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Isoflurane Aggravates Pre-Existing Proteotoxicity in Adult Nematodes by Suppressing Mitochondrial Fitness

ABSTRACT: Post operative delirium (POD) is an acute complication characterized by fluctuating attention and confusion which may develop and persist into cognitive decline. POD is most commonly observed in elderly patients, particularly those with preexisting cognitive impairments. Isoflurane, as a widely used volatile anesthetic, is associated with POD. Utilizing the nematode C. elegans, we found that isoflurane enhances protein aggregation and long-lasting decline in protein homeostasis (proteostasis) of adult animals that express neurodegeneration-causing, abnormally long poly-glutamine stretches. Isoflurane-induced proteostasis impairments are dependent on the aging-regulating transcription factors DAF- 16/FOXO and SKN-1/NRF. We also show that reducing the activity of a certain components of the mitophagy mechanism and inducing mitochondrial biogenesis protect worms that exhibit weakened proteostasis, from isoflurane-induced proteotoxicity. Our observations provide novel insights into the mechanism that links isoflurane and POD, and highlight the potential of mitophagy modulators as alleviators of POD in elder patients with preexisting cognitive impairments.

INSTRUMENT(S):

ORGANISM(S): Caenorhabditis Elegans

TISSUE(S): Whole Body

SUBMITTER: Tayir Elami

LAB HEAD: Ehud Cohen

PROVIDER: PXD054547 | Pride | 2025-09-13

REPOSITORIES: Pride

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	20230124-T1-04.raw	Raw
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	20230124-T12-28.raw	Raw

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Isoflurane Aggravates Pre-Existing Proteotoxicity in Adult Nematodes by Modulating Mitophagy

Project description:Post operative delirium (POD) is an acute complication characterized by fluctuating attention and confusion which may develop and persist into cognitive decline. POD is most commonly observed in elderly patients, particularly those with preexisting cognitive impairments. Isoflurane, as a widely used volatile anesthetic, is associated with POD. Utilizing the nematode C. elegans, we found that isoflurane enhances protein aggregation and long-lasting decline in protein homeostasis (proteostasis) of adult animals that express neurodegeneration-causing, abnormally long poly-glutamine stretches. Isoflurane-induced proteostasis impairments are dependent on the aging-regulating transcription factors DAF-16/FOXO and SKN-1/NRF. We also show that reducing the activity of a certain mitophagy mechanism and inducing mitochondrial biogenesis protect worms that exhibit weakened proteostasis, from isoflurane-induced proteotoxicity. Our observations provide a novel insight into the mechanism that links isoflurane and POD, and highlight the potential of mitophagy modulators as alleviators of POD in elder patients with preexisting cognitive impairments.

2025-08-01 | GSE272857 | GEO

Transcriptional effects of a 6h treatment with 2% isoflurane in the anterior cingulate cortex of the 24h old neonatal piglet brain

Project description:Exposure of the developing brain to general anesthesia during early infancy may adversely affect its neural and cognitive development. In a range of animal species early developmental exposure to general anaesthesia without surgery, induces an increase in brain cell death, reductions in neuro and synapto-genesis, a disruption to the expression of cognitively salient genes and deficits in cognitive function that persist throughout life. We examined the effects of the anesthetic isoflurane (2% concentration for 6h) without surgery on gene expression in the anterior cingulate cortex of the neonatal male piglet brain. The developing piglet brain demonstrates remarkable neurodevelopmental similarities to that seen in the human infant, which has led to extensive use as models of perinatal neural injury. Isoflurane induced significant disruption to the expression of 79 gene transcripts, of these 26 are important for the control of transcription and 23 are important for the mediation of neural plasticity, memory formation and recall. Overall this data may suggest novel additional mechanisms by which isoflurane may induce adverse neural and cognitive development by disrupting the expression of genes mediating activity dependent development of neural circuits, the predictive adaptive responses of the brain, memory formation and recall.

2016-10-04 | E-MTAB-5129 | biostudies-arrayexpress

Cathepsin B Promotes Aβ Proteotoxicity by Modulating Aging Regulating Mechanisms

Project description:While the activities of certain proteases promote proteostasis and prevent neurodegeneration-associated phenotypes, the protease cathepsin B (CTSB) enhances proteotoxicity in Alzheimer’s disease (AD) model mice, and its levels are elevated in brains of AD patients. How CTSB exacerbates the toxicity of the ADcausing Amyloid β (Aβ), is controversial. Using an activity-based probe, aging-altering interventions and the nematode C. elegans we discovered that the CTSB CPR-6 promotes Aβ proteotoxicity but mitigates the toxicity of polyQ stretches. While the knockdown of cpr-6 does not affect lifespan, it alleviates Aβ toxicity by reducing the expression of swsn-3 and elevating the level of the protein SMK-1, both involved in the regulation of aging. These observations unveil a novel mechanism by which CTSB aggravates Aβ– mediated toxicity, indicate that it plays opposing roles in the face of distinct proteotoxic insults and highlight the importance of tailoring specific remedies for distinct neurodegenerative disorders.

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single nucleous RNAseq data from brain tissue provided from patients undergoing neurosurgery

Project description:We have employed a single nucleous sequencing approach using 10x Genomics platform to investigate the pathophysiology of post-operative delirium (POD). POD is related to high mortality and long-term cognitive failure, but its mechanism is still unclear. This study represents the first transcriptome analysis of POD brain and provide new insight into POD pathology and prediction.

2025-03-19 | GSE291019 | GEO

DNA methylation data from brain tissue provided from patients undergoing neurosurgery

Project description:We have employed DNA methylation analysis using resected brain tissues from patients with epilepsy to investigate the pathophysiology of post-operative delirium (POD). POD is related to high mortality and long-term cognitive failure, but its mechanism is still unclear. This study represents the first transcriptome analysis of POD brain and provide new insight into POD pathology and prediction.

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2023-10-25 | PXD043738 | Pride

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