以光學方式觀察紫杉醇注射小鼠痛覺神經的變化

Abstract

化療所引起的周邊神經病變(Chemotherapy-induced peripheral neuropathy,CIPN)是紫杉醇治療的一種劑量限制性的副作用。紫杉醇的神經毒性可以導致神經纖維退化，這可能與動物在服用紫杉醇後的感受傷害行為有關。在我們的研究中，我們分別在第0、2、4和6天將紫杉醇以每公斤體重注射4毫克的劑量注射到基因轉殖小鼠的腹腔內，然後我們進行了一系列的實驗，例如von Frey測試和免疫組織化學染色。Thy 1-eGFP和Nav1.8-tdTomato小鼠分別被用來追蹤大的和小的皮下神經纖維。我們的實驗結果表明，注射紫杉醇的小鼠機械性閾值 (mechanical threshold)會降低，這是痛覺異常的徵兆。此外，我們追踪了紫杉醇注射後幾個時間點在活的小鼠中皮膚神經纖維的變化。大直徑的神經纖維未被發現有明顯變化。在機械性敏感化發生的時間點，Nav1.8-tdTomato小鼠的小直徑神經纖維和神經末端的密度有顯著的下降。我們得出的結論是，小纖維神經病變可能有助於CIPN的發生。

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of paclitaxel treatments. The neurotoxicity of paclitaxel can lead to the degeneration of nerve fibers, which may have a link with nociceptive behaviors in animals after paclitaxel administration. In our study, 4 mg/kg paclitaxel was injected intraperitoneally into transgenic mice on four alternate days (day 0, 2, 4 and 6), and then we conducted a series of experiments, such as von Frey assessment and immunohistochemistry. Thy 1-eGFP and Nav1.8-tdTomato reporter mice were used for tracking large and small subcutaneous nerve fibers respectively. Our results demonstrated that the paclitaxel-injected mice showed a reduced mechanical threshold, which was a sign of allodynia. Furthermore, we tracked the changes of cutaneous nerve fibers in living mice at several time points after paclitaxel injections. No large diameter fiber change was found. The densities of Nav1.8-tdTomato positive small diameter fibers and terminals significantly decreased at the time point at which mechanical sensitization occurred. We concluded that small fibers neuropathy may contribute to CIPN.