Abstract
One of the major instigators leading to neuronal cell death and brain damage following cerebral ischemia is calcium dysregulation. The neuron's inability to maintain calcium homeostasis is believed to be a result of increased calcium influx and impaired calcium extrusion across the plasma membrane. The need to better understand the cellular and biochemical mechanisms of calcium dysregulation contributing to neuronal loss following stroke/cerebral ischemia is essential for the development of new treatments in order to reduce ischemic brain injury. The aim of this paper is to provide a concise overview of the various calcium influx pathways in response to ischemia and how neuronal cells attempts to overcome this calcium overload.
Highlights
IntroductionHigh extracellular glutamate causes excitotoxicity resulting in N-methylD-aspartic acid (NMDA), amino-3-hydroxy5-methyl-4-isoxazolepropionic acid (AMPA), and kainic acid receptor activation allowing the influx of calcium, sodium, and zinc ions into the cell
While there may be circumstances when it operates in calcium entry mode in neurons following cerebral ischemia; it is likely to be the major calcium efflux mechanism in cells that recover from the initial ischemia insult and in which the exchanger has not been severely inactivated by calpain cleavage [74]
Excessive intracellular calcium influx is a major instigator of neuronal cell death following cerebral ischemia
Summary
High extracellular glutamate causes excitotoxicity resulting in NMDA, AMPA, and kainic acid receptor activation allowing the influx of calcium, sodium, and zinc ions into the cell. The initial or milder periods of excitotoxicity can trigger a range of cellular disturbances such as oxidative stress, protein synthesis/folding disturbances, mitochondrial dysfunction, and altered cell signalling The accumulation of these cellular disturbances can eventually cause a secondary rise in intracellular calcium and the activation of cell death pathways (apoptosis, necrosis, autophagy, and necroptosis), leading to the demise of the neuron. Here lie a number of possible therapeutic targets to manipulate intracellular calcium levels after an ischemic episode and thereby reduce neuronal death With this in mind, this paper will focus on providing a concise update of the major modes of calcium influx, efflux, and release from organelles following cerebral ischemia
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