Modern anesthetic compounds and advanced monitoring tools have revolutionized the field of medicine, allowing for complex surgical procedures to occur safely and effectively. Faster induction times and quicker recovery periods of current anesthetic agents have also helped reduce health care costs significantly. Moreover, extensive research has allowed for a better understanding of anesthetic modes of action, thus facilitating the development of more effective and safer compounds. Notwithstanding the realization that anesthetics are a prerequisite to all surgical procedures, evidence is emerging to support the notion that exposure of the developing brain to certain anesthetics may impact future brain development and function. Whereas the data in support of this postulate from human studies is equivocal, the vast majority of animal research strongly suggests that anesthetics are indeed cytotoxic at multiple brain structure and function levels. In this review, we first highlight various modes of anesthetic action and then debate the evidence of harm from both basic science and clinical studies perspectives. We present evidence from animal and human studies vis-à-vis the possible detrimental effects of anesthetic agents on both the young developing and the elderly aging brain while discussing potential ways to mitigate these effects. We hope that this review will, on the one hand, invoke debate vis-à-vis the evidence of anesthetic harm in young children and the elderly, and on the other hand, incentivize the search for better and less toxic anesthetic compounds.
Anesthetics are deemed necessary for all major surgical procedures. However, they have also been found to exert neurotoxic effects when tested on various experimental models, but the underlying mechanisms remain unknown. Earlier studies have implicated mitochondrial fragmentation as a potential target of anesthetic-induced toxicity, although clinical strategies to protect their structure and function remain sparse. Here, we sought to determine if preserving mitochondrial networks with a non-toxic, short-life synthetic peptide—P110, would protect cortical neurons against both inhalational and intravenous anesthetic-induced neurotoxicity. This study provides the first direct and comparative account of three key anesthetics (desflurane, propofol, and ketamine) when used under identical conditions, and demonstrates their impact on neonatal, rat cortical neuronal viability, neurite outgrowth and synaptic assembly. Furthermore, we discovered that inhibiting Fis1-mediated mitochondrial fission reverses anesthetic-induced aberrations in an agent-specific manner. This study underscores the importance of designing mitigation strategies invoking mitochondria-mediated protection from anesthetic-induced toxicity in both animals and humans.
The incidence of depression among humans is growing worldwide, and so is the use of selective serotonin reuptake inhibitors (SSRIs), such as sertraline hydrochloride. Our fundamental understanding regarding the mechanisms by which these antidepressants function and their off-target synaptic effects remain poorly defined, owing to the complexity of the mammalian brain. As all brain functions rely on proper synaptic connections between neurons, we examined the effect of sertraline on synaptic transmission, short-term potentiation underlying synaptic plasticity and synapse formation using identified neurons from the mollusk Lymnaea stagnalis. Through direct electrophysiological recordings, made from soma-soma paired neurons, we demonstrate that whereas sertraline does not affect short-term potentiation, it reduces the efficacy of synaptic transmission at both established and newly formed cholinergic synapses between identified neurons. Furthermore, Lymnaea neurons cultured in the presence of sertraline exhibited a decreased incidence of synaptogenesis. Our study provides the first direct functional evidence that sertraline exerts non-specific effects—outside of its SSRI role—when examined at the resolution of single pre- and post-synaptic neurons.
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