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

TL;DR

This study explores how cancer drugs lapatinib and pazopanib may protect brain cells in a rat model of Huntington’s disease, showing promising results for future treatments.

Contribution

The novel contribution is evaluating lapatinib and pazopanib as potential neuroprotective agents in Huntington’s disease for the first time.

Findings

Lapatinib and pazopanib improved striatal architecture, neuronal survival, and reduced neuroinflammation in HD rats.

Both drugs modulated key signaling pathways like m-Tor/ULK-1/Beclin-1/LC3-II and reduced NF-κB and TNF-α gene expression.

Treatment normalized neurotransmitter levels and showed improved motor and cognitive function in HD rats.

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.

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.

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