Does spreading depolarization facilitate neurnal injury when cerebral tissue is metabolically compromised by the vasoconstrictor endothelin-1?

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All neurons depolarize in the absence of oxygen, but it seems that those that are more resistant to hypoxic/ischemic injury do so gradually. The term spreading depolarization describes the spectrum of abrupt depolarizations, and accumulating evidence suggests that they facilitate neuronal death. Here, we would like to investigate this hypothesis using the rat brain topical endothelin-1 (ET-1) model which allows titrating the constrictive effect of ET-1 on the vasculature. Thus, tissue can be poised close to the threshold where ischemic-metabolic compromise becomes detrimental. Spreading depolarization seems to indicate that this threshold is crossed since we found in neocortex that exposure to ET-1 only caused neuronal death when animals displayed spreading depolarization. Here, we aim to study the ET-1 effect on cerebellum and brainstem which only generate spreading depolarization in presence of conditioning media increasing neuronal excitability. Will conditioning media allow ET-1 to induce spreading depolarization associated with neuronal injury? In neocortex, we aim to investigate, using different ET-1 concentrations, whether faster recovery within the depolarization continuum shifts the cell death from necrosis toward apoptosis. It will also be studied whether two multidrug cocktails inhibiting persistent dendritic inward currents are sufficient to prevent spreading depolarization and neuronal injury when vessels are markedly constricted by ET-1 combined with NO synthase inhibition.