Thiamine and benfotiamine improve cognition and ameliorate GSK-3β-associated stressinduced behaviours in mice

Thiamine deficiency in the brain has been implicated in the development of dementia and symptoms of depression. Indirect evidence suggests that thiamine may contribute to these pathologies by controlling the activities of glycogen synthase kinase (GSK)-3β. While decreased GSK- 3β activity appears to impair memory, increased GSK-3β activity is associated with the distressed/depressed state. However, direct evidence for the effects of thiamine on GSK-3β function were not have not been reported. Here, we administered thiamine or, the more bioavailable precursor, benfotiamine at 200 mg/kg/day for 2 weeks to C57BL/6J mice, to determine whether treatment might affect behaviours that are known to be sensitive to GSK-3β activity and whether such administration impacts on GSK-3β expression within the brain. The mice were tested in models of contextual conditioning and extinction, a 5-day rat exposure stress test, and a modified swim test with repeated testing. Imipramine (7.5 mg/kg/day) was administered as a positive control for thiamine or benfotiamine. As for imipramine, both compounds inhibited the upregulation of GSK-3β induced by predator stress or repeated swimming, and reduced floating scores and the predator stress-induced behavioural changes in anxiety and exploration. Coincident, thiamine and benfotiamine improved learning and extinction of contextual fear, and the acquisition of the step-down avoidance task. Together, our data indicate that thiamine and benfotiamine have antidepressant/anti-stress effects in naïve animals that are associated with reduced GSK-3β expression. Importantly, the treatment also had pro-cognitive actions despite the impact on GSK-3β activity