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Elamipretide (SS-31) Ameliorates Isoflurane-Induced Long-Term Impairments of Mitochondrial Morphogenesis and
Jing Wu1, Shuangying Hao2, Xiao-Ru Sun3
1Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing UniversityNanjing, China.
Abstract:
Mitochondria are supposed to be involved in the early pathogenesis of general anesthesia (GA)-induced neurotoxicity and long-term cognitive deficits in developing brains. However, effective pharmacologic agents targeted on mitochondria during GA exposure are lacking. This study explores the protective effects of mitochondrion-targeted antioxidant elamipretide (SS-31) on mitochondrial morphogenesis and cognition in developing rats exposed to isoflurane. Rat pups at postnatal day (PND) 7 were exposed to 1.5% isoflurane for 6 h following intraperitoneal administration of elamipretide or vehicle with 30 min interval. The hippocampus was immediately removed for biochemical assays. Histopathological studies were conducted at PND 21, and behavioral tests were performed at PND 40 or 60. We found that early exposure to isoflurane caused remarkable reactive oxygen species (ROS) accumulation, mitochondrial deformation and neuronal apoptosis in hippocampus. The injury occurrence ultimately gave rise to long-term cognitive deficits in developing rats. Interestingly, pretreatment with elamipretide not only provided protective effect against oxidative stress and mitochondrial damages, but also attenuated isoflurane-induced cognitive deficits. Our data support the notion that mitochondrial damage is an early and long lasting event of GA-induced injury and suggest that elamipretide might have clinically therapeutic benefits for pediatric patients undertaking GA.
Insights
Mitochondrion-targeted antioxidant elamipretide protects developing rat brains from anesthesia-induced neurotoxicity. Elamipretide (SS-31) reduced oxidative stress and improved cognitive function after isoflurane exposure.
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Anesthesiology
Background:
- Mitochondria play a role in general anesthesia (GA)-induced neurotoxicity and cognitive deficits in developing brains.
- Pharmacologic agents targeting mitochondria during GA are needed.
- Elamipretide (SS-31) is a mitochondrion-targeted antioxidant.
Purpose of the Study:
- To investigate the protective effects of elamipretide on mitochondrial function and cognition in developing rats exposed to isoflurane.
- To determine if elamipretide can prevent long-term cognitive deficits induced by GA.
Main Methods:
- Rat pups (postnatal day 7) received elamipretide or vehicle before isoflurane exposure (1.5% for 6 hours).
- Hippocampal tissues were analyzed for oxidative stress and mitochondrial damage.
- Histopathology and behavioral tests were conducted at later time points (PND 21, 40, 60).
Main Results:
- Isoflurane exposure caused increased reactive oxygen species (ROS), mitochondrial deformation, and neuronal apoptosis in the hippocampus.
- This injury led to long-term cognitive deficits in rats.
- Elamipretide pretreatment protected against oxidative stress and mitochondrial damage.
- Elamipretide attenuated isoflurane-induced cognitive deficits.
Conclusions:
- Mitochondrial damage is an early and persistent consequence of GA-induced injury in developing brains.
- Elamipretide demonstrates potential therapeutic benefits for pediatric patients undergoing GA.
- Targeting mitochondria with antioxidants like elamipretide may mitigate neurotoxicity from anesthesia.
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