Rapamycin may reduce hypothalamic injury after by promoting Pink1/Parkin-mediated mitophagy.
Evidence
In a four-arm preclinical rat experiment with 10 male Sprague-Dawley rats per group, rapamycin improved histology, apoptosis markers, ROS/MDA, mitochondrial membrane potential, and mitophagy-pathway readouts after EHS.
Caveat
The evidence is limited to male rats and mechanistic hypothalamic endpoints, so it does not establish clinical benefit in human heat stroke.
Simplified
(EHS) causes severe central nervous system damage, with mitochondrial dysfunction and oxidative stress playing major roles. Mitophagy, regulated by the Pink1/Parkin pathway, removes damaged mitochondria. Here, we investigated the potential of rapamycin (RAPA) to reduce hypothalamic injury in rats subjected to EHS. Forty healthy male Sprague-Dawley rats were randomly assigned to control, RAPA, EHS, and EHS + RAPA groups (10 rats each). Core temperatures were measured, and survival curves were generated. Hypothalamic tissue underwent hematoxylin-eosin and Nissl staining for histopathological assessment. Hypothalamic mitochondrial membrane potential, reactive oxygen species (ROS), and malonaldehyde (MDA) levels were measured. Western blotting assessed mammalian target of RAPA (mTOR), phosphorylated mTOR, Pink1, Parkin, P62, and microtubule-associated protein 1 Light chain 3 (LC3) expression, and calculated the LC3II/LC3I ratio. Immunofluorescence evaluated Pink1-Parkin and LC3-Tom20 co-localization in hypothalamic tissue. EHS and EHS + RAPA groups showed markedly increased core temperatures. RAPA mitigated pathological injury and apoptosis, reduced ROS and MDA levels, and enhanced mitochondrial membrane potential. It downregulated mTOR and p62 levels, upregulated Pink1 and Parkin, increased LC3II/LC3I ratio, and promoted LC3-Tom20 and Pink1-Parkin interactions in the hypothalamic tissue of rats treated with EHS, thereby alleviating hypothalamic injury and preserving hypothalamic function.
Key numbers
< 0.0001
Decrease in Apoptotic Index
Apoptotic index in + group vs. group
< 0.05
Increase in LC3II/LC3I Ratio
LC3II/LC3I ratio in + group vs. group
< 0.0001
Decrease in Levels
levels in + group vs. group
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