Possible neurotoxicity of the anesthetic propofol: evidence for the inhibition of complex II of the respiratory chain in area CA3 of rat hippocampal slices

Abstract

Propofol is the most frequently used intravenous anesthetic for induction and maintenance of anesthesia. Propofol acts first and formost as a GABAA-agonist, but effects on other neuronal receptors and voltage-gated ion channels have been described. Besides its direct effect on neurotransmission, propofol-dependent impairment of mitochondrial function in neurons has been suggested to be responsible for neurotoxicity and postoperative brain dysfunction. To clarify the potential neurotoxic effect in more detail, we investigated the effects of propofol on neuronal energy metabolism of hippocampal slices of the stratum pyramidale of area CA3 at different activity states. We combined oxygen-measurements, electrophysiology and flavin adenine dinucleotide (FAD)-imaging with computational modeling to uncover molecular targets in mitochondrial energy metabolism that are directly inhibited by propofol. We found that high concentrations of propofol (100 µM) significantly decrease population spikes, paired pulse ratio, the cerebral metabolic rate of oxygen consumption (CMRO2), frequency and power of gamma oscillations and increase FAD-oxidation. Model-based simulation of mitochondrial FAD redox state at inhibition of different respiratory chain (RC) complexes and the pyruvate-dehydrogenase show that the alterations in FAD-autofluorescence during propofol administration can be explained with a strong direct inhibition of the complex II (cxII) of the RC. While this inhibition may not affect ATP availability under normal conditions, it may have an impact at high energy demand. Our data support the notion that propofol may lead to neurotoxicity and neuronal dysfunction by directly affecting the energy metabolism in neurons.Electronic supplementary materialThe online version of this article (10.1007/s00204-018-2295-8) contains supplementary material, which is available to authorized users.

Emergence delirium in children is not related to intraoperative burst suppression – prospective, observational electrography study

“…Pediatric anaesthesiologists are concerned, since it has been proposed that anaesthetic agents may be neurotoxic to the developing brain [4, 5].…”

Anesthetics: from modes of action to unconsciousness and neurotoxicity

“…Although the mechanisms by which sevoflurane and desflurane produce such cytotoxicity are yet to be determined, the involvement of Drp1, Fas, and mitochondrial permeability transition pore activation-mediated fission are a few possibilities (Zhang and Xie 2012). Similar mitochondrial impairments have been reported with propofol (Berndt et al 2018;Twaroski et al 2015) and ketamine (Bosnjak et al 2012;Braun et al 2010;Ito et al 2015).…”

“…The evidence derived from animal studies is abundant, with initial studies showing that early exposure to isoflurane and nitrous oxide causes neurodegeneration and cognitive deficits in young rats (Jevtovic-Todorovic et al 2003). Since then, multiple GABA agonistic and NMDA antagonistic agents including sevoflurane (Istaphanous et al 2011;Lu et al 2010;Sun et al 2019;Wang et al 2013;Xie et al 2017;Xu et al 2016Xu et al , 2018, isoflurane (Istaphanous et al 2011;Lemkuil et al 2011;Talpos et al 2019;Tao et al 2016;Xu et al 2016Xu et al , 2018Zhang et al 2010;Zhu et al 2010), desflurane (Istaphanous et al 2011Tao et al 2016;Xu et al 2016), nitrous oxide (Jevtovic-Todorovic and Carter 2005;Jevtović-Todorović et al 1998;Talpos et al 2019), propofol (Berndt et al 2018;Bosnjak et al 2016;Pearn et al 2012;Xu et al 2018), and ketamine (Brambrink et al 2012a;Ito et al 2015;Slikker et al 2007) have been found to compromise neuronal health, synaptic network assembly, and learning and memory in both young and aged brains in a number of species ranging from invertebrates, to rodents, to nonhuman primates (Slikker et al 2007;Talpos et al 2019). Evidence of neurotoxicity in young nonhuman primates stands out because of its relevancy to humans.…”

Early cognitive function changes after dexmedetomidine added to propofol-based sedation for gastrointestinal endoscopy

“…Propofol is a commonly used intravenous anesthetic agent for gastrointestinal endoscopy may lead to cognitive impairment [2] . Mounting evidence from experimental models has demonstrated that propofol could induce a similar neurotoxic effect [9][10][11] . Allampati et al [12] have reported that in humans,cognitive exibility returns to baseline within 30-45 min after propofol sedation despite delayed return of psychomotor speed and reaction time.…”