Abstract
The mood-stabilizing agents lithium and valproic acid (VPA) increase DNA binding activity and transactivation activity of AP-1 transcription factors, as well as the expression of genes regulated by AP-1, in cultured cells and brain regions involved in mood regulation. In the present study, we found that VPA activated extracellular signal-regulated kinase (ERK), a kinase known to regulate AP-1 function and utilized by neurotrophins to mediate their diverse effects, including neuronal differentiation, neuronal survival, long term neuroplasticity, and potentially learning and memory. VPA-induced activation of ERK was blocked by the mitogen-activated protein kinase/ERK kinase inhibitor PD098059 and dominant-negative Ras and Raf mutants but not by dominant-negative stress-activated protein kinase/ERK kinase and mitogen-activated protein kinase kinase 6 mutants. VPA also increased the expression of genes regulated by the ERK pathway, including growth cone-associated protein 43 and Bcl-2, promoted neurite growth and cell survival, and enhanced norepinephrine uptake and release. These data demonstrate that VPA is an ERK pathway activator and produces neurotrophic effects.
Highlights
Mood-stabilizing agents are a very small group of pharmacologic agents utilized in the treatment of manic-depressive illness; they include lithium, valproic acid (VPA)1 (2-propylpentanoic acid), and carbamazepine [1]
We have found that VPA at therapeutic concentrations (50 –150 g/ml or 0.41–1.04 mM) [15] stimulates ERK pathway, increases growth cone-associated protein 43 (GAP-43) and Bcl-2 levels, promotes neurite growth and cell survival, and increases norepinephrine (NE) uptake and release
PD098059, a MEK inhibitor [24], blocked VPA-induced increases of AP-1 binding (Fig. 1B); SB203580, a p38 inhibitor [25], was without significant effect (Fig. 1C), suggesting that the ERK pathway is required for the effects of VPA
Summary
Vol 276, No 34, Issue of August 24, pp. 31674 –31683, 2001 Printed in U.S.A. The Mood Stabilizer Valproic Acid Activates Mitogen-activated Protein Kinases and Promotes Neurite Growth*. Mood-stabilizing agents are a very small group of pharmacologic agents utilized in the treatment of manic-depressive illness; they include lithium, valproic acid (VPA) (2-propylpentanoic acid), and carbamazepine [1] Despite their highly dissimilar structures, both lithium (a monovalent cation) and VPA (a branched fatty acid) increase the DNA binding activity of AP-1 transcription factor [2,3,4] and expression of genes known to be regulated by AP-1, tyrosine hydroxylase [5,6,7], and c-Jun [8, 9]. These results are similar to those elicited by several neurotrophic factors in the same cell line (16 –19), suggesting that VPA exerts neurotrophic actions
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