化療引起周邊神經病變（chemotherapy-induced peripheral neuropathy, CIPN）是抗腫瘤藥物中具漸進式且常見的副作用。 CIPN的症狀包括四肢感覺異常、麻木和嚴重疼痛，不僅影響患者生活品質，並且可能導致抗癌療程中止。然而，迄今仍無有效藥物可來用於預防或治療CIPN。因此，本研究旨在開發對太平洋紫杉醇引起周邊神經病變具有保護效果的化合物。在研究策略上，利用高通量藥物篩選平台搭配化合物資料庫，篩選出具有潛力之神經保護化合物以對抗太平洋紫杉醇對周邊神經－背根神經節（dorsal root ganglion，DRG）細胞之毒性。從先前高通量藥物篩選過程中，發現化合物CIX2X對太平洋紫杉醇所引起之神經毒性具有顯著的保護作用。因此，接下來利用電子式機械力閾值測量儀（electronic von Frey test）及溫浴甩尾法（tail immersion test）等小鼠行為測試，驗證CIX2X於生物體內的神經保護作用。在接受太平洋紫杉醇處理之組別中，觀察到小鼠接受機械力時其閾值降低與感受溫度之閾值增高的情況。在施打抗癌藥物前，給予CIX2X可以減緩太平洋紫杉醇所引起之機械性痛覺反應，亦可回復對溫度的感受性。重要的是，太平洋紫杉醇與CIX2X本身並不影響血液循環之穩定性與運動功能。在小鼠坐骨神經之電子顯微圖像中發現，CIX2X可以減少太平洋紫杉醇對非髓鞘神經纖維與小型之髓鞘神經纖維所造成的傷害。此外， 在小鼠背根神經節組織切片中，發現CIX2X可抑制由太平洋紫杉醇所引起巨噬細胞浸潤之現象。然而，在藥物作用機制的研究顯示，CIX2X不會改變太平洋紫杉醇引起之神經細胞內鈣離子恆定失調。綜合以上研究結果所述，CIX2X可作為具研發潛力的神經保護化合物，以預防CIPN的發展、減緩周邊神經損傷並抑制神經發炎反應。

Chemotherapy-induced peripheral neuropathy (CIPN) is a progressive and common side-effect of antineoplastic agents. The symptoms of CIPN including paresthesia, numbness, and severe pain, not only jeopardize patients’ daily ability but also cause the discontinuation of cancer treatment. To date, no medication has been approved to prevent or treat CIPN. My research aims to discover and develop the potential neuroprotective compounds on paclitaxel-induced neuropathic pain. First, an image-based high-content screening of compound libraries was applied for identifying neuroprotective agents against paclitaxel-induced neurotoxicity in dorsal root ganglion (DRG) neurons. In our previous screening, CIX2X exhibited significant protective efficacy against paclitaxel-induced neurotoxicity. Next, mouse behavioral tests including von Frey filament and tail immersion test were obtained to validate the in vivo neuroprotective effects of CIX2X. Decreased mechanical threshold and enhanced thermal threshold were observed in the paclitaxel-treated mice. Interestingly, pretreatment of CIX2X protected mice from mechanical allodynia and thermal hypesthesia induced by paclitaxel. Hemodynamic stability and motor function were not affected by paclitaxel and CIX2X alone. As electron micrographs of mouse sciatic nerves shown, CIX2X reduced the damages caused by paclitaxel in the smaller myelinated fibers. In addition, CIX2X suppressed paclitaxel-induced macrophage infiltration in mouse DRGs. However, the mechanistic study on DRG neurons revealed that CIX2X did not alter the dysregulation of intracellular calcium homeostasis provoked by paclitaxel. The above findings suggest that CIX2X as a potential neuroprotective compound prevented the development of CIPN, alleviated peripheral nerve damage and dampened the inflammatory responses.

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