Ezeldine-Elmahalawy Nada, Abdelkader Noha F, Zaki Hala F, Elbrairy Amany I, Gad Sameh S
Postgraduate program in Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA University), Giza, Egypt.
Inflammopharmacology. 2025 Sep 10. doi: 10.1007/s10787-025-01933-5.
The neuroprotective potential of tyrosine kinase inhibitors (TKIs), potent anticancer drugs, was verified against various neurodegenerative insults, but not Huntington's disease (HD). These promising outcomes were due to their ability to modulate various intracellular signalling pathways. Hence, the current study aimed to evaluate the neuroprotective effects of lapatinib and pazopanib in the 3-nitropropionic (3-NP)-induced HD model in rats. After 14 days of 3-NP administration, rats received saline, lapatinib, or pazopanib for 21 days. Treatment with lapatinib or pazopanib improved the striatal microscopic architecture, neuronal survival, and neuroinflammatory responses, with a pronounced effect observed for pazopanib. At the molecular level, lapatinib and pazopanib reduced the striatal gene expression of NF-κB and TNF-α receptors, curbed the glutamate/calpain-2 axis, and modified the striatal content of inflammatory molecules as well as neurotransmitters. In addition, they activated the neuroprotective trajectory viz., m-Tor/ULK-1/Beclin-1/LC3-II, an effect dependent on tyrosine kinase inhibition. Moreover, treated groups showed normalised tyrosine hydroxylase and glial fibrillary acidic protein in the striatum. In conclusion, this study provides strong evidence that lapatinib or pazopanib significantly improved motor function, alleviated cognitive decline, and attenuated neurodegeneration in HD rats via modulating key signalling pathways implicated in HD pathogenesis. These results underscore the promising therapeutic potential of TKIs in managing HD and warrant further investigation into their clinical application.
酪氨酸激酶抑制剂（TKIs）作为强效抗癌药物，其神经保护潜力已在多种神经退行性损伤模型中得到验证，但在亨廷顿舞蹈病（HD）模型中尚未得到验证。这些令人鼓舞的结果归因于它们调节各种细胞内信号通路的能力。因此，本研究旨在评估拉帕替尼和帕唑帕尼在3-硝基丙酸（3-NP）诱导的大鼠HD模型中的神经保护作用。在给予3-NP 14天后，大鼠接受生理盐水、拉帕替尼或帕唑帕尼治疗21天。拉帕替尼或帕唑帕尼治疗改善了纹状体的微观结构、神经元存活和神经炎症反应，其中帕唑帕尼的效果更为显著。在分子水平上，拉帕替尼和帕唑帕尼降低了纹状体中NF-κB和TNF-α受体的基因表达，抑制了谷氨酸/钙蛋白酶-2轴，并改变了炎症分子和神经递质的纹状体含量。此外，它们激活了神经保护途径，即m-Tor/ULK-1/Beclin-1/LC3-II，这一作用依赖于酪氨酸激酶抑制。此外，治疗组纹状体中的酪氨酸羟化酶和胶质纤维酸性蛋白恢复正常。总之，本研究提供了有力证据，表明拉帕替尼或帕唑帕尼通过调节HD发病机制中涉及的关键信号通路，显著改善了HD大鼠的运动功能，减轻了认知衰退，并减轻了神经退行性变。这些结果强调了TKIs在治疗HD方面具有广阔的治疗潜力，值得进一步研究其临床应用。
