Desloratadine ameliorates paclitaxel-induced peripheral neuropathy and hypersensitivity reactions in mice  

作　　者：Jian Lu Xue-jian Zhao Yuan Ruan Xiao-jing Liu Xuan Di Rui Xu Jia-ying Wang Min-yi Qian Hong-ming Jin Wen-jun Li Xu Shen 

机构地区：[1]School of Medicine,Nanjing University of Chinese Medicine,Nanjing,210023,China [2]School of Pharmacy,Experiment Center for Science and Technology,Nanjing University of Chinese Medicine,Nanjing,210023,China

出　　处：《Acta Pharmacologica Sinica》2024年第10期2061-2076,共16页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(82273930);Innovative Research Team of Six Talent Peaks Project in Jiangsu Province(TD-SWYY-013);the National Natural Science Foundation for Young Scientists of China(82304468);the Natural Science Foundation for Young Scientists of Nanjing University of Chinese Medicine(XPT82304468);the National Natural Science Foundation for Young Scientists of China(82204486);the Natural Science Foundation for Young Scientists of Nanjing University of Chinese Medicine(XPT82204486);the Open Project of Chinese Materia Medica First-Class Discipline of Nanjing University of Chinese Medicine(No.2020YLXK018)and“Qing Lan”project.

摘　　要：Paclitaxel(PTX)serves as a primary chemotherapy agent against diverse solid tumors including breast cancer,lung cancer,head and neck cancer and ovarian cancer,having severe adverse effects including PTX-induced peripheral neuropathy(PIPN)and hypersensitivity reactions(HSR).A recommended anti-allergic agent diphenhydramine(DIP)has been used to alleviate PTX-induced HSR.Desloratadine(DLT)is a third generation of histamine H1 receptor antagonist,but also acted as a selective antagonist of 5HTR2A.In this study we investigated whether DLT ameliorated PIPN-like symptoms in mice and the underlying mechanisms.PIPN was induced in male mice by injection of PTX(4 mg/kg,i.p.)every other day for 4 times.The mice exhibited 50%reduction in mechanical threshold,paw thermal response latency and paw cold response latency compared with control mice.PIPN mice were treated with DLT(10,20 mg/kg,i.p.)30 min before each PTX administration in the phase of establishing PIPN mice model and then administered daily for 4 weeks after the model was established.We showed that DLT administration dose-dependently elevated the mechanical,thermal and cold pain thresholds in PIPN mice,whereas administration of DIP(10 mg/kg,i.p.)had no ameliorative effects on PIPN-like symptoms.We found that the expression of 5HTR2A was selectively elevated in the activated spinal astrocytes of PIPN mice.Spinal cord-specific 5HTR2A knockdown by intrathecal injection of AAV9-5Htr2a-shRNA significantly alleviated the mechanical hyperalgesia,thermal and cold hypersensitivity in PIPN mice,while administration of DLT(20 mg/kg)did not further ameliorate PIPN-like symptoms.We demonstrated that DLT administration alleviated dorsal root ganglion neuronal damage and suppressed sciatic nerve destruction,spinal neuron apoptosis and neuroinflammation in the spinal cord of PIPN mice.Furthermore,we revealed that DLT administration suppressed astrocytic neuroinflammation via the 5HTR2A/c-Fos/NLRP3 pathway and blocked astrocyte-neuron crosstalk by targeting 5HTR2A.We conclude that sp

关 键 词：paclitaxel-induced peripheral neuropathy paclitaxel-induced hypersensitivity reactions DESLORATADINE 5HTR2A NLRP3 astrocytic neuroinflammation 

分 类 号：R749[医药卫生—神经病学与精神病学]