Cognitive enhancing effects of pazopanib in Dgalactose/ovariectomized Alzheimer's rat model: insights into the role of RIPK1/RIPK3/MLKL necroptosis signaling pathway.
Inflammopharmacology
; 31(5): 2719-2729, 2023 Oct.
Article
en En
| MEDLINE
| ID: mdl-37458952
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 (Aß) 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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
6_ODS3_enfermedades_notrasmisibles
Problema de salud:
6_alzheimer_other_dementias
/
6_mental_health_behavioral_disorders
Asunto principal:
Fármacos Neuroprotectores
/
Enfermedad de Alzheimer
Límite:
Animals
Idioma:
En
Revista:
Inflammopharmacology
Asunto de la revista:
FARMACOLOGIA
/
TERAPIA POR MEDICAMENTOS
Año:
2023
Tipo del documento:
Article
País de afiliación:
Egipto