Involvement of glial nitric oxide in central adverse effects induced by immunosuppressants.

点击翻译按钮获取中文摘要

The present study was designed to clarify the mechanisms mediating cyclosporine A (CsA)-induced nausea, vomiting and convusions and to evaluate an involvement of glial nitric oxide (NO) in CsA neurotoxicity. (1) Subchronic treatment with CsA produced a dose- and time-dependent increase in kaolin intake in rats, this being blocked by H1 and muscarinic antagonist. Ovariectomy increased the susceptibility to CsA-induced convulsions by accelerating an inhibitory action of CsA on GABA neural activity in the rat hippocampus. This event was blocked by estrogen replacement. These findings suggest that scopolamine and diphenhydramine may be possible regimens to alleviate and avoid nausea/vomiting in patients.with CsA and that climacterium is included in the risk factors for CsA neurotoxicity and this risk is lowered by estrogen replacement therapy. (2) CsA failed to evoke NO production but increased phenylephrine-evoked NO production, this inhibited by IPS receptor blocker in C6 glioma cells. In the mouse brain endbthelial (MBEC4) cells, CsA stimulated NO production and increased histamine-evoked NO production. The effects of CsA were examined on the permeability of MBEC4 cells cocultured with C6 cells, each cell layer placed on the top and bottom of the insert membrane, respectively. The presence of C6 cells remarkably aggravated CsA-increased permeability of MBEC4 cells to sodium fluorescein. These findings suggest that asrocytes contribute to the occurrence of CsA-induced dysfunction of the blood-brain barrier (BBB) triggering neurotoxicity. The CsA-enhanced NO production in the brain endothelial and glial cells may be operative for the dysfunction of BBB. In light of the present findings, we raised the possible regimens to alleviate and avoid neurotoxicity in patients and patients with climacterium under CsA therapy. CsA-incresed glial and endothelial NO production in the brain may trigger the dysfunction of BBB and neurotoxicity.