From neurotoxicity to neuroprotection: Rethinking GABA_AR-targeting anesthetics

The brain growth spurt (BGS) represents a pivotal window in neurodevelopment, defined by rapid neurogenesis, heightened synaptogenesis, and the dynamic establishment of neural networks. During this phase, heightened brain plasticity significantly enhances learning and memory abilities, while also increasing the brain's susceptibility to disruptions. Anesthetics, particularly those targeting γ-aminobutyric acid type A receptors (GABA_ARs), interfere with GABAergic and glutamatergic systems, disrupt brain-derived neurotrophic factor (BDNF) signaling, and exacerbate neurotoxic effects. These agents activate glial cells, induce inflammation, and contribute to oxidative stress, while also disrupting calcium homeostasis and triggering endoplasmic reticulum stress. Furthermore, anesthetics alter the expression of non-coding RNAs, which affects gene regulation and long-term memory formation. The extent of neurotoxic effects is contingent upon a constellation of factors, including the timing, dosage, and frequency of anesthetic exposure, as well as individual susceptibility. Notably, perioperative administration of anesthetic agents has been implicated in long-term cognitive dysfunction, thereby emphasizing the critical importance of precisely modulated dosing regimens and temporally optimized delivery strategies to mitigate potential neurodevelopmental risks. In contrast, neuroactive steroids demonstrate promising neuroprotective potential by modulating GABA_AR activity, enhancing BDNF release, and regulating oxidative stress and inflammation. New strategies for preventing and reversing anesthetic-induced neurotoxicity could include novel anesthetic combinations, anti-apoptotic agents, antioxidants, or nutritional supplements. These findings underscore the complex and multifactorial effects of anesthetic agents on the developing brain and emphasize the urgent need to establish and refine anesthetic strategies that safeguard neural integrity during vulnerable windows of neurodevelopment.