Rapid modulation of TRH and TRH-like peptide release in rat brain, pancreas, and testis by a GSK-3β inhibitor

Antidepressants have been shown to be neuroprotective and able to reverse damage to glia and neurons. Thyrotropin-releasing hormone (TRH) is an endogenous antidepressant-like neuropeptide that reduces the expression of glycogen synthase kinase-3β (GSK-3β), an enzyme that hyperphosphorylates tau and is implicated in bipolar disorder, diabetes and Alzheimer's disease. In order to understand the potential role of GSK-3β in the modulation of depression by TRH and TRH-like peptides and the therapeutic potential of GSK-3β inhibitors for neuropsychiatric and metabolic diseases, young adult male Sprague-Dawley (SD) rats were (a) injected ip with 1.8 mg/kg of GSK-3β inhibitor VIII (GSKI) and sacrificed 0, 2, 4, 6, and 8 h later or (b) injected with 0, 0.018, 0.18 or 1.8 mg/kg GSKI and bled 4 h later. Levels of TRH and TRH-like peptides were measured in various brain regions involved in mood regulation, pancreas and reproductive tissues. Large, 3-15-fold, increases of TRH and TRH-like peptide levels in cerebellum, for example, as well as other brain regions were noted at 2 and 4 h. In contrast, a nearly complete loss of TRH and TRH-like peptides from testis within 2 h and pancreas by 4 h following GSKI injection was observed. We have previously reported similar acute effects of corticosterone in brain and peripheral tissues. Incubation of a decapsulated rat testis with either GSKI or corticosterone accelerated release of TRH, and TRH-like peptides. Glucocorticoids, via inhibition of GSK3-β activity, may thus be involved in the inhibition of TRH and TRH-like peptide release in brain, thereby contributing to the depressogenic effect of this class of steroids. Corticosterone-induced acceleration of release of these peptides from testis may contribute to the decline in reproductive function and redirection of energy needed during life-threatening emergencies. These contrasting effects of glucocorticoid on peptide release appear to be mediated by GSK-3β.