, 2005) a pharmacological

agent believed to reduce abnormally high glutamatergic activity. The interactions between circadian clocks and neurochemical mechanisms in the brain appear to be complex and may illustrate the pleiotropy of clock genes. This pleiotropy may be key to temporally coordinate and couple mechanistically unrelated physiological pathways such as weight and mood regulation, which once uncoupled may favor development of obesity and depression. Because the circadian system appears to be involved in a number of diseases including obesity and depression, it may be an entry point for the development of treatments for these diseases. As highlighted in this review, light and food can significantly impact the check details circadian system; this implies that lifestyle affects human health via the circadian system with nutrition, movement and light exposure as the key elements involved. Nuclear receptors, kinases, and molecules buy Vorinostat such as melatonin are a part of the circadian system. It is thus plausible that pharmacological agents acting on these components or mimicking their actions may serve as a conduit to ameliorate health problems associated with the circadian clock. One

modulator of kinase activity is lithium, which inhibits GSK3β activity. This kinase regulates clock components such as REV-ERBα (Yin et al., 2006) and PER2 (Iitaka et al., 2005), lengthens the circadian 3-mercaptopyruvate sulfurtransferase period (Li et al., 2012), and thus may relay the beneficial effects of lithium in the treatment of depressive disorders (Johnsson et al., 1983). However, its precise mechanism of action is not understood. Another

potential pharmacological target to alter the circadian clock is casein kinase 1δ (CK1δ). Application of a CK1δ inhibitor (PF-670462) to wild-type mice lengthened circadian period accompanied by nuclear retention of the clock protein PER2. This treatment lengthened the period in a phase specific manner, selectively extending the duration of PER2-mediated transcriptional feedback (Meng et al., 2010). This suggests that CK1δ inhibition might be effective in increasing the synchronization of disrupted circadian oscillators offering an avenue for therapeutic treatment of diseases caused by disrupted or desynchronized circadian rhythms. Recently, longdaysin, a molecule that targets three kinases, CK1α, CK1δ, and ERK2, was discovered during a large-scale chemical screen. Longdaysin inhibition of CK1α reduced PER1 phosphorylation and degradation. As a consequence, the clock periods in human cells and in zebrafish embryos became longer, pointing to a therapeutic potential of longdaysin in manipulating and synchronizing circadian clocks (Hirota et al., 2010b). Another approach to modulate clock activity is through delivery of substances that modulate the action of nuclear receptors.