利用大鼠坐骨神經截斷模型探討太平洋紫杉醇對周邊神經再生之影響

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Title:	利用大鼠坐骨神經截斷模型探討太平洋紫杉醇對周邊神經再生之影響 Effects of Taxol on Regeneration in a Rat Sciatic Nerve Transection Model
Authors:	許世典;Shih-Tien Hsu
Contributors:	基礎醫學研究所博士班
Keywords:	神經再生;太平洋紫杉醇;動物模型;nerve regeneration;taxol;animal model
Date:	2019-01-18
Issue Date:	2019-11-11
Publisher:	中國醫藥大學
Abstract:	背景:太平洋紫杉醇是一種抗腫瘤化學藥劑，對許多惡性腫瘤具有良好療效。太平洋紫杉醇會促進微小管組裝，進而影響微小管功能，可以阻止癌細胞分裂。但副作用包括神經毒性，限制了它的療效。太平洋紫杉醇導致周圍神經病變的嚴重度，取決於給藥劑量，輸注持續時間和給藥方法等。相較於周邊施打太平洋紫杉醇造成的神經毒性，最近的研究反而發現太平洋紫杉醇可促進中樞神經再生，關於紫杉醇對周圍神經再生的影響，目前研究很少。方法與結果:我們使用大鼠坐骨神經截斷並置入神經導管模型，將40隻大鼠分成4組（每組各10隻）：對照組使用生理食鹽水及Cremophor EL，實驗組為含2或6 mg / kg太平洋紫杉醇注射液，四組藥物均採腹膜注射，注射時間為神經截斷後第2、4、6、8天共4次。一個月後評估神經電生理學，動物感覺及運動行為分析，神經導管內再生神經纖維再生數量，巨噬細胞浸潤量及神經生長因子和免疫調節因子的mRNA表現量，另外也觀察脊髓背根降鈣素基因相關?（CGRP）的表現位置和表現量，觀察背根神經節奈米金的表現量，探討探討太平洋紫杉醇對周邊神經再生的影響。在高劑量紫杉醇組（6 mg/kg）中，神經電生理功能顯著受損。感覺功能明顯延遲，但運動協調功能不受影響。再生神經處神經再連接數目，與巨噬細胞密度及脊髓背根神經CGRP大幅減少。在神經生長因子和免疫調節因子的表現量方面下降，而低劑量紫杉醇組（2 mg/kg）則升高。結論:這些結果顯示，太平洋紫杉醇可以調節局部炎症，損害神經再生，並阻礙周圍神經損傷的恢復。 Taxol is an antineoplastic agent and has a broad spectrum of activity to solid cancer including ovarian, endometrial, cervical cancer and breast cancer. Because taxol promotes microtubule assembly, it stops cancer cell diviation. But neurotoxicity limits its use. Clinical use of taxol has led to peripheral neuropathy and this has been demonstrated to be dependent upon the dose administered, the duration of the infusion, and the schedule of administration. However, recent studies describe taxol as a candidate for promoting central nerve regeneration. Few studies were done about the effect of taxol on peripheral nerve regeneration. We investigated the effects of taxol on regeneration using a rat sciatic nerve transection model. 40 Rats were divided into four groups (n = 10 ): normal saline (i.p.) as the control, Cremophor EL vehicle, and 2 or 6 mg/kg of paclitaxel in the Cremophor EL solution (four times in day-2, 4, 6, and 8), respectively. Neuronal electrophysiology, animal behaviour, neuronal connectivity, macrophage infiltration, location and expression levels of calcitonin gene-related peptide (CGRP), and expression levels of both nerve growth factors and immunoregulatory factors were evaluated. In the high-dose taxol group (6 mg/kg), neuronal electrophysiological function was significantly impaired. Licking latencies were significantly changed while motor coordination was unaffected. Neuronal connectivity, macrophage density, and expression levels of CGRP was dramatically reduced. Expression levels of nerve growth factors and immunoregulatory factors was also reduced, while it was increased in the low-dose taxol group (2 mg/kg). These results indicate that taxol can modulate local inflammatory conditions, impair nerve regeneration, and impede recovery of a severe peripheral nerve injury.
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