Abstract
Oryza sativa is a globally recognized staple food, rich in essential phyto-phenolic compounds such as γ-Oryzanol (OZ), Ferulic acid (FA), and Ellagic acid (EA). These phytochemicals are known for their potential to beneficially modulate molecular biochemistry. The present investigation aimed to evaluate the neuroprotective and cognitive enhancement effects of Oryza sativa phyto-phenolics in a model of early-onset Alzheimer's disease (EOAD) induced by Aβ (1-42) in animals. In-silico studies suggested that FA, OZ, and EA have target specificity for Aβ, with EA being further selected based on its potent in-vitro Aβ anti-aggregatory effects for exploring neurodegenerative conditions. The in-vivo experiments demonstrated that EA exerts therapeutic effects in Aβ-induced EOAD, modulating both biochemical and behavioral outcomes. EA treatment at two dose levels, EA70 and EA140 (70 μM and 140 μM, respectively, administered i.c.v.), significantly counteracted Aβ aggregation and modulated the Ca2⁺/Calpain/GSK-3β/CDK5 signaling pathways, exhibiting anti-tauopathy effects. Additionally, EA was shown to exert anti-inflammatory effects by preventing astroglial activation, modulating FAIM-L expression, and protecting against TNF-α-induced apoptotic signals. Moreover, the neuromodulatory effects of EA were attributed to the regulation of CREB levels, Dnm-1 expression, and synaptophysin levels, thereby enhancing LTP and synaptic plasticity. EA also induced beneficial cytological and behavioral changes, improving both long-term and short-term spatial memory as well as associative learning behavior in the animal model, which underscores its cognitive enhancement properties.