mTOR-mediated autophagy in the hippocampus is involved in perioperative neurocognitive disorders in diabetic rats

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 beta (A beta) 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 A beta 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, A beta 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.

Automated summary

The study showed that pretreatment with rapamycin can inhibit mTOR hyperactivation, restore autophagic function, effectively reduce tau hyperphosphorylation, A beta deposition, and apoptosis in the hippocampus in diabetic rats with PND. Furthermore, surgical trauma-induced neurocognitive disorders in diabetic rats can also be reversed by pretreatment with rapamycin.