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

本研究旨在阐明环孢素A(CsA)引起恶心、呕吐和惊厥的机制，并探讨神经胶质细胞一氧化氮(NO)在环孢素A神经毒性中的作用。(1)亚慢性给予CsA后，大鼠高岭土摄入量呈剂量和时间依赖性增加，这种增加可被H1和M受体拮抗剂阻断。卵巢切除通过加速CsA对大鼠海马区GABA神经活动的抑制作用，增加了对CsA诱发惊厥的敏感性。这一事件被雌激素替代疗法阻断。这些结果提示，东莨菪碱和苯海拉明可能是缓解和避免CsA患者恶心/呕吐的可能方案。更年期是CsA神经毒性的危险因素之一，这种风险通过雌激素替代治疗而降低。(2)CsA不能诱导C6胶质瘤细胞产生NO，但可增加苯肾上腺素诱导的NO产生，这种作用可被IPS受体阻断剂所抑制。在小鼠脑内皮细胞(MBEC4)中，CsA刺激NO的产生，并增加组胺诱发的NO的产生。观察CsA对与C6细胞共培养的MBEC4细胞通透性的影响，每层细胞分别放置在植入膜的顶部和底部。C6细胞的存在明显加重了CsA增加的MBEC4细胞对荧光素钠的通透性。这些发现提示，asrocell参与了CsA诱导的血脑屏障(BBB)功能障碍的发生，从而引发神经毒性。CsA促进脑内皮细胞和神经胶质细胞产生NO可能是治疗BBB功能障碍的机制之一。根据目前的研究结果，我们提出了减轻和避免CsA治疗的更年期患者和患者的神经毒性的可能方案。CsA诱导脑内神经胶质细胞和血管内皮细胞产生的NO增加，可能导致血脑屏障功能障碍和神经毒性。

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.