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Dynamic Variations in Brain Glycogen are Involved in Modulating Isoflurane Anesthesia in Mice.

ABSTRACT: General anesthesia severely affects the metabolites in the brain. Glycogen, principally stored in astrocytes and providing the short-term delivery of substrates to neurons, has been implicated as an affected molecule. However, whether glycogen plays a pivotal role in modulating anesthesia-arousal remains unclear. Here, we demonstrated that isoflurane-anesthetized mice exhibited dynamic changes in the glycogen levels in various brain regions. Glycogen synthase (GS) and glycogen phosphorylase (GP), key enzymes of glycogen metabolism, showed increased activity after isoflurane exposure. Upon blocking glycogenolysis with 1,4-dideoxy-1,4-imino-D-arabinitol (DAB), a GP antagonist, we found a prolonged time of emergence from anesthesia and an enhanced ? frequency in the EEG (electroencephalogram). In addition, augmented expression of glycogenolysis genes in glycogen phosphorylase, brain (Pygb) knock-in (Pygb^H11/H11) mice resulted in delayed induction of anesthesia, a shortened emergence time, and a lower ratio of EEG-?. Our findings revealed a role of brain glycogen in regulating anesthesia-arousal, providing a potential target for modulating anesthesia.

SUBMITTER: Fan Z

PROVIDER: S-EPMC7719152 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Dynamic Variations in Brain Glycogen are Involved in Modulating Isoflurane Anesthesia in Mice.

Fan Ze Z Zhang Zhihao Z Zhao Shiyi S Zhu Yuanyuan Y Guo Dong D Yang Bo B Zhuo Lixia L Han Jiao J Wang Rui R Fang Zongping Z Dong Hailong H Li Yan Y Xiong Lize L

Neuroscience bulletin 20201013 12

General anesthesia severely affects the metabolites in the brain. Glycogen, principally stored in astrocytes and providing the short-term delivery of substrates to neurons, has been implicated as an affected molecule. However, whether glycogen plays a pivotal role in modulating anesthesia-arousal remains unclear. Here, we demonstrated that isoflurane-anesthetized mice exhibited dynamic changes in the glycogen levels in various brain regions. Glycogen synthase (GS) and glycogen phosphorylase (GP) ...[more]

PMID: 33048310

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Project description:BackgroundDelayed emergence after general anesthesia tends to occur in the elderly population, but the mechanism remains unclear. Apart from age-related pharmacokinetic changes, the aging-induced structural and functional alterations in the arousal-promoting neural substrates should be considered. The nucleus accumbens (NAc) is a crucial arousal-related nucleus, in which activating medium spiny neurons (MSNs) expressing dopamine D1 receptor (D1R) could facilitate the arousal from natural sleep. Meanwhile, the dopaminergic systems decline with aging in multiple brain regions. However, whether the age-related decline in D1R in the NAc shell attenuates its arousal-promoting capacity from general anesthesia remains to be elucidated.MethodsWe first verified the delayed emergence from isoflurane anesthesia and examined the corresponding changes of electroencephalogram (EEG) power in aged mice. In turn, the arousal-modulating capacity of D1R was characterized in the young and aged cohorts by microinjection of D1R agonist/antagonist into the NAc shell. Furthermore, to address the possible mechanism responsible for the attenuated arousal-modulating capacity of the aged NAc, the expression of D1R in the NAc shell was measured and compared between young and aged mice.ResultsOur data indicated that compared with young mice, the emergence time in aged mice was notably longer, while EEG power in δ band (1-4Hz) was significantly higher and power in β band (12-25Hz) was lower. Activating or inhibiting D1R in the NAc shell by microinjection D1R agonist/antagonist promoted or delayed the emergence process in young mice. Nevertheless, this modulation capacity of D1R in the NAc shell declined in aged mice, respectively. Meanwhile, downregulation of D1R expression in the NAc shell was detected in the aged brain.ConclusionTogether, these results suggest that aging attenuates the arousal-modulating capacity of D1R in the NAc shell probably through downregulation of D1R expression therein, which may provide a potential explanation and a therapeutic target for increased sensitivity to anesthetics in the elderly patients.

Project description:This study demonstrates that in mice subjected to hypoxia-ischemia (HI) brain injury isoflurane anesthesia initiated upon reperfusion limits a release of mitochondrial oxidative radicals by inhibiting a recovery of complex-I dependent mitochondrial respiration. This significantly attenuates an oxidative stress and reduces the extent of HI brain injury. Neonatal mice were subjected to HI, and at the initiation of reperfusion were exposed to isoflurane with or without mechanical ventilation. At the end of HI and isoflurane exposure cerebral mitochondrial respiration, H2O2 emission rates were measured followed by an assessment of cerebral oxidative damage and infarct volumes. At 8 weeks after HI navigational memory and brain atrophy were assessed. In vitro, direct effect of isoflurane on mitochondrial H2O2 emission was compared to that of complex-I inhibitor, rotenone. Compared to controls, 15 minutes of isoflurane anesthesia inhibited recovery of the compex I-dependent mitochondrial respiration and decreased H2O2 production in mitochondria supported with succinate. This was associated with reduced oxidative brain injury, superior navigational memory and decreased cerebral atrophy compared to the vehicle-treated HI-mice. Extended isoflurane anesthesia was associated with sluggish recovery of cerebral blood flow (CBF) and the neuroprotection was lost. However, when isoflurane anesthesia was supported with mechanical ventilation the CBF recovery improved, the event associated with further reduction of infarct volume compared to HI-mice exposed to isoflurane without respiratory support. Thus, in neonatal mice brief isoflurane anesthesia initiated at the onset of reperfusion limits mitochondrial release of oxidative radicals and attenuates an oxidative stress. This novel mechanism contributes to neuroprotective action of isoflurane. The use of mechanical ventilation during isoflurane anesthesia counterbalances negative effect of isoflurane anesthesia on recovery of cerebral circulation which potentiates protection against reperfusion injury.

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Dynamic Variations in Brain Glycogen are Involved in Modulating Isoflurane Anesthesia in Mice.

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Dynamic Variations in Brain Glycogen are Involved in Modulating Isoflurane Anesthesia in Mice.

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