Transforming Growth Factor β1 Ameliorates Microglial Activation in Perioperative Neurocognitive Disorders

Perioperative neurocognitive disorder (PND) is a common complication of surgery and anesthesia, especially among older patients. Microglial activation plays a crucial role in the occurrence and development of PND and transforming growth factor beta 1 (TGF-β1) can regulate microglial homeostasis. In the present study, abdominal surgery was performed on 12-14 months-old C57BL/6 mice to establish a PND model. The expression of TGF-β1, TGF-β receptor 1, TGF-β receptor 2, and phosphor-smad2/smad3 (psmad2/smad3) was assessed after anesthesia and surgery. Additionally, we examined changes in microglial activation, morphology, and polarization, as well as neuroinflammation and dendritic spine density in the hippocampus. Behavioral tests, including the Morris water maze and open field tests, were used to examine cognitive function, exploratory locomotion, and emotions. We observed decreased TGF-β1 expression after surgery and anesthesia. Intranasally administered exogenous TGF-β1 increased psmad2/smad3 colocalization with microglia positive for ionized calcium-binding adaptor molecule 1. TGF-β1 treatment attenuated microglial activation, reduced microglial phagocytosis, and reduced surgery- and anesthesia-induced changes in microglial morphology. Compared with the surgery group, TGF-β1 treatment decreased M1 microglial polarization and increased M2 microglial polarization. Additionally, surgery- and anesthesia-induced increase in interleukin 1 beta and tumor necrosis factor-alpha levels was ameliorated by TGF-β1 treatment at postoperative day 3. TGF-β1 also ameliorated cognitive function after surgery and anesthesia as well as rescue dendritic spine loss. In conclusion, surgery and anesthesia induced decrease in TGF-β1 levels in older mice, which may contribute to PND development; however, TGF-β1 ameliorated microglial activation and cognitive dysfunction in PND mice.