Recent evidence suggests that the level of interleukin‐6 (IL‐6) is elevated in Alzheimer's disease (AD) brains. IL‐6 is produced by reactive glial cells and could potentially affect neuronal survival. Understanding the biochemical mechanism that regulates the production and release of IL‐6 by astrocytic cells may help to identify potential targets for therapeutic intervention in AD. In the present study, glial fibrillary acidic protein‐positive human U373MG astrocytoma cells were used as a model of reactive astrocytes. Production of IL‐6 in response to drug treatment was monitored with an ELISA assay. Histamine (1–100 µM), substance P (SP; 1–100 nM), and human interleukin‐1β (IL‐1β; 1–30 pM) stimulated the release of IL‐6 in a time‐ and concentration‐dependent manner, with EC50 values of 4.5 µM, 8 nM, and 4.5 pM, respectively. The respective effects of histamine, SP, and IL‐1β were effectively blocked by the histamine H1, SP, and IL‐1 receptor antagonists, supporting a receptor‐mediated event for these agents. Both histamine and SP enhanced the formation of inositol phosphates and increase intracellular calcium levels, suggesting that the phosphatidyl‐inositol bisphosphate/protein kinase C pathway may be involved in the IL‐6 release process. Indeed, phorbol 12‐myristate 13‐acetate, a protein kinase C activator, also evoked IL‐6 release from the U373MG cells. On the other hand, IL‐1β, which produces a much more robust release of IL‐6 than histamine or SP, has no effect on inositol phosphate formation or intracellular calcium levels. The biochemical mechanism of the release of IL‐6 in response to IL‐1β remains to be elucidated.
Chlorisondamine, a nicotinic cholinergic receptor antagonist, can block many of the in vivo effects of nicotine for weeks after a single icv injection. The time course of this effect was examined in a single group of rats by assessing the effects of nicotine o n locomotor activity at 1 , 3, and 6 weeks after the icv administration of 23 nmol of chlorisondamine. The effects of nicotine on locomotor activity were biphasic as has been previously reported, with decreases in activity early in the session and increases in activity later in the session. These effects of nicotine were blocked in chlorisondamine-treated rats at 1 or 3 weeks but not 6 weeks after administration of chlorisondamine. Nicotinic receptor binding in the brains of chlorisondamine-treated rats revealed no change in B, , , but a significant increase in affinity (47-59% decrease in Kd) 1, 3, 6, or 7 weeks after treatment. In contrast to i t s effects on affinity when administered icv, chlorisondamine did not alter binding affinity when added directly to the incubation buffer in vitro. Thus, although chlorisondamine significantly alters neuronal nicotinic cholinergic receptor binding affinity, this effect of chlorisondamine on binding affinity does not appear to be a direct effect of chlorisondamine on the receptor or to match the time course of chlorisondamine blockade of nicotine-induced changes in locomotor activity.
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