Isoflurane Enhances Autophagy by Activating AMPK/ULK1, Inhibits NLRP3, and Reduces Cognitive Impairment After Cerebral Ischemia–Reperfusion Injury in Rats

Zhai, Jingwen; Li, Nian; Zhang, Xu; Li, Yan; Ma, Ketao; Qin, Xinlei; Yin, Jiangwen; Wang, Sheng

doi:10.1007/s12031-023-02135-w

Cited by 6 publications

(4 citation statements)

References 38 publications

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“…TASK-1/3 potassium channels are strongly expressed in neurons throughout the CNS ( Talley et al, 2001 ; Fan et al, 2022 ) as well as in mitochondria ( Szewczyk et al, 2009 ). Numerous studies have found isoflurane to have neuroprotective and cardioprotective properties in various injury models through actions on TASK-1/3 and other potassium channels ( Liu et al, 2005 ; Park et al, 2005 ; Khatibi et al, 2011 ; Taheri et al, 2014 ; Altay et al, 2020 ; Zhai et al, 2023 ). Studies on TASK-1 and TASK-3 knockout mice suggest that TASK-3 channels are the potassium channels most involved in the anesthetic actions of halogenated ethers including halothane and isoflurane ( Pang et al, 2009 ) and mutagenesis studies have provided support for this conclusion ( Luethy et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Brief isoflurane administration as an adjunct treatment to control organophosphate-induced convulsions and neuropathology

Puthillathu,

Moffett,

Korotcov

et al. 2023

Front. Pharmacol.

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Organophosphate-based chemical agents (OP), including nerve agents and certain pesticides such as paraoxon, are potent acetylcholinesterase inhibitors that cause severe convulsions and seizures, leading to permanent central nervous system (CNS) damage if not treated promptly. The current treatment regimen for OP poisoning is intramuscular injection of atropine sulfate with an oxime such as pralidoxime (2-PAM) to mitigate cholinergic over-activation of the somatic musculature and autonomic nervous system. This treatment does not provide protection against CNS cholinergic overactivation and therefore convulsions require additional medication. Benzodiazepines are the currently accepted treatment for OP-induced convulsions, but the convulsions become refractory to these GABAA agonists and repeated dosing has diminishing effectiveness. As such, adjunct anticonvulsant treatments are needed to provide improved protection against recurrent and prolonged convulsions and the associated excitotoxic CNS damage that results from them. Previously we have shown that brief, 4-min administration of 3%–5% isoflurane in 100% oxygen has profound anticonvulsant and CNS protective effects when administered 30 min after a lethal dose of paraoxon. In this report we provide an extended time course of the effectiveness of 5% isoflurane delivered for 5 min, ranging from 60 to 180 min after a lethal dose of paraoxon in rats. We observed substantial effectiveness in preventing neuronal loss as shown by Fluoro-Jade B staining when isoflurane was administered 1 h after paraoxon, with diminishing effectiveness at 90, 120 and 180 min. In vivo magnetic resonance imaging (MRI) derived T2 and mean diffusivity (MD) values showed that 5-min isoflurane administration at a concentration of 5% prevents brain edema and tissue damage when administered 1 h after a lethal dose of paraoxon. We also observed reduced astrogliosis as shown by GFAP immunohistochemistry. Studies with continuous EEG monitoring are ongoing to demonstrate effectiveness in animal models of soman poisoning.

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Section: Discussionmentioning

confidence: 99%

Brief isoflurane administration as an adjunct treatment to control organophosphate-induced convulsions and neuropathology

Puthillathu,

Moffett,

Korotcov

et al. 2023

Front. Pharmacol.

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“…These pro-inflammatory factors can cross the placenta and the immature fetal blood-brain barrier and reach the fetal brain, where they induce an inflammatory response after birth (Entringer et al, 2010;Zhao et al, 2015). A previous study found that isoflurane exposure downregulated the pro-inflammatory factors (such as in rats suffering from cerebral ischemia-reperfusion injury, and improved neuroinflammation and cognitive function (Zhai et al, 2023). However, one study showed that IL-6 was significantly upregulated in the brains of offspring mice exposed to sevoflurane for 3 h on GD15.5, and this was accompanied by learning impairment, as assessed in the Y-maze test (Hirotsu et al, 2019).…”

Section: Maternal Sleep Deprivation Exacerbates the Neuroinflammation...mentioning

confidence: 99%

Subsequent maternal sleep deprivation aggravates cognitive impairment by modulating hippocampal neuroinflammatory responses and synaptic function in maternal isoflurane‐exposed offspring mice

