Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm

Abstract

The mechanisms of brain tissue damage in stroke are strongly linked to the phenomenon of excitotoxicity, which is defined as damage or death of neural cells due to excessive activation of receptors for the excitatory neurotransmitters glutamate and aspartate. Under physiological conditions, ionotropic glutamate receptors mediate the processes of excitatory neurotransmission and synaptic plasticity. In ischemia, sustained pathological release of glutamate from neurons and glial cells causes prolonged activation of these receptors, resulting in massive depolarization and cytoplasmic Ca 2+ overload. The NMDA subtype of glutamate receptors is particularly important as it represents the main initial route for the Ca 2+ influx. High cytoplasmic levels of Ca 2+ activate many degradative processes that, depending on the metabolic status, cause immediate or delayed death of neural cells. This traditional view has been expanded by a number of observations that implicate Cl − channels and several types of non-channel transporter proteins, such as the Na + ,K + ,2Cl − cotransporter, Na + /H + exchanger, and Na + /Ca 2+ exchanger, in the development of glutamate toxicity. Some of these ion transporters increase tissue damage by promoting pathological cell swelling and necrotic cell death, while others contribute to a long term accumulation of cytoplasmic Ca 2+ . This brief review is aimed at illustrating how the dysregulation of various ion transport processes combine in a 'perfect storm' that disrupts neural ionic homeostasis and culminates in the irreversible damage and death of neural cells. The clinical relevance of individual transporters as targets for therapeutic intervention in stroke is also briefly discussed.

Fixed negative charge and the Donnan effect: a description of the driving forces associated with brain tissue swelling and oedema

“…Many studies have identified and characterized ion channels (Liang et al 2007), water channels (Marmarou 2007) and the pathological responses to injury (Mongin 2007) that may contribute to cell swelling. Those studies, however, identify facilitators of oedema formation that control the rate of swelling.…”

DCPIB, the Proposed Selective Blocker of Volume-Regulated Anion Channels, Inhibits Several Glutamate Transport Pathways in Glial Cells

“…The Best1-mediated anion currents are transiently activated by agonists for numerous phospholipase Clinked G-protein-coupled receptors, including metabotropic purinergic receptors (Park et al, 2009). Therefore, to test if astrocytes release glutamate via the Best1 permeability pathway and if such a pathway is sensitive to DCPIB, we exposed astrocytic cultures to 100 mM ATP, a treatment that is known to cause glutamate/D-[ 3 H]aspartate release via stimulation of several types of metabotropic P2Y receptors (Mongin andKimelberg, 2002, 2003). As seen in Fig.…”

“…Buildup of glutamate in the extracellular space causes excessive activation of neuronal Ca 21 -permeable glutamate receptor channels of the NMDA family (N-methyl-D-aspartateis the selective agonist of thesereceptors), leading to cytosolic Ca 21 overload and neuronal death (Choi, 1992). On the basis of potent reductions of ischemic brain damage by DCPIB and tamoxifen, VRAC have been suggested to represent a new and promising therapeutic target in stroke (Kimelberg, 2005;Mongin and Kimelberg, 2005;Mongin, 2007).…”

Noncanonical cell death programs in the nematode Caenorhabditis elegans

“…Mutant ion channels that are all neurotoxic can conduct calcium, 83 and thus elevated calcium influx through plasma membrane ion channels appears to be a common necrosis-triggering event. In mammals, analogous glutamate excitotoxicity 88 and DEG/ENaC channel hyperactivation 89 are important in neuronal death consequent to stroke and ischemia.…”