Abstract
Delayed cerebral ischemia (DCI) remains a challenging but very important condition, because DCI is preventable and treatable for improving functional outcomes after aneurysmal subarachnoid hemorrhage (SAH). The pathologies underlying DCI are multifactorial. Classical approaches to DCI focus exclusively on preventing and treating the reduction of blood flow supply. However, recently, glutamate-mediated neuroelectric disruptions, such as excitotoxicity, cortical spreading depolarization and seizures, and epileptiform discharges, have been reported to occur in high frequencies in association with DCI development after SAH. Each of the neuroelectric disruptions can trigger the other, which augments metabolic demand. If increased metabolic demand exceeds the impaired blood supply, the mismatch leads to relative ischemia, resulting in DCI. The neuroelectric disruption also induces inverted vasoconstrictive neurovascular coupling in compromised brain tissues after SAH, causing DCI. Although glutamates and the receptors may play central roles in the development of excitotoxicity, cortical spreading ischemia and epileptic activity-related events, more studies are needed to clarify the pathophysiology and to develop novel therapeutic strategies for preventing or treating neuroelectric disruption-related DCI after SAH. This article reviews the recent advancement in research on neuroelectric disruption after SAH.
Highlights
A rupture of an intracranial aneurysm causes subarachnoid hemorrhage (SAH), for which the prognosis remains poor [1]
The affinity of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors for glutamates is relatively low, and the number of glutamate molecules bound to AMPA receptors determines the open probability; in contrast, NMDA receptors have a higher affinity for glutamates and desensitize slower than AMPA receptors, but the slow binding rate puts a considerable limit on the opening probability of NMDA receptors during the short-lived glutamate peak [21]
In early brain injury (EBI), massive aneurysmal rupture causes severe elevation of intracranial pressure (ICP), followed by transient cerebral circulation arrest, which leads to cessation of neuronal electrical activity within seconds, mitochondrial dysfunction associated with decreased production of adenosine triphosphate to deteriorate the energy state and to disrupt the Na+-K+ pump, and ion homeostasis, resulting in disturbed membrane ion gradients, Ca2+ influx, and extracellular release of a large amount of glutamates from depolarized nerve terminals and astrocytes within minutes [61]
Summary
A rupture of an intracranial aneurysm causes subarachnoid hemorrhage (SAH), for which the prognosis remains poor [1]. Delayed cerebral ischemia (DCI) is an important modifiable prognostic factor and develops at day four or later post-SAH in patients surviving the initial aneurysmal rupture [4]. EBI may be a precursor or a contributor to DCI, and some pathophysiologies may be shared or interrelated between EBI and DCI [6] These shared or interrelated pathophysiologies may include cortical spreading depolarization (CSD) [7], which is intimately related to epileptic discharge and excitotoxicity, leading to metabolic derangement, that is, mismatch of metabolic supply and demand, with the resultant relative cerebral ischemia and neuronal death [8,9]. Recent clinical studies reported that CSD and epileptic discharge were in frequently observed in association with the development of DCI after aneurysmal SAH [10,11]. A common inducer of CSD and epileptic discharge, glutamate, was reported to increase in brain parenchyma after SAH, followed by the development of DCI [12].
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