Susceptibility of the cerebral cortex to spreading depolarization in neurological disease states: The impact of aging

Abstract

Secondary injury following acute brain insults significantly contributes to poorer neurological outcome. The spontaneous, recurrent occurrence of spreading depolarization events (SD) has been recognized as a potent secondary injury mechanism in subarachnoid hemorrhage, malignant ischemic stroke and traumatic brain injury. In addition, SD is the underlying mechanism of the aura symptoms of migraineurs. The susceptibility of the nervous tissue to SD is subject to the metabolic status of the tissue, the ionic composition of the extracellular space, and the functional status of ion pumps, voltage-gated and other cation channels, glutamate receptors and excitatory amino acid transporters. All these mechanisms tune the excitability of the nervous tissue. Aging has also been found to alter SD susceptibility, which appears to be highest at young adulthood, and decline over the aging process. The lower susceptibility of the cerebral gray matter to SD in the old brain may be caused by the age-related impairment of mechanisms implicated in ion translocations between the intra-and extracellular compartments, glutamate signaling and surplus potassium and glutamate clearance. Even though the aging nervous tissue is thus less able to sustain SD, the consequences of SD recurrence in the old brain have proven to be graver, possibly leading to accelerated lesion maturation. Taken that recurrent SDs may pose an increased burden in the aging injured brain, the benefit of therapeutic approaches to restrict SD generation and propagation may be particularly relevant for elderly patients.

Microglia alter the threshold of spreading depolarization and related potassium uptake in the mouse brain

“…Moreover, we show that SD alters microglial responses that include enhanced interaction between microglia and neurons, which is associated with sustained potassium uptake and altered neuronal activity after SD. Indeed, c-fos expression induced by SD is attenuated by the inhibition of NMDA receptors or voltage-gated calcium channels, 44,45 both involved in physiological neuronal signaling, 46 SD evolution 47 and excitotoxic injury. 48 Our results also provide mechanistic insight into how microglial responses are altered by SD, in part via P2Y12R.…”

Brain Aging and Electrophysiological Signaling: Revisiting the Spreading Depression Model

“…In the aged brain, physiological and pathological conditions can modulate the electrophysiological mechanisms involved in brain signaling (Guedes et al, 1996; Farkas et al, 2011) and brain ability to produce and propagate CSD (Hertelendy et al, 2018). These last authors discussed the possibility that aging may impair physiologic processes such as ion channel function and ion pump activity that can be implicated in elicitation and propagation of CSD.…”

“…These last authors discussed the possibility that aging may impair physiologic processes such as ion channel function and ion pump activity that can be implicated in elicitation and propagation of CSD. Descriptions of the two-dimensional pattern of CSD propagation, based on magnetoencephalography (Eiselt et al, 2004) and optical imaging recording (Fujita et al, 2016), suggest an inhomogeneity of the cortical tissue, which also include age-related vascular hyporesponsivity and neuronal and glial density changes (Farkas et al, 2011; Hertelendy et al, 2018). These factors could be affected by aging and therefore influence the variability of CSD parameters.…”

Chitosan nanoparticles release nimodipine in response to tissue acidosis to attenuate spreading depolarization evoked during forebrain ischemia

“…The focus of stroke therapy is the salvage of non-functional but viable penumbra tissue surrounding the ischemic core beyond rescue. Spreading depolarization (SD) has been recognized as a central mechanism of injury progression and of the conversion of penumbra tissue to the ischemic core (Nedergaard et al, 1996;Hossmann, 1996;Woitzik et al, 2013;Hartings et al, 2017;Hertelendy et al, 2019). Delayed cerebral ischemia after aneurismal subarachnoid hemorrhage (SAH) has been also linked to SD (Dreier et al, 2006), and SD-induced ischemia (Dreier et al, 2009).…”