Glycogen synthase kinase-3 inhibition prevents learning deficits in diabetic mice.
There is an increasing awareness that diabetes has an impact on the central nervous system, with reports of impaired learning, memory, and mental flexibility being more common in diabetic subjects than in the general population. Insulin-deficient diabetic mice also display learning deficits associated with defective insulin-signaling in the brain and increased activity of GSK3. In the present study, AR-A014418, a GSK3β inhibitor, and TX14(A), a neurotrophic factor with GSK3 inhibitory properties, were tested against the development of learning deficits in mice with insulin-deficient diabetes. Treatments were started at onset of diabetes and continued for 10 weeks. Treatment with AR-A014418 or TX14(A) prevented the development of learning deficits, assessed by the Barnes maze, but only AR-A014418 prevented memory deficits, as assessed by the object recognition test. Diabetes-induced increased levels of amyloid β protein and phosphorylated tau were not significantly affected by the treatments. However, the diabetes-induced decrease in synaptophysin, a presynaptic protein marker of hippocampal plasticity, was partially prevented by both treatments. These results suggest a role for GSK3 and/or reduced neurotrophic support in the development of cognitive deficits in diabetic mice that are associated with synaptic damage.
Department of Pathology, School of Medicine, University of California San Diego, La Jolla, California, USA.
Matthew R
MR
King
Nicholas J
NJ
Anderson
Lucie S
LS
Guernsey
Corinne G
CG
Jolivalt
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003072:Cognition Disorders / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000378:metabolism; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects*; D051379:Mice; D009048:Motor Skills / Q000187:drug effects; D009414:Nerve Growth Factors / Q000494:pharmacology; D021641:Recognition, Psychology / Q000187:drug effects*; D045442:Rotarod Performance Test; D013844:Thiazoles / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
D009414:Nerve Growth Factors; D013844:Thiazoles; C101246:prosaptide; C479831:N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea; D014508:Urea; D038362:Glycogen Synthase Kinase 3