Lapatinib ditosylate rescues memory impairment in D-galactose/ovariectomized rats: Potential repositioning of an anti-cancer drug for the treatment of Alzheimer's disease

Abstract

Epidermal growth factor receptor (EGFR) signaling plays a substantial role in learning and memory. The upregulation of EGFR has been embroiled in the pathophysiology of Alzheimer's disease (AD). Nevertheless, most of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have been extensively studied for non-CNS diseases such as cancer and rheumatoid arthritis. TKIs targeting-based research in neurodegenerative disorders sounds to be lagging behind those of other diseases. Hence, this study aims to explore the molecular signaling pathways and the efficacy of treatment with lapatinib ditosylate (LAP), as one of EGFR-TKIs that has not yet been investigated in AD, on cognitive decline induced by ovariectomy (OVX) with chronic administration of D-galactose (D-gal) in female Wistar albino rats. OVX rats were injected with 150 mg/kg/day D-gal ip for 8 weeks to induce AD. Administration of 100 mg/kg/day LAP p.o. for 3 weeks starting after the 8th week of D-gal administration improved memory and debilitated histopathological alterations. LAP decreased the expression of GFAP, p-tau, and Aβ 1-42. Besides, it reduced EGFR, HER-2, TNF-α, NOX-1, GluR-II, p38 MAPK, and p-mTOR. LAP increased nitrite, and neuronal pro-survival transduction proteins; p-PI3K, p-AKT, and p-GSK-3β levels. Taken together, these findings suggest the role of LAP in ameliorating D-gal-induced AD in OVX rats via activating the pro-survival pathway; PI3K-Akt-GSK-3β, while inhibiting p-mTOR, NOX-1, and p38 MAPK pathways. Moreover, this research offered a significant opportunity to advance awareness of the repositioning of TKI anti-cancer drugs for the treatment of AD.