Cerebral Ischemic Preconditioning: the Road So Far…

Abstract

Cerebral preconditioning constitutes the brain's adaptation to lethal ischemia when first exposed to mild doses of a subtoxic stressor. The phenomenon of preconditioning has been largely studied in the heart, and data from in vivo and in vitro models from past 2-3 decades have provided sufficient evidence that similar machinery exists in the brain as well. Since preconditioning results in a transient protective phenotype labeled as ischemic tolerance, it can open many doors in the medical warfare against stroke, a debilitating cerebrovascular disorder that kills or cripples thousands of people worldwide every year. Preconditioning can be induced by a variety of stimuli from hypoxia to pharmacological anesthetics, and each, in turn, induces tolerance by activating a multitude of proteins, enzymes, receptors, transcription factors, and other biomolecules eventually leading to genomic reprogramming. The intracellular signaling pathways and molecular cascades behind preconditioning are extensively being investigated, and several first-rate papers have come out in the last few years centered on the topic of cerebral ischemic tolerance. However, translating the experimental knowledge into the clinical scaffold still evades practicality and faces several challenges. Of the various preconditioning strategies, remote ischemic preconditioning and pharmacological preconditioning appears to be more clinically relevant for the management of ischemic stroke. In this review, we discuss current developments in the field of cerebral preconditioning and then examine the potential of various preconditioning agents to confer neuroprotection in the brain.

Ischemia-Triggered Glutamate Excitotoxicity From the Perspective of Glial Cells

“…Since then, many investigators have been engaged in finding molecular mechanisms that lie beneath the minimization of neuronal damage and the facilitation of regenerative processes. These mechanisms include complex biological cascades that are specific to the applied stimulus and employ both neuronal as well as glial pathways (for review, see Thushara Vijayakumar et al, 2016). These are mainly the immune response that involves the microglial activation of the pro-inflammatory cytokines, such as interleukins 1β and 6 (IL-1β, IL-6), and TNFα (Karikó et al, 2004), the nitric oxide synthase (NOS) cascade (Gidday et al, 1999) or the activation of certain enzymes, such as stress-activated kinases, cyclooxygenase-2 (COX-2; Iadecola et al, 2001;Colangelo et al, 2004) or sphingosine kinase 2 (SPK-2; Yung et al, 2012).…”

White matter injury in ischemic stroke

“…In this phenomenon, subtoxic insults promote the recovery of cells or tissues from a subsequent, more severe ischemic and hypoxic episode (N et al, 2015). The mechanisms underlying the induction and maintenance of ischemic/hypoxic resistance in the brain are complex and intertwined, and include the reinforcement of the neurovascular network, improvements in cerebral circulation, regulation of the expression of neurotrophin, reductions in inflammation, and modulation of survival/ apoptotic signaling pathways (Wang et al, 2015).…”

Hypoxia after stroke: a review of experimental and clinical evidence

“…Normally the re-uptake of glutamate is an active energy-driven process. In the absence of ATP this process fails, resulting in an extracellular accumulation of glutamate, which continually stimulates receptors leading to a persistent influx of calcium ions [12]. Furthermore, the Na+/Ca2+ ATP driven pump normally used to eliminate calcium fails, also due to a lack of ATP [13].…”

“…Aside from rendering this unusable by mitochondria, ATP also stimulates the P2X7 receptor, which again leads to significant calcium influx and ultimately cell death [13]. The other major mechanism of cellular demise is via the formation of free radicals facilitated by the reduction of iron from its ferric (Fe3+) to its ferrous (Fe2+) form and the initiation of inflammatory cascades [12]. …”