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<p>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&#xa0;days of 3-NP administration, rats received saline, lapatinib, or pazopanib for 21&#xa0;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<i>.</i>, 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.</p> Graphical abstract <p>Schematic representation summarising the mechanisms underlying the neuroprotective effects of Lapatinib and Pazopanib in 3-NP induced Huntington disease in rats. <i>LAP</i> Lapatinib, <i>PAZO</i> pazopanib, <i>ACh</i> acetylcholine, <i>NE</i> norepinephrine, <i>DA</i> dopamine, <i>5-HT</i> 5-hydroxytryptophan, <i>Glu</i> glutamate, <i>LC3</i> microtubule-associated protein 1A/1B-light chain, <i>ULK-1</i> Unc-51 like autophagy activating kinase, <i>m-Tor</i> mammalian target of rapamycin, <i>AKT</i> protein kinase B, <i>PI3K</i> phosphoinositide 3-kinase, <i>TNF-α</i> tumour necrosis alpha, <i>NFκB</i> nuclear factor kappa B, <i>GFAP</i> glial fibrillary acidic protein, <i>TH</i> tyrosine hydroxylase.</p> <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月10日

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

摘要

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.

Graphical abstract

Schematic representation summarising the mechanisms underlying the neuroprotective effects of Lapatinib and Pazopanib in 3-NP induced Huntington disease in rats. LAP Lapatinib, PAZO pazopanib, ACh acetylcholine, NE norepinephrine, DA dopamine, 5-HT 5-hydroxytryptophan, Glu glutamate, LC3 microtubule-associated protein 1A/1B-light chain, ULK-1 Unc-51 like autophagy activating kinase, m-Tor mammalian target of rapamycin, AKT protein kinase B, PI3K phosphoinositide 3-kinase, TNF-α tumour necrosis alpha, NFκB nuclear factor kappa B, GFAP glial fibrillary acidic protein, TH tyrosine hydroxylase.