Glycogen synthase kinase-3 inhibitors: Rescuers of cognitive impairments

Pharmacol Ther. 2014 Jan;141(1):1-12. doi: 10.1016/j.pharmthera.2013.07.010. Epub 2013 Jul 31.


Impairment of cognitive processes is a devastating outcome of many diseases, injuries, and drugs affecting the central nervous system (CNS). Most often, very little can be done by available therapeutic interventions to improve cognitive functions. Here we review evidence that inhibition of glycogen synthase kinase-3 (GSK3) ameliorates cognitive deficits in a wide variety of animal models of CNS diseases, including Alzheimer's disease, Fragile X syndrome, Down syndrome, Parkinson's disease, spinocerebellar ataxia type 1, traumatic brain injury, and others. GSK3 inhibitors also improve cognition following impairments caused by therapeutic interventions, such as cranial irradiation for brain tumors. These findings demonstrate that GSK3 inhibitors are able to ameliorate cognitive impairments caused by a diverse array of diseases, injury, and treatments. The improvements in impaired cognition instilled by administration of GSK3 inhibitors appear to involve a variety of different mechanisms, such as supporting long-term potentiation and diminishing long-term depression, promotion of neurogenesis, reduction of inflammation, and increasing a number of neuroprotective mechanisms. The potential for GSK3 inhibitors to repair cognitive deficits associated with many conditions warrants further investigation of their potential for therapeutic interventions, particularly considering the current dearth of treatments available to reduce loss of cognitive functions.

Keywords: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; AD; APP; Alzheimer's disease; Aβ; CNS; FX; Fragile X; Fragile X syndrome; GSK3; Glycogen synthase kinase-3; LTD; LTP; Learning; Lithium; MTPT; SCA1; TBI; amyloid precursor protein; amyloid-β peptide; central nervous system; glycogen synthase kinase-3; long-term depression; long-term potentiation; spinocerebellar ataxia type 1; traumatic brain injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Cognition Disorders / chemically induced
  • Cognition Disorders / drug therapy*
  • Disease Models, Animal
  • Glycogen Synthase Kinases / antagonists & inhibitors*
  • Humans
  • Inflammation / drug therapy
  • Neurogenesis / drug effects
  • Neuronal Plasticity / drug effects
  • Nootropic Agents / pharmacology*
  • Nootropic Agents / therapeutic use*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use*


  • Nootropic Agents
  • Protein Kinase Inhibitors
  • Glycogen Synthase Kinases