Inhibition of Glycogen Synthase Kinase 3β Attenuates Neurocognitive Dysfunction Resulting from Cranial Irradiation

Abstract

There are now more than 10 million cancer survivors in the United States. With these numbers, chronic sequelae that result from cancer therapy have become a major health care problem. Although radiation therapy of the brain has improved cancer cure rates, learning disorders and memory deficits are a common consequence of this therapy. Here we show that glycogen synthase kinase 3B (GSK-3B) is required for radiation-induced hippocampal neuronal apoptosis and subsequent neurocognitive decline. Inhibition of GSK-3B either by small molecules (SB216763 or SB415286) or by ectopic expression of kinase-inactive GSK-3B before irradiation significantly attenuated radiation-induced apoptosis in hippocampal neurons. GSK-3B inhibition with SB216763 or SB415286 also decreased apoptosis in the subgranular zone of the hippocampus in irradiated mice, leading to improved cognitive function in irradiated animals. Studies of the molecular mechanisms of the cytoprotective effect showed that GSK-3B activity in hippocampal neurons was not significantly altered by radiation, pointing to the indirect involvement of this enzyme in radiation-induced apoptosis. At the same time, radiation led to increased accumulation of p53, whereas inhibition of the basal level of GSK-3B activity before radiation prevented p53 accumulation, suggesting a possible mechanism of cytoprotection by GSK-3B inhibitors. These findings identify GSK-3B signaling as a key regulator of radiationinduced damage in hippocampal neurons and suggest that GSK-3B inhibitors may have a therapeutic role in protecting both pediatric and adult cancer patients and may help to improve quality of life in cancer survivors. [Cancer Res 2008;68(14):5859-68]

GSK-3 – at the crossroads of cell death and survival

“…This damage could be prevented in mice with the administration of GSK-3 inhibitors, and rescued hippocampal neurons as well as intestinal crypt cells when the animals were treated with cirradiation (Thotala et al, 2010;Thotala et al, 2008). These data support the role of GSK-3 in the induction of Puma and in apoptosis upon DNA damage in vivo, and might open a therapeutic avenue for protection of healthy tissue from chemotherapy-induced damage, a major side effect during cancer therapy.…”

Glycogen Synthase Kinase 3β Sustains Invasion of Glioblastoma via the Focal Adhesion Kinase, Rac1, and c-Jun N-Terminal Kinase-Mediated Pathway

“…There is increasing evidence to show that GSK3b has neurodegenerative effects and that its inhibition has neuroprotective consequences (9). This has been observed for example with cranial irradiation-induced neurocognitive dysfunction (50). Therefore, the inhibition of GSK3b can provide dual benefits for the treatment of patients with glioblastoma by first reducing tumor invasion and therapy resistance, and second by protecting the host brain tissue from injury.…”

Lithium-mediated protection of hippocampal cells involves enhancement of DNA-PK–dependent repair in mice

“…The mechanisms of lithium-mediated neuroprotection have been previously attributed to activation of the prosurvival PI3K/ Akt pathway and inhibition of the GSK-3 enzyme (6,26,27,39). In response to DNA damage, Akt is ultimately activated as part of the cellular survival response (40)(41)(42)(43).…”