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Published on: January 11, 2013
mTOR-mediated autophagy in the hippocampus is involved in perioperative neurocognitive disorders in diabetic rats
Xiaohui Chen1, Fei Gao1, Cuicui Lin2
1Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China.
Introduction:
Perioperative neurocognitive disorders (PND) are common neurological complications after surgery. Diabetes mellitus (DM) has been reported to be an independent risk factor for PND, but little is known about its mechanism of action. Mammalian target of rapamycin (mTOR) signaling is crucial for neuronal growth, development, apoptosis, and autophagy, but the dysregulation of mTOR signaling leads to neurological disorders. The present study investigated whether rapamycin can attenuate PND by inhibiting mTOR and activating autophagy in diabetic rats.
Methods:
Male diabetic Sprague-Dawley rats underwent tibial fracture surgery under isoflurane anesthesia to establish a PND model. Cognitive functions were examined using the Morris water maze test. The levels of phosphorylated mTOR (p-mTOR), phosphorylated tau (p-tau), autophagy-related proteins (Beclin-1, LC3), and apoptosis-related proteins (Bax, Bcl-2, cleaved caspase-3) in the hippocampus were examined on postoperative days 3, 7, and 14 by Western blot. Hippocampal amyloid β (Aβ) levels were examined by immunohistochemistry.
Results:
The data showed that surgical trauma and/or DM impaired cognitive function, induced mTOR activation, and decreased Beclin-1 levels and the LC3-II/I ratio. The levels of Aβ and p-tau and the hippocampal apoptotic responses were significantly higher in diabetic or surgery-treated rats than in control rats and were further increased in diabetic rats subjected to surgery. Pretreatment of rats with rapamycin inhibited mTOR hyperactivation and restored autophagic function, effectively decreasing tau hyperphosphorylation, Aβ deposition, and apoptosis in the hippocampus. Furthermore, surgical trauma-induced neurocognitive disorders were also reversed by pretreatment of diabetic rats with rapamycin.
Conclusion:
The results demonstrate that mTOR hyperactivation regulates autophagy, playing a critical role in the mechanism underlying PND, and reveal that the modulation of mTOR signaling could be a promising therapeutic strategy for PND in patients with diabetes.
Insights
Rapamycin treatment reversed neurocognitive deficits in diabetic rats after surgery by inhibiting mTOR signaling and enhancing autophagy. This suggests targeting mTOR is a potential therapy for preventing perioperative neurocognitive disorders in diabetic patients.
Area of Science:
- Neuroscience
- Endocrinology
- Pharmacology
Background:
- Perioperative neurocognitive disorders (PND) are common after surgery, with diabetes mellitus (DM) as a risk factor.
- The exact mechanism linking DM to PND is unclear, but mammalian target of rapamycin (mTOR) signaling dysregulation is implicated in neurological disorders.
Purpose of the Study:
- To investigate if rapamycin can reduce PND in diabetic rats by inhibiting mTOR and activating autophagy.
- To explore the role of mTOR signaling in the pathogenesis of PND in the context of diabetes.
Main Methods:
- Diabetic rats underwent tibial fracture surgery to model PND.
- Cognitive function was assessed using the Morris water maze test.
- Hippocampal levels of p-mTOR, p-tau, autophagy proteins (Beclin-1, LC3), apoptosis markers (Bax, Bcl-2, cleaved caspase-3), and amyloid-beta (Aβ) were analyzed via Western blot and immunohistochemistry.
Main Results:
- Surgery and/or DM impaired cognitive function, increased mTOR activation, and reduced autophagy.
- Diabetic rats subjected to surgery showed elevated Aβ, p-tau, and apoptosis.
- Rapamycin pretreatment inhibited mTOR, restored autophagy, and reduced Aβ, p-tau, and apoptosis, reversing PND.
Conclusions:
- mTOR hyperactivation critically regulates autophagy in PND pathogenesis.
- Modulating mTOR signaling represents a promising therapeutic strategy for PND in diabetic individuals.
