Ionic Regulation of Cell Volume Changes and Cell Death after Ischemic Stroke

Abstract

Stroke is a leading cause of human death and disability in the US and around the world. Shortly after the cerebral ischemia, cell swelling is the earliest morphological change in injured neuronal, glial and endothelial cells. Cytotoxic swelling directly results from increased Na+ (with H2O) and Ca2+ influx into cells via ionic mechanisms evoked by membrane depolarization and a number of harmful factors such as glutamate accumulation and the production of oxygen reactive species (ROS). During the sub-acute and chronic phases after ischemia, injured cells may show a phenotype of cell shrinkage due to complex processes involving membrane receptors/channels and programmed cell death signals. This review will introduce some progress in the understanding of the regulation of pathological cell volume changes and the involved receptors and channels, including NMDA and AMPA receptors, acid-sensing ion channels (ASIC), hemichannels, transient receptor potential (TRP) channels and KCNQ channels. Moreover, accumulating evidence supports a key role of energy deficiency and dysfunction of Na+/K+-ATPase in ischemia-induced cell volume changes and cell death. Specifically, the Na+ pump failure is a prerequisite for disruption of ionic homeostasis including a pro-apoptotic disruption of the K+ homeostasis. Finally, we will introduce the concept of hybrid cell death as a result of the Na+ pump failure in cultured cells and the ischemic brain. The goal of this review is to outline recent understanding of the ionic mechanism of ischemic cytoxicity and suggest innovative ideas for future translational research.

The 5-Lipoxygenase Inhibitor Zileuton Confers Neuroprotection against Glutamate Oxidative Damage by Inhibiting Ferroptosis

“…When excessively released, glutamate induces both receptor-dependent excitotoxicity and non-receptor-mediated oxidative toxicity, which are implicated in a number of neurodegeneration diseases, such as stroke. [1][2][3][4][5][6] Thus, targeting glutamate-induced oxidative toxicity is a promising strategy for treating neurological diseases. 1,2) Lipoxygenases (LOXs) are the enzymes responsible for lipid peroxidation.…”

Ischemic Stroke Mechanisms, Prevention, and Treatment: The Anesthesiologist’s Perspective

“…Concurrently, presynaptic reuptake of glutamate is reduced due to the lack of energy needed to activate ion pumps, which further exacerbates the increased extracellular glutamate concentration. The excess glutamate binds AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) and NMDA (Nmethyl-D -aspartate) receptors to increase the influx of water, sodium, and calcium into neurons, inducing a host of signaling events that cause cell swelling, activation of catabolic activity, and eventual cell death (11,12 cium influx initiates a series of cytoplasmic, nuclear, and mitochondrial events that directly contribute to the development of tissue damage, for example, via activation of proteases (13). Uncontrolled activation of calcium-dependent enzymes leads to further ATP depletion and accelerates cell death.…”

“…Indeed, many other ion channels have been implicated in calcium accumulation and toxicity. Sodiumcalcium exchangers, gap junctions, volume-regulated anion channels, transient receptor potential channels, acid-sensing channels, and other non-selective cation channels contribute to ion imbalance (12,17). There is ample space for research on the influence of specific receptors to ion imbalance after acute infarction, and how targeting these receptors may provide therapeutic benefits.…”

“…In an evolutionary sense, programmed necrosis is believed to provide defense against intracellular pathogens that block apoptosis activation (57). Necroptosis has been documented in stroke, but its significance needs further study (12,14,54,67,70).…”

İnme ve Terapötik Hipotermi

“…Enerji yetersizliği nedeniyle membran potansiyeli azalır, nöronlar ve glia depolarize olur 23 , glutamat gibi ekzitotoksik amino asitler, ekstraselüler kompartmana salınır ve ödemi arttırır [23][24][25][26][27] . Hipotermi, ekzitotoksik aminoasitlerin salınımını 28,29 , nitrik oksit sentezini, N-metil-Daspartat (NMDA) reseptör fosforilizasyonunu baskılar 30 .…”