Zhang,

Wei,

Jing

et al. 2024

Brain and Behavior

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IntroductionPregnant women may need to undergo non‐obstetric surgery under general anesthesia owing to medical needs, and pregnant women frequently experience sleep disturbances during late gestation. Preclinical studies demonstrated that maternal isoflurane exposure (MISO) or maternal sleep deprivation (MSD) contributed to cognitive impairments in offspring. Research studies in mice have revealed that SD can aggravate isoflurane‐induced cognitive deficits. However, it remains unclear whether MSD aggravates MISO‐induced cognitive deficits in offspring. The purpose of this research was to explore the combined effects of MSD and MISO on offspring cognitive function and the role of neuroinflammation and synaptic function in the process of MSD + MISO.MethodsPregnant mice were exposed to 1.4% isoflurane by inhalation for 4 h on gestational day (GD) 14. Dams were then subjected to SD for 6 h (12:00–18:00 h) during GD15–21. At 3 months of age, the offspring mice were subjected to the Morris water maze test to assess cognitive function. Then the levels of inflammatory and anti‐inflammatory markers and synaptic function‐related proteins were assessed using molecular biology methods.ResultsThe results of this study demonstrated that MISO led to cognitive dysfunction, an effect that was aggravated by MSD. In addition, MSD exacerbated the maternal isoflurane inhalation, leading to an enhancement in the expression levels of interleukin (IL)‐1β, IL‐6, and tumor necrosis factor‐alpha and a reduction in the hippocampal levels of IL‐10, synaptophysin, post‐synaptic density‐95, growth‐associated protein‐43, and brain‐derived neurotrophic factor.ConclusionOur findings revealed that MSD aggravated the cognitive deficits induced by MISO in male offspring mice, and these results were associated with neuroinflammation and alternations in synaptic function.

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“…In ischemic stroke, the NLRP3-related protein expression that mitigates autophagy activation includes AMPK, mTOR, and ULK1. They have improved cognitive impairment and attenuated inflammation ( Huang et al, 2021 ; Zhai et al, 2023 ). SINO, an anti-inflammatory drug, inhibits AMPK-mediated NLRP3 inflammasome activation against ischemic-induced brain injury ( Qiu et al, 2016 ).…”

Section: The Nlrp3 Inflammasome and Its Function In Ischemic Strokementioning

confidence: 99%

Pharmacological intervention of curcumin via the NLRP3 inflammasome in ischemic stroke

Du,

Amin,

et al. 2023

Front. Pharmacol.

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Ischemic-induced neuronal injury arises due to low oxygen/nutrient levels and an inflammatory response that exacerbates neuronal loss. NOD-like receptor family pyrin domain-containing 3 (NLRP3) is an important regulator of inflammation after ischemic stroke, with its inhibition being involved in nerve regeneration. Curcumin, a main active ingredient in Chinese herbs, plays a positive role in neuronal repair and neuroprotection by regulating the NLRP3 signaling pathway. Nevertheless, the signaling mechanisms relating to how curcumin regulates NLRP3 inflammasome in inflammation and neural restoration following ischemic stroke are unknown. In this report, we summarize the main biological functions of the NLRP3 inflammasome along with the neuroprotective effects and underlying mechanisms of curcumin via impairment of the NLRP3 pathway in ischemic brain injury. We also discuss the role of medicinal interventions that target the NLRP3 and potential pathways, as well as possible directions for curcumin therapy to penetrate the blood–brain barrier (BBB) and hinder inflammation in ischemic stroke. This report conclusively demonstrates that curcumin has neuroprotective properties that inhibit inflammation and prevent nerve cell loss, thereby delaying the progression of ischemic brain damage.

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Isoflurane Enhances Autophagy by Activating AMPK/ULK1, Inhibits NLRP3, and Reduces Cognitive Impairment After Cerebral Ischemia–Reperfusion Injury in Rats

Cited by 6 publications

References 38 publications

Brief isoflurane administration as an adjunct treatment to control organophosphate-induced convulsions and neuropathology

Brief isoflurane administration as an adjunct treatment to control organophosphate-induced convulsions and neuropathology

Subsequent maternal sleep deprivation aggravates cognitive impairment by modulating hippocampal neuroinflammatory responses and synaptic function in maternal isoflurane‐exposed offspring mice

Pharmacological intervention of curcumin via the NLRP3 inflammasome in ischemic stroke

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