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  • Other enzymes outside of the circadian clock

    2019-07-12

    Other Carmustine outside of the circadian clock also have effects on CR. Lithium, a drug used to treat bipolar disorder, has been shown to lengthen τ in a variety of systems [17]. While the molecular mechanism whereby lithium exerts its therapeutic effect is unclear, it is known to be an inhibitor of the enzyme glycogen synthase kinase 3beta (GSK-3β) [17]. Lithium at therapeutic concentrations has been shown to inhibit GSK-3β and this subsequently inhibits the phosphorylation of Rev-erb α [18].
    CK1 Inhibitors
    Preclinical Animal Models The pharmacologic inhibition of CK1ε/CK1δ by PF-670462 10 has consistently shown modulation of circadian activity in rat, mouse, and nonhuman primate models. Under 12:12 light:dark conditions, 10 (10 and 30mg/kg) administered at zeitgeber time (ZT) 11 generated robust dose-dependent phase delays in rat [62]. In the same study, Sprouse et al. also demonstrated that administration of 10 at ZT 6 produced a smaller phase shift which was not significantly different from controls at the 10mg/kg dose [62]. These results are consistent with the phase response curve reported for 10[43] and suggest that the pharmacodynamics of CK1 inhibition follows cyclic changes in period protein (PER) levels [63]. These data further suggest that if used in patients, the clinical efficacy of a CK1ε/CK1δ inhibitor may be influenced by the timing of drug administration. The effects of 10 on circadian activity in socially housed Macaca fasicularis; a diurnal nonhuman primate species with a circadian period similar to humans has been investigated. Administration of 10 (10 and 32mg/kg) at ZT 10:30 under 12:12 light:dark conditions elicited dose-dependent phase delays in M. fasicularis[64]. These data are consistent with studies in singly house monkeys [65] and suggest that CK1 inhibition would induce phase delays in other diurnal species, including humans. The aforementioned models demonstrate the effects of CK1 inhibition in animals with normal CRs. Although these observations are important, central to the development of CK1 inhibitors as therapeutic agents for psychiatric indications is the ability to modulate circadian activity in arrhythmic or disrupted circadian paradigms. Meng et al. have established that 10 can restore circadian rhythmicity in two different mouse models of circadian asynchrony [66]. The vasoactive intestinal peptide receptor 2 knockout mouse (Vipr2) exhibits an arrhythmic or weakly rhythmic circadian phenotype due to disrupted signal transduction in the SCN [67], [68]. Robust entrainment of Vipr2 mice can be induced and sustained by daily 10 treatment [65]. Meng et al. also demonstrated that treatment with 10 prevented constant light-induced circadian asynchrony in wild-type mice [66].
    Conclusions The depth of understanding of CR has greatly increased over the past decade. Confirmation of CK1 as a drug-able target has been validated by identification of chemical matter consistent with drug-like attributes, including good LE, LLE, and brain availability. Moreover, these compounds have provided the in vivo translation of the science and have shown CR entrainment and phase shifts in nonhuman primates, in addition to rodents. In particular, the dissection of CK1 subtype selectivity was demonstrated with 35 (CK1ε selective), with 10 (CK1ε/CK1εδ dual inhibitor) exhibiting in vivo efficacy at modulating of CR. Selective CK1 tool compounds have enabled a greater understanding of the role this kinase plays in modulating CR. Although no CK1 compound has been reported in the clinic; clinical evaluation of the CR hypothesis using selective CK1 inhibitors is now within the realm of possibility.
    Introduction The cyclin-dependent kinase 1 (Cdk1) associated with cyclin B plays a central role in M phase of the mitotic cell cycle (Enserink and Kolodner, 2010). The meiotic cell cycle consists of two successive divisions, meiosis I and meiosis II, which are also driven by cyclin B-Cdk1 (Marston and Amon, 2004). In vertebrates, mature oocytes (or unfertilized eggs) are arrested at metaphase of meiosis II, or Meta-II, to await fertilization (Sagata, 1996). This arrest is caused by a cytoplasmic activity called cytostatic factor (CSF) (Masui and Markert, 1971). CSF inhibits the anaphase-promoting complex/cyclosome (APC/C), a multisubunit E3 ubiquitin ligase (Peters, 2006), thereby preventing cyclin B degradation and exit from Meta-II (Tunquist and Maller, 2003). CSF consists mainly of the classical Mos-MAPK pathway (Kishimoto, 2003, Nebreda and Ferby, 2000, Sagata, 1996, Tunquist and Maller, 2003) and Emi2 (also called Erp1), a direct inhibitor of the APC/C (Schmidt et al., 2005, Shoji et al., 2006, Tung et al., 2005). Both Mos and Emi2 are synthesized during oocyte maturation and degraded upon fertilization, although Emi2 is resynthesized shortly after fertilization (Liu et al., 2006, Madgwick et al., 2006, Ohe et al., 2007, Sagata et al., 1989, Schmidt et al., 2005).