Cognitive enhancing effect of diapocynin in D-galactose-ovariectomy-induced Alzheimer's-like disease in rats: Role of ERK, GSK-3β, and JNK signaling.

NADPH oxidase (NOX) has been identified as a crucial contender of oxidative damage in Alzheimer's disease (AD). However, the capability of diapocynin, a NOX inhibitor, to offer neuroprotection in AD models is still a matter of debate. Hence, the current work is dedicated to investigate the influence of diapocynin on cognitive impairment prompted by ovariectomy combined with D-galactose injection in rats (an AD animal model), and to elucidate the signaling mechanisms regulating diapocynin-induced effects. Female rats were exposed to ovariectomy or sham operation. Ovariectomized rats were injected intraperitoneally with D-galactose (150 mg/kg/day) for 70 days and, on day 43, they were orally treated with diapocynin (10 mg/kg/day) for 28 days. Diapocynin amended cognitive functions as confirmed using novel object recognition and Morris water maze tests along with histopathological improvement. It caused a prominent decrement in β-secretase, p-tau, and amyloid β, contrary to α-secretase elevation in hippocampus and hampered neuroinflammation and oxidative stress, manifested by declined levels of NOX1, tumor necrosis factor-α, and nuclear factor-kappa B p65. In addition, diapocynin augmented synaptophysin, brain-derived neurotrophic factor, and phospho-cAMP response element binding protein and enhanced protein expression of phosphorylated forms of phosphoinositide 3-kinase (PI3K), glycogen synthase kinase-3β (GSK-3β), protein kinase B (Akt), extracellular signal-regulated kinase (ERK) 1/2, ERK kinase kinase (Raf-1), and ERK kinase (MEK) 1/2, while inhibiting those of c-Jun and c-Jun N-terminal kinase (JNK). In conclusion, diapocynin attenuated memory impairment and AD-like anomalies via activating Raf-1/MEK/ERK and PI3K/Akt/GSK-3β, while inhibiting JNK/c-Jun signaling cascades.