科研之友
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摘要
Rationale One theory for therapeutic effects of the lithium ion (Li+) in bipolar disorder is that myo-inositol, needed for phospholipase C-mediated signaling, is depleted by Li+-induced inhibition of inositolphosphate hydrolysis or of myo-inositol uptake, an effect demonstrated in cultured mouse astrocytes at high myo-inositol concentrations. In contrast, myo-inositol uptake is inhibited at low concentrations, reflecting that it occurs both by the high-affinity Na+-dependent myo-inositol transporter (SMIT) and the lower-affinity H+-dependent inositol transporter (HMIT). Increased intracellular pH (pH(i)) stimulates SMIT but inhibits HMIT, suggesting that the effect of Li+ could be caused by intracellular alkalinization. In this study, we therefore investigated Li+ effects on intracellular pH in astrocytes, measured by 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF) fluorescence. @@@ Results Chronic treatment with the therapeutically relevant Li+ concentration of 1 mM for 2 or 3 weeks increased pH(i) by similar to 0.10, whereas 0.5 mM was ineffective, and 2 mM caused a larger increase. The alkalinization resulted from acute stimulation of the Na+/H+ exchanger (NHE) by extracellular Li+, demonstrated after acid load with NH4Cl. In response to continuous stimulation, NHE1 mRNA was down-regulated, but protein was not. @@@ Conclusions Chronic treatment with pharmacologically relevant Li+ concentrations increases pH(i) in astrocytes, creating conditions for decreased uptake of high myo-inositol concentrations and increased uptake of low concentrations. The pharmacological relevance of this effect is supported by literature data suggesting brain acidosis in bipolar patients and by preliminary observations that carbamazepine and valproate also increase pH(i) in astrocytes. Stimulation of NHE1-stimulated sodium ion uptake might also trigger uptake of chloride ions and osmotically obliged water.
