Glycogen Synthase Kinase 3β Promotes Postoperative Cognitive Dysfunction by Inducing the M1 Polarization and Migration of Microglia

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.

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The neuroprotective effect of lithium chloride on cognitive impairment through glycogen synthase kinase-3β inhibition in intracerebral hemorrhage rats

European Journal of Pharmacology ◽

10.1016/j.ejphar.2018.10.019 ◽

2018 ◽

Vol 840 ◽

pp. 50-59 ◽

Cited By ~ 8

Author(s):

Zhen Liu ◽

Rui Li ◽

Cheng Jiang ◽

Sha Zhao ◽

Weishan Li ◽

...

Keyword(s):

Cognitive Impairment ◽

Intracerebral Hemorrhage ◽

Lithium Chloride ◽

Glycogen Synthase ◽

Neuroprotective Effect ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3Β

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Retracted: Phosphorylated Glycogen Synthase Kinase-3β (GSK-3β) Improves Cognition in Rats with Diabetes-Associated Cognitive Decline

Medical Science Monitor ◽

10.12659/msm.919343 ◽

2019 ◽

Vol 25 ◽

pp. 6291-6291

Author(s):

Boxi Ke ◽

Rong Lu ◽

Xu Zhang

Keyword(s):

Cognitive Decline ◽

Glycogen Synthase ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3Β ◽

Gsk 3Β

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Dextromethorphan Attenuates NADPH Oxidase-Regulated Glycogen Synthase Kinase 3β and NF-κB Activation and Reduces Nitric Oxide Production in Group A Streptococcal Infection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02045-17 ◽

2018 ◽

Vol 62 (6) ◽

pp. e02045-17 ◽

Cited By ~ 4

Author(s):

Chia-Ling Chen ◽

Miao-Huei Cheng ◽

Chih-Feng Kuo ◽

Yi-Lin Cheng ◽

Ming-Han Li ◽

...

Keyword(s):

Nitric Oxide ◽

Nadph Oxidase ◽

Nuclear Translocation ◽

Glycogen Synthase ◽

Glycogen Synthase Kinase ◽

Streptococcal Toxic Shock Syndrome ◽

Glycogen Synthase Kinase 3Β ◽

Diphenylene Iodonium ◽

Group A ◽

Gsk 3Β

ABSTRACTGroup AStreptococcus(GAS) is an important human pathogen that causes a wide spectrum of diseases, including necrotizing fasciitis and streptococcal toxic shock syndrome. Dextromethorphan (DM), an antitussive drug, has been demonstrated to efficiently reduce inflammatory responses, thereby contributing to an increased survival rate of GAS-infected mice. However, the anti-inflammatory mechanisms underlying DM treatment in GAS infection remain unclear. DM is known to exert neuroprotective effects through an NADPH oxidase-dependent regulated process. In the present study, membrane translocation of NADPH oxidase subunit p47phoxand subsequent reactive oxygen species (ROS) generation induced by GAS infection were significantly inhibited via DM treatment in RAW264.7 murine macrophage cells. Further determination of proinflammatory mediators revealed that DM effectively suppressed inducible nitric oxide synthase (iNOS) expression and NO, tumor necrosis factor alpha, and interleukin-6 generation in GAS-infected RAW264.7 cells as well as in air-pouch-infiltrating cells from GAS/DM-treated mice. GAS infection caused AKT dephosphorylation, glycogen synthase kinase-3β (GSK-3β) activation, and subsequent NF-κB nuclear translocation, which were also markedly inhibited by treatment with DM and an NADPH oxidase inhibitor, diphenylene iodonium. These results suggest that DM attenuates GAS infection-induced overactive inflammation by inhibiting NADPH oxidase-mediated ROS production that leads to downregulation of the GSK-3β/NF-κB/NO signaling pathway.

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