Abstract
The effects of anaesthetic agents on brain energy metabolism may explain their shared neurophysiological actions but remain poorly understood. The brain lactate shuttle hypothesis proposes that lactate, provided by astrocytes, is an important neuronal energy substrate. Here we tested the hypothesis that anaesthetic agents impair the brain lactate shuttle by interfering with astrocytic glycolysis. Lactate biosensors were used to record changes in lactate release by adult rat brainstem and cortical slices in response to thiopental, propofol and etomidate. Changes in cytosolic nicotinamide adenine dinucleotide reduced (NADH) and oxidized (NAD+) ratio as a measure of glycolytic rate were recorded in cultured astrocytes. It was found that in brainstem slices thiopental, propofol and etomidate reduced lactate release by 7.4 ± 3.6% (P < 0.001), 9.7 ± 6.6% (P < 0.001) and 8.0 ± 7.8% (P = 0.04), respectively. In cortical slices, thiopental reduced lactate release by 8.2 ± 5.6% (P = 0.002) and propofol by 6.0 ± 4.5% (P = 0.009). Lactate release in cortical slices measured during the light phase (period of sleep/low activity) was ~25% lower than that measured during the dark phase (period of wakefulness) (326 ± 83 μM vs 430 ± 118 μM, n = 10; P = 0.04). Thiopental and etomidate induced proportionally similar decreases in cytosolic [NADH]:[NAD+] ratio in astrocytes, indicative of a reduction in glycolytic rate. These data suggest that anaesthetic agents inhibit astrocytic glycolysis and reduce the level of extracellular lactate in the brain. Similar reductions in brain lactate release occur during natural state of sleep, suggesting that general anaesthesia may recapitulate some of the effects of sleep on brain energy metabolism.
Highlights
Anaesthetic agents induce a reversible state of unconsciousness by altering the neuronal activity through enhancing inhibitory, and/or inhibiting excitatory synaptic interactions (Garcia et al, 2010)
The effects are similar to that of a naturally occurring state of sleep, suggesting that general anaesthesia may recapitulate some of the effects of sleep on brain energy metabolism
A potent gamma-aminobutyric acid A (GABAA) agonist, applied in concentration 100 μM had no effect on brain lactate release (0.9 ± 4.5%; n = 8, P = 0.5) (Fig. 2)
Summary
Anaesthetic agents induce a reversible state of unconsciousness by altering the neuronal activity through enhancing inhibitory, and/or inhibiting excitatory synaptic interactions (Garcia et al, 2010). Many injectable anaesthetics, including propofol (fast-acting nonbarbiturate), etomidate (nonbarbiturate imidazolic derivative), and thiopental (barbiturate) share a common mechanism of action by enhancing the efficacy of signalling via the inhibitory gamma-aminobutyric acid A (GABAA) receptors (Canbek et al, 2015). Anaesthesia and sleep may share some common neurophysiological mechanisms (Vacas et al, 2013), including suppression of arousal via enhanced activity of GABAergic pathways (Lu et al, 2008). In brain regions that promote wakefulness, such as dorsal raphé, hypothalamic tuberomammillary nucleus, medial preoptic area and others, facilitated GABAergic inhibition has been shown to promote sleep, – an effect similar to that of anaesthetic agents that target GABAA receptor-mediated mechanisms (Watson et al, 2010). Changes in cerebral blood flow and cerebral metabolic rate of oxygen have been reported with the use of propofol (Kaisti et al, 2003), etomidate (Cold et al, 1985) and thiopental (Wechsler et al, 1951)
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