Rapamycin alleviates hypothalamic injury in exertional heat stroke rats by activating mitophagy through the mTOR/Pink1/Parkin pathway

Oct 23, 2025Scientific reports

Rapamycin helps protect the brain’s temperature-control area in heat stroke rats by boosting cell cleanup through the mTOR/Pink1/Parkin pathway

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Abstract

Rapamycin treatment significantly alleviated hypothalamic injury in rats subjected to .

Exertional heat stroke led to increased core temperatures in both EHS and EHS + RAPA groups.
RAPA treatment reduced pathological injury and apoptosis in hypothalamic tissue.
Levels of reactive oxygen species and malonaldehyde were decreased with RAPA treatment.
Mitochondrial membrane potential was enhanced in rats that received RAPA.
RAPA downregulated mTOR and p62, while upregulating Pink1 and Parkin in hypothalamic tissue.
RAPA treatment increased the LC3II/LC3I ratio and promoted interactions between LC3-Tom20 and Pink1-Parkin.

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(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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Rapamycin alleviates hypothalamic injury in exertional heat stroke rats by activating mitophagy through the mTOR/Pink1/Parkin pathway

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