Valproic Acid Phase Shifts the Rhythmic Expression of PERIOD2::LUCIFERASE

Abstract

Valproic acid (VPA) is an anticonvulsant used to treat bipolar disorder, a psychiatric disease associated with disturbances in circadian rhythmicity. Little is known about how VPA affects circadian rhythms. The authors cultured tissues containing the master brain pacemaker for circadian rhythmicity, the suprachiasmatic nuclei (SCN), and skin fibroblasts from transgenic PERIOD2::LUCIFERASE (PER2::LUC) mice and studied the effect of VPA on the circadian PER2::LUC rhythm by measuring bioluminescence. VPA (1 mM) significantly phase advanced the PER2::LUC rhythm when applied at a time point corresponding to the lowest (trough, ~ZT 0) PER2::LUC expression but phase delayed the PER2::LUC rhythm when the drug was administered at the time of highest (peak, ~ZT 12) protein expression. In addition, it significantly increased the overall amplitude of PER2::LUC oscillations at time points at or close to ZT 12 but had no effect on period. Real-time PCR analyses on mouse and human fibroblasts revealed that expressions of other clock genes were increased after 2 h treatment with VPA. Because VPA is known to inhibit histone deacetylation, the authors treated cultures with an established histone deacetylation inhibitor, trichostatin A (TSA; 20 ng/mL), to compare the effect of VPA and TSA on molecular rhythmicity. They found that TSA had similar effects on the PER2::LUC rhythm as VPA. Furthermore, VPA and TSA significantly increased acetylation on histone H3 but in comparison little on histone H4. Lithium is another commonly used treatment for bipolar disorder. Therefore, the authors also studied the impact of lithium chloride (LiCl; 10 mM) on the PER2::LUC rhythm. LiCl delayed the phase, but in contrast to VPA and TSA, LiCl lengthened the PER2::LUC period and had no effect on histone acetylation. These results demonstrate that VPA can delay or advance the phase, as well as increase the amplitude, of the PERIOD2::LUCIFERASE rhythm depending on the circadian time of application. Furthermore, the authors show that LiCl delays the phase and lengthens the period of the PER2::LUC rhythm, confirming previous reports on circadian lithium effects. These different molecular effects may underlie differential chronotherapeutic effects of VPA and lithium.

The mood stabilizer valproic acid opposes the effects of dopamine on circadian rhythms

“…Previous work has shown that VPA shifts the phase and increases amplitude of PER2 rhythms in cultured SCN explants and fibroblasts (Johansson et al, 2011). In hamsters, low concentrations of VPA had no effect on circadian period (Klemfuss and Kripke, 1995).…”

The bipolarity of light and dark: A review on Bipolar Disorder and circadian cycles

“…It has been demonstrated that it can also affect circadian rhythms. Valproic Acid, in different circadian timings, can alter the phase (delay or advance) and increase the amplitude of Per2 gene rhythm (Johansson, Brask et al 2011).…”

Chronobiology of Bipolar Disorder: Therapeutic Implication

“…The mood stabilizer valproic acid shifts phase and increases amplitude of clock gene expression rhythms in SCN and fibroblasts [118], but it has less consistent effects on circadian period compared to lithium [119]. It also influences the expression of several circadian genes in the amigdala [120].…”