Review Cerebral Ischemic Tolerance and Preconditioning: Methods, Mechanisms, Clinical Applications, and Challenges

Abstract

Stroke is one of the leading causes of morbidity and mortality worldwide, and it is increasing in prevalence. The limited therapeutic window and potential severe side effects prevent the widespread clinical application of the venous injection of thrombolytic tissue plasminogen activator and thrombectomy, which are regarded as the only approved treatments for acute ischemic stroke. Triggered by various types of mild stressors or stimuli, ischemic preconditioning (IPreC) induces adaptive endogenous tolerance to ischemia/reperfusion (I/R) injury by activating a multitude cascade of biomolecules, for example, proteins, enzymes, receptors, transcription factors, and others, which eventually lead to transcriptional regulation and epigenetic and genomic reprogramming. During the past 30 years, IPreC has been widely studied to confirm its neuroprotection against subsequent I/R injury, mainly including local ischemic preconditioning (LIPreC), remote ischemic preconditioning (RIPreC), and cross preconditioning. Although LIPreC has a strong neuroprotective effect, the clinical application of IPreC for subsequent cerebral ischemia is difficult. There are two main reasons for the above result: Cerebral ischemia is unpredictable, and LIPreC is also capable of inducing unexpected injury with only minor differences to durations or intensity. RIPreC and pharmacological preconditioning, an easy-to-use and non-invasive therapy, can be performed in a variety of clinical settings and appear to be more suitable for the clinical management of ischemic stroke. Hoping to advance our understanding of IPreC, this review mainly focuses on recent advances in IPreC in stroke management, its challenges, and the potential study directions.

Epigenetic Conditioning Induces Intergenerational Resilience to Dementia in a Mouse Model of Vascular Cognitive Impairment

“…Overall, our findings in a chronic neurodegenerative disease model suggest that the efficacy of appropriately titrated conditioning-based therapeutics can extend beyond acute cerebral injuries like stroke and trauma (Stetler et al, 2014; Gidday, 2015; Verges et al, 2015; Baillieul et al, 2017; Sprick et al, 2019; Hao et al, 2020). Indeed, there is evidence that repetitive patterns of hypoxic conditioning lessen disease severity in preclinical models of AD.…”

“…An epigenetics-based VCID therapeutic strategy may be able to meet this clinical challenge. Specifically, preconditioning the brain to activate changes in gene expression is a well-established approach to promote endogenous pathways of cell survival and tissue resistance to injury (Sprick et al, 2019;Hao et al, 2020). We and others have previously shown the efficacy of hypoxic preconditioning in inducing protection against acute stroke (Miller et al, 2001;Stowe et al, 2011;Wacker et al, 2012;Gidday, 2015).…”

Brain acute ischemia mechanisms: implications to experimental and clinical treatment

“…Кальций в составе с комплексами белков-регуляторов, как вторичный посредник, активирует кальцийзависимые пути апоптоза [38,41,42]. Митохондрии при ишемии активируют образование свободных радикалов и реализуют апоптоз [43,44]. Общее нарушение ионных градиентов приводит к цитотоксическому отеку клеток, в результате чего происходит осмотический разрыв мембраны и некроз [17].…”

“…В условиях умеренной ишемии наблюдается деполяризация внутренней мембраны митохондрий, в результате происходит разобщение электронотранспортной цепи и возрастает утечка электронов с образованием супероксида и пероксида. Внутри митохондрий они выступают в роли вторичных «редокс-посредников», воздействуя на тиоловые группы регуляторных белков, что активирует сигнальные каскады, способствующие выживанию клетки [43,121]. Образование АФК возможно только при наличии кислорода, что ограничивает область их действия зоной пенумбры.…”

Leonurine, a potential drug for the treatment of cardiovascular system and central nervous system diseases

“…Stroke, also known as cerebral apoplexy, is one of the main clinical types of cerebrovascular diseases, including ischemic stroke (IS) and hemorrhagic stroke, in which IS is the most common type of stroke, and is known as cerebral infarction (Xu et al., 2017; Zhang, Wang, et al., 2019). IS is caused by inadequate blood supply to the brain for various reasons, which results in cerebral ischemia and hypoxic necrosis (Hao et al., 2020). Leonurine has a good therapeutic effect on IS and may be a very good choice for the treatment of stroke.…”