Possible Interaction: Melatonin and Valproic Acid

“The ability of valproate to decrease the sensitivity of melatonin to light may relate to its therapeutic effect in bipolar disorder—an ability to lengthen circadian period similar to that of lithium.”

“ Valproate significantly decreased the sensitivity of melatonin to light.”

“The anticonvulsant and mood stabilizer, valproic acid (VPA), up‐regulates melatonin MT1 and/or MT2 receptor expression in cultured cells and in the rat brain.”

“Using time-lapse confocal microscopy, we showed in living cells that valproic acid interfered with the internalization kinetics of MTNR1A in the presence of melatonin.”

“However, in subsequent experiments using a different (MCF-7B) subline, which expressed higher levels of MT1 receptor mRNA and showed modest sensitivity to melatonin , a combination of this hormone with valproic acid produced a significant synergistic inhibition of cell proliferation.”

“MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assays revealed a concentration-dependent … MCF-7 cell proliferation by valproic acid (0.5, 1.0 or 5 mM), but melatonin (1 or 10 nM) was … or in combination with valproic acid , in the first (…-7A) subline examined.”

“Moreover, the enhanced antiproliferative effect observed with a combination of valproic acid and melatonin suggests that a similar therapeutic approach may be beneficial in breast cancer.”

“These findings indicate that clinically relevant concentrations of valproic acid upregulate melatonin MT1 receptor expression in human breast cancer cells.”

“Treatment of MCF-7 cells with valproic acid (0.5 or 1 mM) for 24 or 72 h caused a significant increase in melatonin MT1 receptor mRNA or protein expression, as shown by reverse transcription-polymerase chain reaction (RT-PCR) analysis and western blotting, respectively.”

“We have reported that valproic acid upregulates melatonin MT1 receptor expression in rat C6 glioma cells.”

“Given the efficacy of melatonin, both centrally and peripherally, in the prevention of the effects of multiple inducers of hyperammonemia [6, 8] , the coadministration of melatonin would be likely to protect against valproate side effects and cognitive decline.”

“ Valproate has many side effects, including thrombocytopenia, leucopenia, and hyperammonemia, all of which can be alleviated to some degree by melatonin [6] .”

“The present study investigated whether carbamazepine and valproate alter serum concentrations of melatonin.”

“Therefore, we investigated the protective effects of melatonin against the reductions of memory and neurogenesis caused by VPA.”

“These findings suggest that melatonin is able to prevent the spatial and non-spatial memory impairments and a reduction in hippocampal neurogenesis simultaneously induced by VPA.”

“In addition, melatonin prevented VPA induced alterations in non-enzymatic antioxidant defence reduced glutathione (GSH) and activities of synaptosomal integral enzymes such as AChE, Na+, K+ -ATPase and MAO.”

“We found that chronic melatonin (1.0 or 5.0 mg/kg/day, 28 days) treatment significantly rescued valproic acid (VPA, 600 mg/kg)‐induced decreases in CaMKII (Thr286), NMDAR1 (Ser896), and PKA (Thr197) phosphorylation in the hippocampus without affecting total protein levels.”

“We have reported that clinically relevant concentrations of valproic acid (VPA) upregulate the G protein-coupled melatonin MT1 receptor in rat C6 glioma cells, and both MT1 and MT2 receptors in the rat hippocampus.”