The effect of general anaesthetics on brain lactate release

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.

Sleep Dependent Changes of Lactate Concentration in Human Brain

“…14 Similar to natural sleep, anesthesia reduces astrocytic glycolysis and brain lactate concentration. 49 Interestingly, lactate concentration measured from cortical brain slices harvested from young adult rats in wake (dark) and sleep (light) periods, was reduced 25% in sleep compared to wake states 49 , and the administration of anesthetic agents dynamically reduced extracellular lactate despite a preparation that must disrupt key components important in glymphatic physiology. 13,49 Unlike muscle or liver, the brain does not possess large stores of glycogen to provide a reserve carbon source and extracellular lactate might partially fulfill this need.…”

“…49 Interestingly, lactate concentration measured from cortical brain slices harvested from young adult rats in wake (dark) and sleep (light) periods, was reduced 25% in sleep compared to wake states 49 , and the administration of anesthetic agents dynamically reduced extracellular lactate despite a preparation that must disrupt key components important in glymphatic physiology. 13,49 Unlike muscle or liver, the brain does not possess large stores of glycogen to provide a reserve carbon source and extracellular lactate might partially fulfill this need. Glycogen stores within the brain (~7.8 umol/g brain about 1/4 that found for muscle 50 ) are localized primarily within astrocytes and these stores can serve as a reservoir for lactate.…”

Recent Advances in In Vivo Neurochemical Monitoring

“…Neurons in an injured brain that are starved of glucose may switch to a lactate-based metabolism, relying on local astrocytes for their energy needs [ 16 , 17 ]. Lactate biosensors have been used to verify that hypothesis and show that anesthetic agents can impair the brain’s lactate shuttle by interfering with astrocytic gliosis, and thus reduce the energy supply to neurons [ 18 ].…”

Recent update on barbiturate in relation to brain disorder

“…However, barbituric acid itself is not a centrally acting depressant. Diethylbarbituric acid (Veronal) is the first ever barbiturate with hypnotic properties that was used as early as 1903 (Hadjihambi et al, 2020[ 5 ]). The drug induced sleep both in human and animals.…”

“…We review recent research on the role of barbiturates in brain disorders in this letter (Table 1 (Tab. 1) ; References in Table 1: Brandt et al, 2018[ 1 ]; Chakraborty and Hocker, 2019[ 2 ]; Colton et al, 2014[ 3 ]; Forsyth et al, 2003[ 4 ]; Hadjihambi et al, 2020[ 5 ]; Hocker et al, 2018[ 6 ]; Klein et al, 2015[ 7 ]; Lewis and Adams, 2021[ 8 ]; Mairinger et al, 2012[ 9 ]; Mansour et al, 2013[ 10 ]; Murphy et al, 2020[ 11 ]; Ryu et al, 2019[ 12 ]; Sakuma et al, 2020[ 13 ]; Sánchez Fernández et al, 2019[ 14 ]; Schizodimos et al, 2020[ 15 ]; Shein et al, 2016[ 17 ]; Specchio and Pietrafusa, 2020[ 18 ]; Tat et al, 2017[ 19 ]; Töllner et al, 2014[ 20 ]; Tremont-Lukats et al, 2008[ 21 ]; Velle et al, 2019[ 22 ]; Wang et al, 2018[ 24 ]; Xie et al, 2009[ 25 ]; Young et al, 2016[ 26 ]; Zhang et al, 2019[ 27 ]).…”