scholarly journals Lithium posttreatment confers neuroprotection through glycogen synthase kinase-3β inhibition in intracerebral hemorrhage rats

2017 ◽  
Vol 127 (4) ◽  
pp. 716-724 ◽  
Author(s):  
Jian Zheng ◽  
Zhen Liu ◽  
Weishan Li ◽  
Jiaxin Tang ◽  
Dongwei Zhang ◽  
...  
Keyword(s):  
Cell Death ◽  
Intracerebral Hemorrhage ◽  
Glycogen Synthase ◽  
Autologous Blood ◽  
Glycogen Synthase Kinase ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Secondary Brain Injury ◽  
Glycogen Synthase Kinase 3Β ◽  
Cox 2 ◽  
Gsk 3Β

OBJECTIVEInflammation and apoptosis are two key factors contributing to secondary brain injury after intracerebral hemorrhage (ICH). The objective of this study was to evaluate the effects of lithium posttreatment on behavior, brain atrophy, inflammation, and perihematomal cell death. Furthermore, the authors aimed to determine the role of the pro-apoptotic glycogen synthase kinase-3β (GSK-3β) after experimental ICH.METHODSMale Sprague-Dawley rats (n = 108) were subjected to intracerebral infusion of semicoagulated autologous blood. Window of opportunity and dose optimization studies of lithium on ICH-induced injury were performed by measuring neurological deficits. Animals with ICH received vehicle administration or lithium posttreatment (60 mg/kg) for up to 21 days. Hemispheric atrophy was evaluated. Perihematomal cell death was quantified through terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling (TUNEL). The number of myeloperoxidase (MPO)-positive neutrophils and OX42-positive microglia in the perihematomal areas were calculated. Western blotting was used for the quantification of GSK-3β, heat shock protein 70 (HSP70), nuclear factor-κB p65 (NF-κB p65), and cy-clooxygenase-2 (COX-2).RESULTSLithium, at a dose of 60 mg/kg initiated from 2 hours after injury, exhibited the best effects of improving neurological outcomes 3, 5, 7, 14, 21, and 28 days after ICH, reduced the hemispheric atrophy at 42 days after surgery, and reduced the number of TUNEL-positive cells, MPO-positive neutrophils, and OX42-positive microglia in the perihematomal areas. Furthermore, lithium posttreatment modulated GSK-3β, increased HSP70, and decreased NF-κB p65 and COX-2 expression in the ipsilateral hemisphere.CONCLUSIONSLithium posttreatment at a dose of 60 mg/kg, initiated beginning 2 hours after injury, improves functional and morphological outcomes, and inhibits inflammation and perihematomal cell death in a rat model of semicoagulated autologous blood ICH through inactivation of GSK-3β.

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

2018 ◽  
Vol 62 (6) ◽  
pp. e02045-17 ◽  
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.

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

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Jingjin Li ◽  
Chonglong Shi ◽  
Zhengnian Ding ◽  
Wenjie Jin
Keyword(s):  
Cognitive Dysfunction ◽  
Lithium Chloride ◽  
Glycogen Synthase ◽  
Postoperative Cognitive Dysfunction ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Central Nervous System Complication ◽  
Proinflammatory Mediators ◽  
M1 Polarization ◽  
Gsk 3Β

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.

scholarly journals Celecoxib Induces Functional Recovery after Intracerebral Hemorrhage with Reduction of Brain Edema and Perihematomal Cell Death

2004 ◽  
Vol 24 (8) ◽  
pp. 926-933 ◽  
Author(s):  
Kon Chu ◽  
Sang-Wuk Jeong ◽  
Keun-Hwa Jung ◽  
So-Young Han ◽  
Soon-Tae Lee ◽  
...  
Keyword(s):  
Cell Death ◽  
Intracerebral Hemorrhage ◽  
Brain Edema ◽  
Functional Recovery ◽  
Autologous Blood ◽  
Prostaglandin E ◽  
Dependent Manner ◽  
Behavioral Tests ◽  
Adult Rats ◽  
Cox 2

The selective cyclooxygenase-2 (COX-2) inhibitor has been reported to have antiinflammatory, neuroprotective, and antioxidant effects in ischemia models. In this study, the authors examined whether a selective COX-2 inhibitor (celecoxib) reduces cerebral inflammation and edema after intracerebral hemorrhage (ICH), and whether functional recovery is sustained with longer treatment. ICH was induced using collagenase in adult rats. Celecoxib (10 or 20 mg/kg) was administered intraperitoneally 20 minutes, 6 hours, and 24 hours after ICH and then daily thereafter. Seventy-two hours after ICH induction, the rats were killed for histologic assessment and measurement of brain edema and prostaglandin E2. Behavioral tests were performed before and 1, 7, 14, 21, and 28 days after ICH. The brain water content of celecoxib-treated rats decreased both in lesioned and nonlesioned hemispheres in a dose-dependent manner. Compared with the ICH-only group, the number of TUNEL-positive, myeloperoxidase-positive, or OX42-positive cells was decreased in the periphery of hematoma and brain prostaglandin E2 level was reduced in the celecoxib-treated group. Celecoxib-treated rats recovered better by the behavioral tests at 7 days after ICH throughout the 28-day period, and the earlier the drug was administered, the better the functional recovery. Evidence of similar effects in an autologous blood–injected model showed that direct collagenase toxicity was not the major cause of inflammation or cell death. These data suggest that celecoxib treatment after ICH reduces prostaglandin E2 production, brain edema, inflammation, and perihematomal cell death in the perihematomal zone and induces better functional recovery.

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