Introduction: Sevoflurane acts as a gamma-aminobutyric acid subtype A receptor agonist and can induce widespread apoptosis of immature dentate granule cells in postnatal day 21 mice. The dentate granule cells of postnatal day 21 mice undergo a developmental stage when gamma-aminobutyric acid (GABA) shifts from inducing the depolarization of neurons to causing hyperpolarization. However, it is unclear whether sevoflurane induces apoptosis of immature granule cells by facilitating the depolarization or hyperpolarization of neurons. Methods:We utilized bumetanide, an Na + -K + -2Cl − cotransporter isoform 1 (NKCC1) antagonist, to determine whether the NKCC1-mediated GABA depolarization of neurons plays a role in sevoflurane-induced neuroapoptosis. We also investigated whether sevoflurane exposure is related to long-term cognitive dysfunction in postnatal day 21 mice and explored the possible protective effects of bumetanide.Results: Bumetanide attenuated the sevoflurane-induced apoptosis of dentate granule cells in postnatal day 21 mice. Exposure to sevoflurane at postnatal day 21 mice did not affect their motor ability or anxiety level, and it had no effect on spatial learning or memory functions. However, sevoflurane exposure at postnatal day 21 impaired the pattern separation ability in the contextual fear discrimination test; bumetanide mitigated this effect of sevoflurane as well. Conclusion:Bumetanide attenuates sevoflurane-induced apoptosis and is a promising prospect for protecting against anesthesia-induced neurotoxicity in the developing brain.
Ketamine (KET) and isoflurane (ISO) are two widely used general anesthetics, yet their distinct and shared neurophysiological mechanisms remain elusive. In this study, we conducted a comparative analysis of KET and ISO effects on c-Fos expression across the brain, utilizing principal component analysis (PCA) and c-Fos-based functional network analysis to evaluate the responses of individual brain regions to each anesthetic. Our findings demonstrate that KET significantly activates cortical and subcortical arousal-promoting nuclei, with the somatosensory cortex (SS) serving as a hub node, corroborating the top-down general anesthesia theory for dissociative anesthesia. In contrast, ISO activates the nuclei in the hypothalamus and brainstem, with the locus coeruleus (LC) as a hub node, implying a bottom-up mechanism for anesthetic-induced unconsciousness. Notably, the coactivation of sleep-wakefulness regulation, analgesia-related, neuroendocrine-related nuclei (e.g., prelimbic area (PL) and infralimbic areas (ILA), and the anterior paraventricular nucleus (aPVT), Edinger-Westphal nucleus (EW), locus coeruleus (LC), parabrachial nucleus (PB), solitary tract nucleus (NTS)) by both anesthetics underscores shared features such as unconsciousness, analgesia, and autonomic regulation, irrespective of their specific molecular targets. In conclusion, our results emphasize the distinct actions of KET and ISO while also uncovering the commonly activated brain regions, thus contributing to the advancement of our understanding of the mechanisms underlying general anesthesia.
Ketamine (KET) and isoflurane (ISO) are two widely used general anesthetics, yet their distinct and shared neurophysiological mechanisms remain elusive. In this study, we conducted a comparative analysis of KET and ISO effects on c-Fos expression across the brain, utilizing principal component analysis (PCA) and c-Fos-based functional network analysis to evaluate the responses of individual brain regions to each anesthetic. Our findings demonstrate that KET significantly activates cortical and subcortical arousal-promoting nuclei, with the somatosensory cortex (SS) serving as a hub node, corroborating the top-down general anesthesia theory for dissociative anesthesia. In contrast, ISO activates the nuclei in the hypothalamus and brain-stem, with the locus coeruleus (LC) as a hub node, implying a bottom-up mechanism for anesthetic-induced unconsciousness. Notably, the coactivation of sleep-wakefulness regulation, analgesia-related, neuroendocrine-related nuclei (e.g., prelimbic area (PL) and infralimbic areas (ILA), and the anterior paraventricular nucleus (aPVT), Edinger-Westphal nucleus (EW), locus coeruleus (LC), parabrachial nucleus (PB), solitary tract nucleus (NTS)) by both anesthetics underscores shared features such as unconsciousness, analgesia, and autonomic regulation, irrespective of their specific molecular targets. In conclusion, our results emphasize the distinct actions of KET and ISO while also uncovering the commonly activated brain regions, thus contributing to the advancement of our understanding of the mechanisms under-lying general anesthesia.
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