Isoflurane lowers the cerebral metabolic rate of oxygen and prevents hypoxia during cortical spreading depolarization in vitro: An integrative experimental and modeling study

Abstract

Cortical spreading depolarization (SD) imposes a massive increase in energy demand and therefore evolves as a target for treatment following acute brain injuries. Anesthetics are empirically used to reduce energy metabolism in critical brain conditions, yet their effect on metabolism during SD remains largely unknown. We investigated oxidative metabolism during SD in brain slices from Wistar rats. Extracellular potassium ([K+]o), local field potential and partial tissue oxygen pressure (ptiO2) were measured simultaneously. The cerebral metabolic rate of oxygen (CMRO2) was calculated using a reaction-diffusion model. By that, we tested the effect of clinically relevant concentrations of isoflurane on CMRO2 during SD and modeled tissue oxygenation for different capillary pO2 values. During SD, CMRO2 increased 2.7-fold, resulting in transient hypoxia in the slice core. Isoflurane decreased CMRO2, reduced peak [K+]o, and prolonged [K+]o clearance, which indicates reduced synaptic transmission and sodium-potassium ATPase inhibition. Modeling tissue oxygenation during SD illustrates the need for increased capillary pO2 levels to prevent hypoxia. In the absence thereof, isoflurane could improve tissue oxygenation by lowering CMRO2. Therefore, isoflurane is a promising candidate for pre-clinical studies on neuronal survival in conditions involving SD.

Spreading depolarizations exhaust neuronal ATP in a model of cerebral ischemia

“…This causes a rise in ATP consumption and demand. In response, ATP production by oxidative phosphorylation is thought to increase, which has been experimentally demonstrated by measurements of higher cerebral metabolic rate of oxygen (CMRO2) (Mayevsky & Weiss, 1991;Piilgaard & Lauritzen, 2009;Schoknecht, Maechler, et al, 2023). At the same time, overall tissue ATP concentrations were shown to decrease by around 50% even in otherwise healthy parenchyma despite increased ATP synthesis in some studies (Mies & Paschen, 1984;Selman et al, 2004).…”

“…There is evidence that both ATP consumption and ATP production increase following SDs, the former via stimulation of Na + /K + -ATPase activity due to rising [K + ]o and [Na + ]i ( (Crambert et al, 2000;Horisberger & Kharoubi-Hess, 2002;Larsen et al, 2014) and Introduction) and the latter via stimulation of glycolysis and oxidative phosphorylation, as concluded from measurements of reduced brain glucose concentrations as well as increased cerebral metabolic rate of oxygen (CMRO2) ( (Balança et al, 2017;Lourenço et al, 2017;Mayevsky & Weiss, 1991;Piilgaard & Lauritzen, 2009;Schoknecht, Maechler, et al, 2023)). Here, [ATP]i was transiently reduced following SDs in presence of oxygen and glucose, which indicates ATP consumption in excess of production (Fig.…”