Age or ischemia uncouples the blood flow response, tissue acidosis, and direct current potential signature of spreading depolarization in the rat brain

Abstract

Spreading depolarization (SD) events contribute to lesion maturation in the acutely injured human brain. Neurodegeneration related to SD is thought to be caused by the insufficiency of the cerebral blood flow (CBF) response; yet the mediators of the CBF response, or their deficiency in the aged or ischemic cerebral cortex, remain the target of intensive research. Here, we postulated that tissue pH effectively modulates the magnitude of hyperemia in response to SD, the coupling of which is prone to be dysfunctional in the aged or ischemic cerebral cortex. To test this hypothesis, we conducted systematic correlation analysis between the direct current (DC) potential signature of SD, SD-associated tissue acidosis, and hyperemic element of the CBF response in the isoflurane-anesthetized, young or old, and intact or ischemic rat cerebral cortex. The data demonstrate that the amplitude of the SD-related DC potential shift, tissue acidosis, and hyperemia are tightly coupled in the young intact cortex; ischemia and old age uncouples the amplitude of hyperemia from the amplitude of the DC potential shift and acidosis; the duration of the DC potential shift, hyperemia and acidosis positively correlate under ischemia alone; and old age disproportionally elongates the duration of acidosis with respect to the DC potential shift and hyperemia under ischemia. The coincidence of the variables supports the view that local CBF regulation with SD must have an effective metabolic component, which becomes dysfunctional with age or under ischemia. Finally, the known age-related acceleration of ischemic neurodegeneration may be promoted by exaggerated tissue acidosis. The hyperemic element of the cerebral blood flow response to spreading depolarization is effectively modulated by tissue pH in the young intact rat cerebral cortex. This coupling becomes dysfunctional with age or under ischemia, and tissue acidosis lasts disproportionally longer in the aged cortex, making the tissue increasingly more vulnerable.

The impact of dihydropyridine derivatives on the cerebral blood flow response to somatosensory stimulation and spreading depolarization

“…while it was seldom encountered in many of our previous studies using isoflurane (Menyhárt et al, 2015;Menyhárt et al, 2017;Varga et al, 2016). Finally, the global ischaemia model we routinely use produces a considerable drop of CBF following 2VO under isoflurane anaesthesia (e.g., to 27 ± 13%, Varga et al, 2016, to more moderate under α-chloralose anaesthesia here (Figure 3b).…”

“…The amplitude of SD appears to be fairly conserved, since neither ischaemia nor age can alter the SD-related DC potential amplitude (Menyhárt et al, 2015;Menyhárt et al, 2017). The amplitude of SD appears to be fairly conserved, since neither ischaemia nor age can alter the SD-related DC potential amplitude (Menyhárt et al, 2015;Menyhárt et al, 2017).…”

“…Even though LA1011 treatment did not achieve a detectable change in neuronal activity with somatosensory stimulation in our experiments, it greatly enhanced the amplitude of SD, consistent in all experimental conditions created. The amplitude of SD appears to be fairly conserved, since neither ischaemia nor age can alter the SD-related DC potential amplitude (Menyhárt et al, 2015;Menyhárt et al, 2017). However, several pharmacological manipulations have proven to reduce the amplitude of SD.…”

Impact of age on cardiovascular function, inflammation, and oxidative stress in experimental asphyxial cardiac arrest

“…Some studies indicate that decreased CBF seen in the aged animals may potentially cause neuronal injury, whereas other studies imply that cerebral blood flow is sufficient to support the brain metabolism during the subsequent hypoperfusion phase after CA and is not associated with poor outcome . Recent studies do, however, support the former, as the aged brain is more susceptible to ischemia due to uncoupling of the neuronal depolarization and the resulting cerebral hyperemia causing tissue acidosis and injury . Concurrent with the attenuated hyperdynamic response, a significant decline in MAP from baseline to end of follow‐up was seen in aged rats, indicating reduced cardiovascular function.…”

The impact of age on the elicitation of spreading depolarization and the implication of prostanoids in the associated cerebral blood flow response Hertelendy Péter

“…Low pH may restrict SD evolution via NMDA receptor inhibition or by the adjustment of the conductance and gating properties of Kv, Nav, and Cav channels (Tombaugh and Somjen, 1996). Recent analysis has refined the view that acidosis impedes SD by presenting that lower tissue pH predicted smaller SD amplitude in the normally perfused cerebral cortex only, while the positive correlation between tissue pH and SD amplitude was lost under ischemia in anesthetized rats (Menyhart et al, 2017a). In the ischemic tissue, the SD suppressing effect of tissue acidosis was proposed to be obscured by glutamate and K + , present at high concentration.…”