Spreading depolarizations in the rat endothelin-1 model of focal cerebellar ischemia

Abstract

Focal brain ischemia is best studied in neocortex and striatum. Both show highly vulnerable neurons and high susceptibility to spreading depolarization (SD). Therefore, it has been hypothesized that these two variables generally correlate. However, this hypothesis is contradicted by findings in cerebellar cortex, which contains highly vulnerable neurons to ischemia, the Purkinje cells, but is said to be less susceptible to SD. Here, we found in the rat cerebellar cortex that elevated K+ induced a long-lasting depolarizing event superimposed with SDs. Cerebellar SDs resembled those in neocortex, but negative direct current (DC) shifts and regional blood flow responses were usually smaller. The K+ threshold for SD was higher in cerebellum than in previous studies in neocortex. We then topically applied endothelin-1 (ET-1) to the cerebellum, which is assumed to cause SD via vasoconstriction-induced focal ischemia. Although the blood flow decrease was similar to that in previous studies in neocortex, the ET-1 threshold for SD was higher. Quantitative cell counting found that the proportion of necrotic Purkinje cells was significantly higher in ET-1-treated rats than sham controls even if ET-1 had not caused SDs. Our results suggest that ischemic death of Purkinje cells does not require the occurrence of SD.

Brainstem and Cortical Spreading Depolarization in a Closed Head Injury Rat Model

“…To confirm the propagating pattern of the recorded SDs, changes in cortical surface intrinsic optical signaling (IOS) were measured in parallel with the electrocortical recordings in a subgroup of animals (n = 18), using an open cranial window. A slowly propagating change in IOS was measured during spreading depolarization, likely reflecting cytotoxic edema [22,47] and the hemodynamic response to SD [48], confirming the propagating nature of the observed voltage deflection (Figure 1f and Video S1) [49][50][51].…”

Ischemia-Triggered Glutamate Excitotoxicity From the Perspective of Glial Cells

“…Nevertheless, it is necessary to mention that in the ischemic core, also surviving and even newly formed viable neurons have been detected (Zhang et al, 2017). On the contrary, there is a residual blood flow in the penumbra due to the presence of collateral arteries (Harukuni and Bhardwaj, 2006;Jung et al, 2017), with only lowered concentrations of ATP, to some extent maintained ionic concentrations, recurrent episodes of cortical spreading depression (or peri-infarct depolarization; Hinzman et al, 2015;Oliveira-Ferreira et al, 2019), and apoptosis as typical cellular death (Rossi et al, 2007;Doyle et al, 2008; Figure 1). Moreover, glial elements, astrocytes and NG2 glia, in this area form the so-called glial scar that prevents detrimental compounds from entering the spared nervous tissue (Adams and Gallo, 2018), while NG2 cells also display a multipotent differentiation potential .…”

Direct electrophysiological evidence that spreading depolarization-induced spreading depression is the pathophysiological correlate of the migraine aura and a review of the spreading depolarization continuum of acute neuronal mass injury

“…Unfortunately, the IOS in vivo is not only a marker for the injury depolarization but also strongly influenced by the cerebral blood volume. This renders the interpretation of the IOS in vivo difficult, but it can still be used for the assessment of the spatial expansion of the injury depolarization because the depolarization typically triggers a neurovascular response, as explained below, that secondarily affects the cerebral blood volume (Oliveira-Ferreira et al 2019;Santos et al 2017;Scholl et al 2017).…”

“…Large injury depolarization as a network event however occurs in the cerebellum when ischemia is more severe. Accordingly, the characteristic sequence of a terminal large negative DC shift in the wake of circulatory arrest does not differ significantly between cerebellum and neocortex (Fifkova et al 1961;Kraig et al 1983;Nicholson et al 1977;Oliveira-Ferreira et al 2019).…”