Cellular and molecular mechanisms underlying anesthetic-induced cytotoxicity, and their impact on learning and memory
Date
2022-01
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Abstract
Anesthetics are required for most – if not all – clinical procedures, ranging from surgery to dentistry practices. However, the precise mechanisms underlying anesthetic modes of action remain to be fully defined. Moreover, notwithstanding their essential requirements for all surgical procedures, recent animal studies have raised concerns regarding anesthetic’s long-term cytotoxic effects – especially on the nervous tissue. I designed this study to first, search for potential sites of anesthetic toxicity, and then aimed to decipher potential mitigating strategies accordingly. To achieve my objectives both in vitro and in vivo rodent models were used. For the in vitro studies, frontal cortical and hippocampal neurons were extracted from rat pups at postnatal day zero, and these were then exposed to various clinically relevant concentrations of sevoflurane and dexmedetomidine (DEX). Specifically, I tested sevoflurane, to determine its effects on cell viability, growth, synapse formation, mitochondrial function and morphology using a variety of morphological and molecular tools. All of the above-mentioned aspects examined in this study were compromised by sevoflurane. Furthermore, the sevoflurane-induced effects were then compared with DEX, which is thought to be less toxic and deemed potentially neuroprotective. I found that indeed DEX was not only safer, but it also exerted neuroprotective effects, rescuing neurons from sevoflurane-induced cytotoxicity. To test for the effects of these compounds on long-term effects on learning and memory, I used a battery of memory tests, which included open field, Morris water maze, novel object recognition testing and contextual fear-conditioning. I discovered that sevoflurane exposure of the neonates compromised learning and memory in the adult animals in several subtle, albeit important ways. Some, but not all aspects of sevoflurane-induced learning and memory deficits were however rescued by DEX pre-treatment. Moreover, the expression patterns of a host of genes were also found to be specifically perturbed by sevoflurane. These data were then correlated with the observed effects on cellular viability and learning and memory. This study thus underscores the importance of re-examining our position vis-à-vis the long-term effects of anesthetic exposure on the developing brain and invoking behavioural enrichment strategies in instances where anesthetic use becomes unavoidable.
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Keywords
Anesthetics, Sevoflurane, Dexmedetomidine, Cognition, Behaviour, Mitochondria, Neuron
Citation
Jimenez Tellez, N. (2022). Cellular and molecular mechanisms underlying anesthetic-induced cytotoxicity, and their impact on learning and memory (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.