Potential repurposing of lapatinib and pazopanib as neuroprotective agents in a rat model of Huntington's disease.

IF 5.3 2区医学 Q2 IMMUNOLOGY

Inflammopharmacology Pub Date : 2025-09-10 DOI:10.1007/s10787-025-01933-5

Nada Ezeldine-Elmahalawy, Noha F Abdelkader, Hala F Zaki, Amany I Elbrairy, Sameh S Gad

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引用次数: 0

Abstract

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.

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拉帕替尼和帕唑帕尼在亨廷顿病大鼠模型中作为神经保护剂的潜在用途

酪氨酸激酶抑制剂（TKIs）是一种有效的抗癌药物，对各种神经退行性损伤具有神经保护作用，但对亨廷顿氏病（HD）没有作用。这些有希望的结果是由于它们调节各种细胞内信号通路的能力。因此，本研究旨在评价拉帕替尼和帕唑帕尼在3-硝基丙酸（3-NP）诱导的HD大鼠模型中的神经保护作用。3-NP给药14天后，大鼠接受生理盐水、拉帕替尼或帕唑帕尼21天。拉帕替尼或帕唑帕尼治疗可改善纹状体显微结构、神经元存活和神经炎症反应，帕唑帕尼治疗效果显著。在分子水平上，拉帕替尼和帕唑帕尼降低了NF-κB和TNF-α受体纹状体基因表达，抑制了谷氨酸/calpain-2轴，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轨迹，即m-Tor/ULK-1/Beclin-1/LC3-II，这种作用依赖于酪氨酸激酶抑制。此外，治疗组在纹状体中显示正常的酪氨酸羟化酶和胶质纤维酸性蛋白。总之，本研究提供了强有力的证据，表明拉帕替尼或帕唑帕尼通过调节与HD发病机制相关的关键信号通路，显著改善HD大鼠的运动功能，减轻认知能力下降，并减轻神经退行性变。这些结果强调了TKIs在治疗HD方面的治疗潜力，值得进一步研究其临床应用。

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来源期刊

Inflammopharmacology IMMUNOLOGYTOXICOLOGY-TOXICOLOGY

CiteScore

8.00

自引率

3.40%

发文量

200

期刊介绍： Inflammopharmacology is the official publication of the Gastrointestinal Section of the International Union of Basic and Clinical Pharmacology (IUPHAR) and the Hungarian Experimental and Clinical Pharmacology Society (HECPS). Inflammopharmacology publishes papers on all aspects of inflammation and its pharmacological control emphasizing comparisons of (a) different inflammatory states, and (b) the actions, therapeutic efficacy and safety of drugs employed in the treatment of inflammatory conditions. The comparative aspects of the types of inflammatory conditions include gastrointestinal disease (e.g. ulcerative colitis, Crohn''s disease), parasitic diseases, toxicological manifestations of the effects of drugs and environmental agents, arthritic conditions, and inflammatory effects of injury or aging on skeletal muscle. The journal has seven main interest areas: -Drug-Disease Interactions - Conditional Pharmacology - i.e. where the condition (disease or stress state) influences the therapeutic response and side (adverse) effects from anti-inflammatory drugs. Mechanisms of drug-disease and drug disease interactions and the role of different stress states -Rheumatology - particular emphasis on methods of measurement of clinical response effects of new agents, adverse effects from anti-rheumatic drugs -Gastroenterology - with particular emphasis on animal and human models, mechanisms of mucosal inflammation and ulceration and effects of novel and established anti-ulcer, anti-inflammatory agents, or antiparasitic agents -Neuro-Inflammation and Pain - model systems, pharmacology of new analgesic agents and mechanisms of neuro-inflammation and pain -Novel drugs, natural products and nutraceuticals - and their effects on inflammatory processes, especially where there are indications of novel modes action compared with conventional drugs e.g. NSAIDs -Muscle-immune interactions during inflammation [...]