Valproic acid inhibits substance P‐induced activation of protein kinase C epsilon and expression of the substance P receptor

Abstract

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.

Substance P-Stimulated Interleukin-8 Expression in Human Colonic Epithelial Cells Involves Protein Kinase Cδ Activation

“…SP can directly stimulate IL-8 gene expression in human astrocytoma U373MG (Lieb et al, 1997) and in NK-1R stably transfected nontransformed human colonocytes (Zhao et al, 2002). Although PKCs (Palma et al, 1995), including PKC␦ (Soltoff and Toker, 1995) and PKC⑀ (Lieb et al, 2003), have been associated with SP/ NK-1R signaling, their involvement in SP-induced colonocyte proinflammatory responses has never been explored. We report here for the first time that SP rapidly and persistently activates PKC␦, and this event is involved in SP-associated activation of the NF-B pathway leading to IL-8 gene transcription.…”

“…Since SP can transiently stimulate PKC␦ tyrosine (Soltoff and Toker, 1995) and PKC⑀ serine phosphorylation (Lieb et al, 2003), we first examined whether SP activates these as well as other PKC members in human colonic epithelial cells by Western blot analyses using phospho-specific PKC antibodies. To do this, NCM460-NK-1R cells were stimulated with SP (10 Ϫ7 M) for 1 to 60 min, and equal amounts of cell protein were used to determine phosphorylation of various PKCs.…”

“…The third group of PKC isoforms includes the atypical PKC isoforms , /, and , which are regulated by Ca 2ϩ or DAG. It was previously shown that, among these PKCs, SP could transiently induce tyrosine phosphorylation of PKC␦ in rat parotid acinar cells (Soltoff and Toker, 1995) and Ser729 phosphorylation of PKC⑀ in U373 MG human astrocytoma cells and primary rat astrocytes (Lieb et al, 2003). However, the physiological significance of activation of these PKCs is not known yet.…”

Bipolar Disorder: Diagnosis, Neuroanatomical and Biochemical Background

“…Substance P is a neuropeptide that is widely distributed throughout the central and peripheral nervous system (Pioro et al, 1990;Dudas and Merchenthaler, 2002;Lieb et al, 2003) and it has been shown to play a role in the pathomechanism of bipolar disorder (Lieb et al, 2003). Substance P regulates the release of acetylcholine in the cortex and co-localizes with dopamine in the midbrain and striatum, with GABA in the cortex, and with serotonin in the raphe nuclei (Jakab et al, 1997).…”

“…Substance P, along with its receptor, the neurokinin 1 receptor (NK1R), is distributed in numerous areas of the brain including hippocampus, amygdala, frontal cortex and hypothalamus, and it appears to be involved in regulating responses to stress and fear (Herpfer and Lieb, 2005). Alterations of substance P content in these regions have been noted to influence the stress response and affective states (Lieb et al, 2003). Administration of substance P produces fear-related behaviors while blockade of NK1/2R or NK1/2/3R is associated with anxiolytic effects (Herpfer and Lieb, 2005).…”