Cognitive enhancing effects of pazopanib in D‑galactose/ovariectomized Alzheimer’s rat model: insights into the role of RIPK1/RIPK3/MLKL necroptosis signaling pathway

Abstract

Necroptosis, a programmed form of necrotic cell death carried out by receptor-interacting serine/threonine protein kinase 1 (RIPK1) and RIPK3, has been found to be implicated in the pathogenesis of Alzheimer’s disease (AD). An FDA-approved anti-cancer drug, pazopanib, is reported to possess potent inhibitory effect against necroptosis via interfering with RIPK1. So far, there are no existing data on the influence of pazopanib on necroptotic pathway in AD. Thus, this study was designed to explore the impact of pazopanib on cognitive impairment provoked by ovariectomy (OVX) together with D-galactose (D-Gal) administration in rats and to scrutinize the putative signaling pathways underlying pazopanib-induced effects. Animals were allocated into four groups; the first and second groups were exposed to sham operation and administered normal saline and pazopanib (5 mg/kg/day, i.p.), respectively, for 6 weeks, while the third and fourth groups underwent OVX then were injected with D-Gal (150 mg/kg/day, i.p.); concomitantly with pazopanib in the fourth group for 6 weeks. Pazopanib ameliorated cognitive deficits as manifested by improved performance in the Morris water maze besides reversing the histological abnormalities. Pazopanib produced a significant decline in p-Tau and amyloid beta (Aβ) plaques. The neuroprotective effect of pazopanib was revealed by hampering neuroinflammation, mitigating neuronal death and suppressing RIPK1/RIPK3/MLKL necroptosis signaling pathway. Accordingly, hindering neuroinflammation and the necroptotic RIPK1/RIPK3/MLKL pathway could contribute to the neuroprotective effect of pazopanib in D-Gal/OVX rat model. Therefore, this study reveals pazopanib as a valuable therapeutic agent in AD that warrants future inspection to provide further data regarding its neuroprotective effect.

RIPK3 promotes islet amyloid-induced β-cell loss and glucose intolerance in a humanized mouse model of type 2 diabetes

“…This model is in line with studies in other cell types that show caspase 8 and RIPK3 coordinately regulate caspase-dependent apoptosis and caspase-independent necroptosis signaling [ 22 , 24 , 45 ]. Our findings are also in agreement with recent observations of RIPK3 in AD pathogenesis [ 20 , 46 ] and suggest potential overlapping mechanisms of amyloid-associated cytotoxicity in AD and T2D.…”

“…This protection was not related to decreased amyloid deposition per se , indicating that RIPK3 mediates β-cell cytotoxicity downstream of amyloid formation via effects on amyloid-induced cytokine production and/or β-cell death signaling. Although RIPK3 has been identified as a potential therapeutic target in several diseases including cancer [ 57 , 58 ], acute kidney injury [ 59 , 60 ] and neurodegenerative diseases [ 20 , 22 , 46 , 61 ], this work shows that therapeutics targeting RIPK3 may also reduce β-cell cytotoxicity and promote glucose homeostasis during T2D pathogenesis.…”