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

本研究旨在阐明环孢素A （CsA）引起的恶心、呕吐和抽搐的机制，并评估神经胶质一氧化氮（NO）在CsA神经毒性中的作用。(1) CsA亚慢性治疗使大鼠高岭土摄取量呈剂量和时间依赖性增加，这被H1和毒蕈碱拮抗剂阻断。卵巢切除术通过加速CsA对大鼠海马GABA神经活动的抑制作用，增加了对CsA诱导的惊厥的易感性。雌激素替代可阻断这一事件。这些发现表明东莨菪碱和苯海拉明可能是缓解和避免患者恶心/呕吐的可能方案。而更年期是CsA神经毒性的危险因素之一雌激素替代疗法可以降低这种风险。(2) CsA在C6胶质瘤细胞中不能诱导NO的产生，但能增加苯肾上腺素诱导的NO的产生，而IPS受体阻滞剂能抑制这种作用。在小鼠脑内皮（MBEC4）细胞中，CsA刺激NO的产生，并增加组胺诱发的NO的产生。CsA对MBEC4细胞与C6细胞共培养的通透性的影响，每层细胞分别放置在插入膜的顶部和底部。C6细胞的存在显著加重了csa，增加了MBEC4细胞对荧光素钠的通透性。这些发现表明，凝血细胞有助于csa诱导的血脑屏障功能障碍（BBB）的发生，从而引发神经毒性。csa增强脑内皮细胞和神经胶质细胞NO生成可能是脑血脑屏障功能障碍的重要原因。根据目前的研究结果，我们提出了可能的方案，以减轻和避免神经毒性的患者和患者的更年期接受CsA治疗。csa增加脑内胶质细胞和内皮细胞NO生成可能引发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.