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Glycogen Synthase Kinase 3β Promotes Postoperative Cognitive Dysfunction by Inducing the M1 Polarization and
Jingjin Li1, Chonglong Shi1, Zhengnian Ding1
1Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Abstract:
Postoperative cognitive dysfunction (POCD) is a common postoperative central nervous system complication, especially in the elderly. It has been consistently reported that the pathological process of this clinical syndrome is related to neuroinflammation and microglial proliferation. Glycogen synthase kinase 3β (GSK-3β) is a widely expressed kinase with distinct functions in different types of cells. The role of GSK-3β in regulating innate immune activation has been well documented, but as far as we know, its role in POCD has not been fully elucidated. Lithium chloride (LiCl) is a widely used inhibitor of GSK-3β, and it is also the main drug for the treatment of bipolar disorder. Prophylactic administration of lithium chloride (2 mM/kg) can inhibit the expression of proinflammatory mediators in the hippocampus, reduce the hippocampal expression of NF-κB, and increase both the downregulation of M1 microglial-related genes (inducible nitric oxide synthase and CD86) and upregulation of M2 microglial-related genes (IL-10 and CD206), to alleviate the cognitive impairment caused by orthopedic surgery. In vitro, LiCl reversed LPS-induced production of proinflammatory mediators and M1 polarization of microglia. To sum up these results, GSK-3β is a key contributor to POCD and a potential target of neuroprotective strategies.
Insights
Glycogen synthase kinase 3 beta (GSK-3β) inhibition with lithium chloride reduces neuroinflammation and alleviates cognitive impairment after surgery. This suggests GSK-3β is a key target for treating postoperative cognitive dysfunction.
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Postoperative cognitive dysfunction (POCD) is a frequent central nervous system complication, particularly in elderly patients.
- Neuroinflammation and microglial proliferation are implicated in the pathology of POCD.
- Glycogen synthase kinase 3 beta (GSK-3β) plays a role in innate immune activation, but its specific role in POCD is not fully understood.
Purpose of the Study:
- To investigate the role of GSK-3β in POCD.
- To evaluate the neuroprotective effects of lithium chloride (LiCl), a GSK-3β inhibitor, in a model of POCD.
Main Methods:
- Prophylactic administration of LiCl (2 mM/kg) in an orthopedic surgery model.
- Assessment of hippocampal proinflammatory mediators, NF-κB expression, and microglial polarization (M1/M2 markers).
- In vitro experiments using lipopolysaccharide (LPS) to induce inflammation and assess LiCl's effects on microglia.
Main Results:
- LiCl administration inhibited hippocampal expression of proinflammatory mediators and NF-κB.
- LiCl downregulated M1 microglial markers (inducible nitric oxide synthase, CD86) and upregulated M2 markers (IL-10, CD206).
- LiCl reversed LPS-induced proinflammatory mediator production and M1 microglial polarization in vitro, alleviating cognitive impairment.
Conclusions:
- GSK-3β is a key contributor to the development of POCD.
- Inhibition of GSK-3β using LiCl demonstrates neuroprotective effects against surgery-induced cognitive impairment.
- GSK-3β represents a potential therapeutic target for neuroprotective strategies against POCD.
