Role of glycogen synthase kinase-3β in ketamine-induced developmental neuroapoptosis in rats

Abstract

Ketamine-induced neuroapoptosis has been attributed to diverse stress-related mechanisms. Glycogen synthase kinase-3 (GSK-3) is a multifunctional kinase that is active in neuronal development and linked to neurodegenerative disorders. We hypothesized that ketamine would enhance GSK-3-induced neuroapopotosis, and that lithium, an inhibitor of GSK-3, would attenuate this response in vivo. Protein levels of cleaved caspase-3, protein kinase B (AKT), GSK-3, and cyclin D1 were measured in post-natal day 7 rat pups after 1.5, 3, 4.5, and 6 h exposure to ketamine. A cohort of rat pups was randomized to a 6 h exposure to ketamine with and without lithium. Neuroapoptosis was measured by cleaved caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling staining by immunohistochemistry. Protein levels of cleaved caspase-3 and -9 and the total and phosphorylated forms of AKT, GSK-3, and cyclin D1 (cell cycle protein) were also measured. Ketamine produced a duration-dependent increase in cleaved caspase-3 and cyclin D1, which corresponded to decreases in phosphorylated AKT and GSK-3. Co-administration of lithium with ketamine attenuated this response. Ketamine-induced neuroapoptosis is associated with a temporal decrease in GSK-3 phosphorylation, and simultaneous administration of lithium mitigated this response. These findings suggest that GSK-3 is activated during this ketamine-induced neuroapoptosis.