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Recent in-vitro data indicate that depletion of neural cells of myo-inositol by virtue of down-regulation of the high-affinity sodium-myo-inositol co-transporter (SMIT) may be a common mechanism of action of the mood stabilizers lithium, valproate and carbamazepine. The authors sought to investigate whether or not down-regulation of SMIT also occurs in vivo in bipolar patients. Expression of SMIT mRNA was measured in neutrophils of bipolar patients either unmedicated or treated with lithium salts or valproate and in neutrophils of unmedicated, matched healthy controls using quantitative real-time PCR. The content of SMIT mRNA was significantly reduced in neutrophils of lithium-treated bipolar patients compared to controls and to untreated bipolar patients. Untreated bipolar I patients but not bipolar II patients exhibited a significantly higher expression of SMIT mRNA than controls. Neutrophils of bipolar I patients treated with valproate exhibited a significantly lower expression of SMIT mRNA than untreated bipolar I patients but did not differ from controls. These results suggest that lithium and valproate down-regulate SMIT mRNA in vivo in patients. In addition the data provide first evidence that up-regulation of SMIT might be associated with an increased risk for bipolar I disorder.

The “regulators of g-protein signalling” (RGS) comprise a large family of proteins that limit by virtue of their GTPase accelerating protein domain the signal transduction of G-protein coupled receptors. RGS proteins have been implicated in various neuropsychiatric diseases such as schizophrenia, drug abuse, depression and anxiety and aggressive behaviour. Since conditions associated with a large increase of adenosine in the brain such as seizures or ischemia were reported to modify the expression of some RGS proteins we hypothesized that adenosine might regulate RGS expression in neural cells. We measured the expression of RGS-2,-3, and -4 in both transformed glia cells (human U373 MG astrocytoma cells) and in primary rat astrocyte cultures stimulated with adenosine agonists. Expression of RGS-2 mRNA as well as RGS2 protein was increased up to 30-fold by adenosine agonists in astrocytes. The order of potency of agonists and the blockade by the adenosine A2B-antagonist MRS1706 indicated that this effect was largely mediated by adenosine A2B receptors. However, a smaller effect was observed due to activation of adenosine A2A receptors. In astrocytoma cells adenosine agonists elicited an increase in RGS-2 expression solely mediated by A2B receptors. Expression of RGS-3 was inhibited by adenosine agonists in both astrocytoma cells and astrocytes. However while this effect was mediated by A2B receptors in astrocytoma cells it was mediated by A2A receptors in astrocytes as assessed by the order of potency of agonists and selective blockade by the specific antagonists MRS1706 and ZM241385 respectively. RGS-4 expression was inhibited in astrocytoma cells but enhanced in astrocytes by adenosine agonists.

Objective. T lymphocytes are known to interact with cellular and structural components of the extracelMar matrix. We investigated whether T lymphocytes could also contribute to matrix breakdown by expression of a matrix metalloproteinase (MMP) gene.Methods. Complementary DNA (cDNA) was synthesized from messenger RNA extracted from cultured peripheral blood T lymphocytes after exposure to phorbol myristate acetate and calcium ionophore A23187 and amplified by the polymerase chain reaction with primers derived from two conserved domains in MMP genes.Results. An amplification product of 402 basepairs was generated and cloned; sequence analysis revealed identity to human stromelysin-2 cDNA. Using the amplified stromelysin-2 cDNA as a probe for Northern analyses, we detected a 1.8-kilobase transcript in stimulated T lymphocytes.Conclusion. T lymphocytes are a potential source of stromei'ysin-2 transcripts and may have a role in the degradation of extracellular matrix constituents.The irreversible destruction of the joint architecture in rheumatoid arthritis, which occurs during late stages of the disease, is accounted for by the action of a group of enzymes that belong to the gene family of the neutral matrix metalloproteinases (MMPs) (1). The copious expression of MMPs, particularly collagenase and stromelysin, by resident cells in the synovial lining layer (2) is probably a conseDr. Conca's work was supported by a grant from the Bundesministerium fur Forschung und Technologie.

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