Spreading depolarization remarkably exacerbates ischemia-induced tissue acidosis in the young and aged rat brain

Abstract

Spreading depolarizations (SDs) occur spontaneously in the cerebral cortex of subarachnoid hemorrhage, stroke or traumatic brain injury patients. Accumulating evidence prove that SDs exacerbate focal ischemic injury by converting zones of the viable but non-functional ischemic penumbra to the core region beyond rescue. Yet the SD-related mechanisms to mediate neurodegeneration remain poorly understood. Here we show in the cerebral cortex of isoflurane-anesthetized, young and old laboratory rats, that SDs propagating under ischemic penumbra-like conditions decrease intra and- extracellular tissue pH transiently to levels, which have been recognized to cause tissue damage. Further, tissue pH after the passage of each spontaneous SD event remains acidic for over 10 minutes. Finally, the recovery from SD-related tissue acidosis is hampered further by age. We propose that accumulating acid load is an effective mechanism for SD to cause delayed cell death in the ischemic nervous tissue, particularly in the aged brain.

Demonstration of impaired neurovascular coupling responses in TG2576 mouse model of Alzheimer’s disease using functional laser speckle contrast imaging

“…In addition, spectroscopic measurements using multiple wavelengths-rather than a single light source of a specific, narrow rangecan yield quantitative data on hemoglobin saturation parallel with relative changes in CBF assessed by LSCI (Dunn et al 2003). Finally, LSCI has been very successfully integrated into multi-modal imaging systems, which visualize membrane potential changes in the cerebral cortex (i.e., the intensity of the optical signal emitted by a voltage-sensitive fluorescent dye increases with decreasing transmembrane potential) (Farkas et al 2010;Obrenovitch et al 2009), or image variations of pH in the nervous tissue (i.e., fluorescence intensity of a pH-sensitive dye increases with deepening acidosis) (Menyhart et al 2017). These approaches are highly pertinent and very powerful, because the exact spatial and temporal match of individual modalities offers the opportunity to draw specific conclusions about their coupling patterns (i.e., neuronal activation, metabolic status, and CBF).…”

Optogenetic translocation of protons out of penumbral neurons is protective in a rodent model of focal cerebral ischemia

“…It has been accepted that PID plays a central role in the development of cerebral ischemic injury [16]. Occurrence of PID could remarkably exacerbate the tissue acidosis and the severity of the tissue injury [72]. Moreover, PID caused vasoconstriction and CBF reduction, which impeded the brain recovery from stroke [33,73].…”

Spreading depolarization and repolarization during cardiac arrest as an ultra-early marker of neurological recovery in a preclinical model

“…Earlier SD during CA may be neuroprotective It has been posited in multiple recent studies that SD is harmful to the brain, 12,24,67,68 although this hypothesis is often focused on prolonged SD or repetitive SD events. 68,69 However, several studies have suggested that mitochondrial processes that are important in SD can signal pathways to protect neurons and endothelium. 70,71 Indeed, multiple studies have shown beneficial properties of SD, including preconditioning, upregulation of growth factors, and neurogenesisis.…”