Aqueous extract of Ceratonia siliqua L. leaves elicits antioxidant, anti-inflammatory, and AChE inhibiting effects in amyloid-β42-induced cognitive deficit mice: Role of α7-nAChR in modulating Jak2/PI3K/Akt/GSK-3β/β-catenin cascade

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder attributed to several etiological factors including cholinergic dysregulation, neuroinflammation, oxidative stress, beta-amyloidogenesis, and tauopathy. This demands the search for multitarget drugs, especially of natural sources owing to their pleiotropic activities and low adverse effects. The present study was conducted to investigate the cognitive-improving potential of Ceratonia siliqua L. (Cs) extract compared with donepezil, an acetylcholinesterase inhibitor, on AD-like pathological alterations induced by single intracerebroventricular amyloid-beta 42 (A beta 42) injection in mice. A beta 42-injected mice were treated with Cs (100 mg/kg/day, po) with or without methyllycaconitine (MLA; 1 mg/kg/day, ip), an alpha 7-nAChR antagonist. A beta 42-injected animals demonstrated an elevation of hippocampal A beta 42, p-Tau, and acetylcholinesterase. They also showed a decline in phosphorylated levels of Jak2, PI3K, Akt, and GSK-3 beta, leading to induction of neuroinflammation and oxidative stress. Noteworthy, Cs improved the histopathological and behavioral variables in addition to mitigating AD hallmarks. It also exerted neuroprotection by reducing NF-kappa Bp65 and TNF-alpha, while elevating Nrf2 and HO-1, along with stabilizing beta-catenin under the impact of Jak2/PI3K/Akt/GSK-3 beta signaling. These beneficial effects of Cs were abrogated by MLA co-administration signifying the alpha 7-nAChR involvement in Cs-mediated effects. Therefore, Cs can ameliorate A beta 42-induced neurodegeneration by modulating Jak2/PI3K/Akt/GSK-3 beta/beta-catenin axis in an alpha 7-nAChR-dependent manner.