneurogenesis and Peripheral Immunosuppression Reversal

Doeppner

Zechmeister

Kaltwasser

et al. 2018

Front. Cell. Neurosci.

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“…Recently, several studies have shown that RIC may have an exercise equivalent. 2,52 For example, a prospective study showed that dialysates prepared from plasma of human subjects undergoing high-intensity exercise or RIC were both protective in reducing the infarct size of an isolated rabbit heart after I/R injury. 52 Kono et al studied 10 heart failure patients with left ventricular ejection fraction reduced and 10 healthy subjects.…”

Section: Ric Can Improve Cardiac Functionmentioning

confidence: 99%

“…The study showed that compared with the MCAO control group, Notch1 and the intracellular domain expression of Notch1 in the MCAO +RIC group was increased, the artery diameter was enlarged, the leptomeningeal anastomoses branch was significantly increased, and local CBF was also significantly elevated. 2 Therefore, RIC may stimulate the Notch1 signaling pathway to promote collateral circulation generation and improve CBF in ischemic regions, thereby affecting cerebral hemodynamics. The Notch signaling pathway may be a new therapeutic target for ischemic stroke.…”

Section: Notch Signaling Pathwaymentioning

confidence: 99%

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<p>Effects of Remote Ischemic Conditioning on Cerebral Hemodynamics in Ischemic Stroke</p>

Chen¹,

Yan²,

Jin³

et al. 2020

NDT

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Ischemic stroke is one of the most common cerebrovascular diseases and is the leading cause of disability all over the world. It is well known that cerebral blood flow (CBF) is disturbed or even disrupted when ischemic stroke happens. The imbalance between demand and shortage of blood supply makes ischemic stroke take place or worsen. The search for treatments that can preserve CBF, especially during the acute phase of ischemic stroke, has become a research hotspot. Animal and clinical experiments have proven that remote ischemic conditioning (RIC) is a beneficial therapeutic strategy for the treatment of ischemic stroke. However, the mechanism by which RIC affects CBF has not been fully understood. This review aims to discuss several possible mechanisms of RIC on the cerebral hemodynamics in ischemic stroke, such as the improvement of cardiac function and collateral circulation of cerebral vessels, the protection of neurovascular units, the formation of gas molecules, the effect on the function of vascular endothelial cells and the nervous system. RIC has the potential to become a therapeutic treatment to improve CBF in ischemic stroke. Future studies are needed to highlight our understanding of RIC as well as accelerate its clinical translation.

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Effect of Remote Ischemic Conditioning vs Usual Care on Neurologic Function in Patients With Acute Moderate Ischemic Stroke

Chen

Cui

et al. 2022

JAMA

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Question: Does remote ischemic conditioning improve neurological function in patients with acute moderate ischemic stroke? Findings: In this randomized clinical trial that included 1893 participants with acute moderate ischemic stroke, excellent neurological function at 90 days in those randomized to remote ischemic conditioning compared with usual care occurred in 67.4% vs 62.0%, a difference that was statistically significant.Meaning: Although remote ischemic conditioning was associated with better neurological function in patients with acute moderate ischemic stroke, this trial requires replication before concluding efficacy for this intervention.

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Limb remote ischemic conditioning increases Notch signaling activity and promotes arteriogenesis in the ischemic rat brain

Cited by 38 publications

References 33 publications

Very Delayed Remote Ischemic Post-conditioning Induces Sustained Neurological Recovery by Mechanisms Involving Enhanced Angioneurogenesis and Peripheral Immunosuppression Reversal

Very Delayed Remote Ischemic Post-conditioning Induces Sustained Neurological Recovery by Mechanisms Involving Enhanced Angioneurogenesis and Peripheral Immunosuppression Reversal

<p>Effects of Remote Ischemic Conditioning on Cerebral Hemodynamics in Ischemic Stroke</p>

Effect of Remote Ischemic Conditioning vs Usual Care on Neurologic Function in Patients With Acute Moderate Ischemic Stroke

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