Valproic acid inhibits substance P-induced activation of protein kinase C epsilon and expression of the substance P receptor.
The neuropeptide substance P (SP) has been hypothesized to be involved in the etiopathology of affective disorders. This hypothesis is based on the findings that neurokinin-1-receptor antagonists have antidepressant effects in depressed patients and that SP may worsen mood. In this study, we investigated the effect of the mood-stabilizing agents valproic acid (VPA), carbamazepine, and lithium on SP-induced gene expression. As a model system, we used primary rat astrocytes and human astrocytoma cells, which both express functional SP-receptors and, upon stimulation with SP, synthesize interleukin-6 (IL-6), a cytokine which has been shown to be elevated during the acute depressive state. We found that VPA dose-dependently inhibited SP-induced IL-6 synthesis which was seen with pre-incubation periods of 30 min, 3, 7 and 14 days, whereas carbamazepine and lithium showed no inhibitory effect. The inhibitory effect of VPA was not mediated by inhibition of the stress-regulated kinases p38 and p42/44 (Erk1/2) but by inhibition of protein kinase C epsilon activation. Furthermore, VPA down-regulated the expression of the substance P receptor (neurokinin(NK)-1-receptor) as assessed by real-time PCR. Whether both mechanisms contribute to the mood-stabilizing properties of VPA has to be evaluated in further studies.
Lieb
Klaus
K
Department of Psychiatry and Psychotherapy, University of Freiburg Medical School, Germany. klaus_lieb@psyallg.ukl.uni-freiburg.de
Treffurth
Yvonne
Y
Hamke
Maike
M
Akundi
Ravi Shankar
RS
von Kleinsorgen
Matthias
M
Fiebich
Bernd L
BL
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D018692:Antimanic Agents / Q000494:pharmacology; D002220:Carbamazepine / Q000494:pharmacology; D002478:Cells, Cultured; D004355:Drug Stability; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D008094:Lithium / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D051744:Protein Kinase C-epsilon; D051381:Rats; D017208:Rats, Wistar; D018040:Receptors, Neurokinin-1 / Q000187:drug effects / Q000378:metabolism*; D013373:Substance P / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D014635:Valproic Acid / Q000494:pharmacology*
D000927:Anticonvulsants; D018692:Antimanic Agents; D015850:Interleukin-6; D018040:Receptors, Neurokinin-1; D013373:Substance P; D002220:Carbamazepine; D014635:Valproic Acid; D008094:Lithium; C497257:Prkce protein, rat; C497255:PRKCE protein, human; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon