title: Inhibition of Glycogen Synthase Kinase-3: An Emerging Target in the Treatment of Traumatic Brain Injury.
abstract: Although traumatic brain injury (TBI) has been a major public health concern for decades, the pathophysiological mechanism of TBI is not clearly understood, and an effective medical treatment of TBI is not available at present. Of particular concern is sustained TBI, which has a strong tendency to take a deteriorating neurodegenerative course into chronic traumatic encephalopathy (CTE) and dementia, including Alzheimer's disease. Tauopathy and beta amyloid (Aβ) plaques are known to be the key pathological markers of TBI, which contribute to the progressive deterioration associated with TBI such as CTE and Alzheimer's disease. The multiple lines of evidence strongly suggest that the inhibition of glycogen synthase kinase-3 (GSK-3) is a potential target in the treatment of TBI. GSK-3 constitutively inhibits neuroprotective processes and promotes apoptosis. After TBI, GSK-3 is inhibited through the receptor tyrosine kinase (RTK) and canonical Wnt signaling pathways as an innate neuroprotective mechanism against TBI. GSK-3 inhibition via GSK-3 inhibitors and drugs activating RTK or Wnt signaling is likely to reinforce the innate neuroprotective mechanism. GSK-3 inhibition studies using rodent TBI models demonstrate that GSK-3 inhibition produces diverse neuroprotective actions such as reducing the size of the traumatic injury, tauopathy, Aβ accumulation, and neuronal death, by releasing and activating neuroprotective substrates from GSK-3 inhibition. These effects are correlated with reduced TBI-induced behavioral and cognitive symptoms. Here, we review studies on the therapeutic effects of GSK-3 inhibition in TBI rodent models, and critically discuss the issues that these studies address.
authors.affiliation: 1 Atlanta VA Medical Center, Mental Health Service Line , Decatur, Georgia .
authors.forename: Seong S
authors.initials: SS
authors.lastname: Shim
authors.affiliation: 2 Department of Neuroscience, Rosalind Franklin University/The Chicago Medical School , North Chicago, Illinois.
authors.forename: Grace E
authors.initials: GE
authors.lastname: Stutzmann
mesh_terms: D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy* / Q000201:enzymology*; D016503:Drug Delivery Systems / Q000639:trends; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000077185:Resveratrol; D013267:Stilbenes / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D013267:Stilbenes; D038362:Glycogen Synthase Kinase 3; D000077185:Resveratrol
keywords: Alzheimer's disease; GSK-3; TBI; lithium; tauopathy