Inhalational Anesthetics Induce Neuronal Protein Aggregation and Affect ER Trafficking

Abstract

Anesthetic agents have been implicated in the causation of neurological and cognitive deficits after surgery, the exacerbation of chronic neurodegenerative disease, and were recently reported to promote the onset of the neurologic respiratory disease Congenital Central Hypoventilation Syndrome (CCHS), related to misfolding of the transcription factor Phox2B. To study how anesthetic agents could affect neuronal function through alterations to protein folding, we created neuronal cell models emulating the graded disease severity of CCHS. We found that the gas anesthetic isoflurane and the opiate morphine potentiated aggregation and mislocalization of Phox2B variants, similar to that seen in CCHS, and observed transcript and protein level changes consistent with activation of the endoplasmic reticulum (ER) unfolded protein response. Attenuation of ER stress pathways did not result in a correction of Phox2B misfolding, indicating a primary effect of isoflurane on protein structure. We also observed that isoflurane hindered the folding and activity of proteins that rely heavily on ER function, like the CFTR channel. Our results show how anesthetic drugs can alter protein folding and induce ER stress, indicating a mechanism by which these agents may affect neuronal function after surgery.

Singular and short-term anesthesia exposure in the developing brain induces persistent neuronal changes consistent with chronic neurodegenerative disease

“…A lack of anti-oxidant response proteins in the face of oxidative stress has previously been observed following acute GA exposure, which led to the suggestion that SOD2 may represent a specific anesthesia target 10,29 . Alteration of the mtUPR is consistent with our previously published findings that illustrated how gas anesthetics alter protein folding and induce endoplasmic reticulum stress 36 . Many neurological disorders exhibit intracellular depositions of misfolded protein aggregates, and increases in mtUPR transcriptional regulators is one of the earliest phenotypic changes observed in chronic neurodegenerative diseases 37 .…”

Combination of Isoflurane and Propofol as General Anesthesia During Orthopedic Surgery of Perioperative Cerebral Hypoperfusion Rats to Avoid Cognitive Impairment

“…Inhibition of ER stress overactivation contributed to the relief of isoflurane-induced histopathologic changes (61). Moreover, Coghlan et al confirmed that the induction of ER stress by isoflurane (treatment at a dose of 1.1% for 4 h) occurred after the initiation of protein misfolding (62). These results indicate that cytotoxicity of isoflurane is in a dose-dependent way and related to ER stress.…”

Research Advances on Therapeutic Approaches to Congenital Central Hypoventilation Syndrome (CCHS)

“…It is worth noting that the in vivo aggregation of PHOX2B protein has not been reported so far, and so the role of aggregates and their toxic effects in CCHS is unclear. In favor of the aggregation theory, there is the finding that anesthetic agents can promote LO-CCHS, by inducing aggregation and mislocalization of PHOX2B variants via the endoplasmic reticulum (ER) unfolded protein response (UPR) ( Basu et al, 2017 ; Coghlan et al, 2018 ).…”