Spreading depolarization (SD) is the generic term for all waves of abrupt, near-complete breakdown of the neuronal transmembrane ion gradients that cause cytotoxic edema and propagate at about 3 mm/min in cerebral gray matter. The SD continuum describes the spectrum from short-lasting SDs in metabolically intact tissue to SDs of intermediate duration to terminal SD in severely ischemic tissue. Accordingly, SDs occur in human diseases; from the harmless migraine aura to stroke to circulatory arrest. This means that there are overlaps but also large variations in mechanistic aspects along the continuum. For example, SD induces either transient hyperperfusion variably followed by mild oligemia in normal tissue (normal neurovascular response) or severe hypoperfusion (inverse neurovascular response = spreading ischemia) variably followed by hyperemia in tissue at risk for progressive injury.1
We discovered the phenomenon of inverse neurovascular coupling by coincidence in a rat model mimicking the conditions present at the boundary zone between subarachnoid blood and cortical surface after aneurysmal subarachnoid hemorrhage (aSAH).3 In this model, spreading ischemia resulted from topical application of artificial cerebrospinal fluid (ACSF) containing an elevated K+ concentration ([K+]ACSF) in combination with either the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine (L-NNA) or the NO scavenger hemoglobin to the brain cortex (= NO↓/K+↑-model). Notably, the SD-induced spreading ischemia could be the sole cause of widespread cortical infarcts.2 An NO donor caused spreading ischemia to revert to a normal neurovascular response to SD 5. A decade later, we observed spreading ischemia in aSAH patients for the first time.4 In our recent clinical follow-up study, spreading ischemia occurred in the same time window in which serial neuroimaging-proven brain infarcts developed at the recording site.7 This confirmed our original translational hypothesis that spreading ischemia is involved in the pathogenesis of delayed ischemic stroke after aSAH.3
Following the recent concept of translational medicine by Marc Fisher 6, this development not only included classic translation from bench to bedside but also reverse and lateral translation. Lateral translation occurs when a proven clinical therapy or technology stimulates basic and/or clinical researchers to enhance these proven modalities. Reverse translation occurs when clinical advances encourage basic science researchers to understand more about the mechanisms underlying clinical observations, technologies or therapies. For example, driven by our clinical findings, we have continued to elucidate the mechanism underlying spreading ischemia in rodent experiments.
One of our recent experimental studies has recently suggested that prolonged elevation of the baseline extracellular K+ concentration ([K+]o) causes rundown of the α2 Na+/K+-ATPase, located in a microdomain above the endoplasmic reticulum.8 This may result in increased Ca2+ uptake by internal stores of astrocytes, vascular myocytes and pericytes since Ca2+ outflux via plasmalemmal Na+/Ca2+-exchanger declines. Augmented Ca2+ mobilization from internal stores during SD could then enhance vasoconstriction, thereby contributing to spreading ischemia. However, augmented Ca2+ mobilization activates constitutive NOS, thereby antagonizing vasoconstriction. This could explain why spreading ischemia in the NO↓/K+↑-model requires reduced NO availability in addition to elevated baseline [K+]o. Further insight into the mechanisms underlying inverse neurovascular coupling could help us to find novel treatment strategies in the clinic following the tenet espoused by Max Planck that ‘insight must precede application’.
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