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Ferroptosis contributes to isoflurane-induced neurotoxicity and learning and memory impairment
Pengfei Liu1,2, Jing Yuan1, Yetong Feng3
1Ambulatory Surgical Center, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), 518020, Shenzhen, China.
Abstract:
Ferroptosis is a novel type of programmed cell death, which is different from apoptosis and autophagic cell death. Recently, ferroptosis has been indicated to contribute to the in vitro neurotoxicity induced by isoflurane, which is one of the most common anesthetics in clinic. However, the in vivo position of ferroptosis in isoflurane-induced neurotoxicity as well as learning and memory impairment remains unclear. In this study, we mainly explored the relationship between ferroptosis and isoflurane-induced learning and memory, as well as the therapeutic methods in mouse model. Our results indicated that isoflurane induced the ferroptosis in a dose-dependent and time-dependent manner in hippocampus, the organ related with learning and memory ability. In addition, the activity of cytochrome c oxidase/Complex IV in mitochondrial electron transport chain (ETC) was increased by isoflurane, which might further contributed to cysteine deprivation-induced ferroptosis caused by isoflurane exposure. More importantly, isoflurane-induced ferroptosis could be rescued by both ferroptosis inhibitor (ferrostatin-1) and mitochondria activator (dimethyl fumarate), which also showed effective therapeutic action against isoflurane-induced learning and memory impairment. Taken together, our data indicate the close association among ferroptosis, mitochondria and isoflurane, and provide a novel insight into the therapy mode against isoflurane-induced learning and memory impairment.
Insights
Isoflurane anesthesia triggers ferroptosis, a cell death pathway, in the mouse hippocampus. Inhibiting ferroptosis or activating mitochondria protects against isoflurane-induced memory deficits.
Area of Science:
- Neuroscience
- Cell Biology
- Pharmacology
Background:
- Ferroptosis is a distinct form of programmed cell death.
- Isoflurane, a common anesthetic, causes in vitro neurotoxicity linked to ferroptosis.
- The in vivo role of ferroptosis in isoflurane-induced neurotoxicity and memory impairment is not well understood.
Purpose of the Study:
- To investigate the relationship between ferroptosis and isoflurane-induced learning and memory deficits in a mouse model.
- To explore potential therapeutic strategies targeting ferroptosis for isoflurane-induced neurotoxicity.
Main Methods:
- Mice were exposed to varying doses and durations of isoflurane.
- Ferroptosis markers and mitochondrial activity (cytochrome c oxidase/Complex IV) in the hippocampus were assessed.
- The effects of ferrostatin-1 (ferroptosis inhibitor) and dimethyl fumarate (mitochondria activator) were evaluated.
Main Results:
- Isoflurane induced ferroptosis in the hippocampus in a dose- and time-dependent manner.
- Isoflurane increased mitochondrial electron transport chain (ETC) Complex IV activity, potentially exacerbating cysteine deprivation-induced ferroptosis.
- Ferrostatin-1 and dimethyl fumarate treatment rescued isoflurane-induced ferroptosis and ameliorated learning and memory impairment.
Conclusions:
- Ferroptosis is closely associated with isoflurane-induced neurotoxicity and memory impairment in vivo.
- Mitochondrial dysfunction plays a role in isoflurane-induced ferroptosis.
- Targeting ferroptosis or activating mitochondria offers a promising therapeutic approach for mitigating isoflurane's adverse cognitive effects.
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