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bioRxiv · 10.1101/2024.09.19.613937

Simulated ischemia in live cerebral slices is mimicked by opening the Na+/K+ pump: clues to the generation of spreading depolarization.

Kim, D.·Gagolewicz, P. J.·McQueen, S.·Latour, H.·Tresidder, K.·Jarvis, C. R.·Andrew, R. D.
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Abstract

The gray matter of the higher brain undergoes spreading depolarization (SD) in response to the increased metabolic demand of ischemia, promoting acute neuronal injury and death. The mechanism linking ischemic failure of the Na+/K+ ATPase (NKA) to the subsequent onset of a large inward current driving SD in neurons has remained a mystery because blockade of conventional channels does not prevent SD nor ischemic death. The marine poison palytoxin (PLTX) specifically binds the NKA transporter at extremely low concentrations, converting it to an open cationic channel, causing sudden neuronal Na+ influx and K+ efflux. Pump failure and induction of a strong inward current should induce dramatic SD-like activity. Indeed,1-10 nM PLTX applied to live coronal brain slices induces a propagating depolarization remarkably like SD induced by oxygen/glucose deprivation (OGD) as revealed by imaging. This PLTX depolarization (PD) mimicked other effects of OGD. In neocortex, as the elevated LT front passed by an extracellular pipette, a distinct negative DC shift was recorded, indicating cell depolarization, whether induced by OGD or by bath PLTX. Either treatment induced strong SD-like responses in the same higher and lower brain regions. Further, we imaged identical real-time OGD-SD or PD effects upon live pyramidal neurons using 2-photon microscopy. Taken together, these findings support our proposal that, like most biological poisons, PLTX mimics (and takes advantage of) a biological process,ie is brain ischemia. An endogenous PLTX-like molecule may open the NKA to evoke Na+ influx/K+ efflux that drive SD and the ensuing neuronal damage in its wake. New and NoteworthyWith stroke, traumatic brain injury, or sudden cardiac arrest, there is no therapeutic drug to aid brain protection and recovery. Within 2 minutes of severe ischemia, a wave of spreading depolarization (SD) propagates through gray matter. More SDs arise over hours, expanding injury. This period represents a therapeutic window to inhibit recurring SD and reduce damage but we do not understand the molecular sequence. Here we argue for a novel molecule to target.

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Kim, D., Gagolewicz, P. J., McQueen, S., Latour, H., Tresidder, K., Jarvis, C. R., Andrew, R. D.. 2024-09-20. Simulated ischemia in live cerebral slices is mimicked by opening the Na+/K+ pump: clues to the generation of spreading depolarization.. https://doi.org/10.1101/2024.09.19.613937

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