Sevoflurane Effects on Neuronal Energy Metabolism Correlate with Activity States While Mitochondrial Function Remains Intact

Abstract

During general anesthesia, alterations in neuronal metabolism may induce neurotoxicity and/or neuroprotection depending on the dose and type of the applied anesthetic. In this study, we investigate the effects of clinically relevant concentrations of sevoflurane (2% and 4%, i.e., 1 and 2 MAC) on different activity states in hippocampal slices of young Wistar rats. We combine electrophysiological recordings, partial tissue oxygen (ptiO2) measurements, and flavin adenine dinucleotide (FAD) imaging with computational modeling. Sevoflurane minimally decreased the cerebral metabolic rate of oxygen (CMRO2) while decreasing synaptic transmission in naive slices. During pharmacologically induced gamma oscillations, sevoflurane impaired network activity, thereby decreasing CMRO2. During stimulus-induced neuronal activation, sevoflurane decreased CMRO2 and excitability while basal metabolism remained constant. In this line, stimulus-induced FAD transients decreased without changes in basal mitochondrial redox state. Integration of experimental data and computer modeling revealed no evidence for a direct effect of sevoflurane on key enzymes of the citric acid cycle or oxidative phosphorylation. Clinically relevant concentrations of sevoflurane generated a decent decrease in energy metabolism, which was proportional to the present neuronal activity. Mitochondrial function remained intact under sevoflurane, suggesting a better metabolic profile than isoflurane or propofol.

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

“…Compared to our other in vitro studies, the SD-related increase in CMRO 2 (2.7-fold) was significantly higher than during other energy-demanding types of network activity, such as gamma oscillations or seizure-like events, which induced a 1.3-fold and 1.4-fold increase in CMRO 2 , respectively. 30,54 This underlines the great metabolic demand induced by SD.…”

“…Previously, calculations of CMRO 2 relied on p ti O 2 depth profiles acquired by vertical movement of one Clark-style oxygen-electrode in constant steps through acute brain slices (Figure 1(a) and (b)). 30,46,52,54 This method can be used to capture steady-state CMRO 2 , but lacks the temporal resolution necessary for capturing the transient paroxysmal changes in p ti O 2 during SD, which reach a minimum seconds after onset (cf. Figure 2(b)).…”

“…As anesthetics are known to reduce brain metabolism, [30][31][32][33] they may reduce SD-associated damage that results from a mismatch of energy supply and demand. In addition, anesthetics may modulate or even prevent SD as shown for ketamine and isoflurane in animals and ketamine in patients.…”

Histone deacetylase 9 plays a role in sevoflurane‐induced neuronal differentiation inhibition by inactivating cAMP‐response element binding protein transcription and inhibiting the expression of neurotrophin‐3

“…In addition, only the differentiation of NSCs into neurons was studied, and the differentiation of NSCs into oligodendrocytes, for example, was not assessed. Moreover, while we utilized the sevoflurane concentrations used in our previous study, 22 clinically relevant concentrations, and those commonly used in vitro experiments, 43,44 we did not test the full range of sevoflurane concentrations. Finally, as the association of HDAC9 with CREB in neural stem cells after sevoflurane exposure is a new finding in our study, the mechanism of interaction remains to be further investigated.…”

The effects of general anesthetics on mitochondrial structure and function in the developing brain

“…Similarly, Xiao et al found PPF exposure in primary rat neurons decreased activation of AMP-activated protein kinase (AMPK), an important cellular signal to promote mitochondrial energy production ( 89 ). Metabolic analysis of isolated rat hippocampal tissue sections indicated that SEV or ISO exposure induces a substantial reduction in metabolic demand proportional to the reduction in neuronal activity, but without any alterations to intrinsic mitochondrial complex activity ( 103 ). These results suggest that reduced bioenergetic signaling and decreased ETC activity may be proportional responses to a GA-induced reduction in neuronal activity.…”