Neuroprotective Effects of Tenoxicam and Phenethyl Isothiocyanate in an Aβ₁₋₄₂-Induced Rat Model of Alzheimer's Disease: Modulation of NF-κB/NLRP3 Signaling and Redox Homeostasis.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, neuroinflammation, oxidative stress, and amyloid pathology, yet effective disease-modifying therapies remain limited. This study asked whether combined targeting of inflammatory and oxidative stress pathways could offer enhanced neuroprotection in an Aβ1-42-induced rat model of AD. Tenoxicam, an oxicam-class non-steroidal anti-inflammatory drug with COX-linked anti-inflammatory activity, and phenethyl isothiocyanate (PEITC), a natural compound known for antioxidant and Nrf2-activating properties, were selected on the basis of their complementary mechanisms; however, their combined potential in this model has not been sufficiently explored, providing the rationale for this hypothesis-driven investigation. Male Wistar rats were assigned to control, disease, standard, tenoxicam, PEITC, and combination treatment groups. Cognitive performance was evaluated using the Morris Water Maze, Y-maze, and Novel Object Recognition tests, while neuroinflammatory and oxidative stress markers, including NF-κB, NLRP3, IL-1β, Nrf2, catalase, and malondialdehyde, were assessed alongside histopathological examination of hippocampal integrity and molecular docking against COX-2, NF-κB, and NLRP3. Aβ1-42 administration induced significant cognitive impairment, neuroinflammation, oxidative stress, and neuronal damage. Tenoxicam and PEITC improved behavioral performance, reduced inflammatory signaling, restored antioxidant defenses, and preserved hippocampal architecture, with the combination showing the most pronounced effects. These findings provide preclinical evidence that dual modulation of inflammatory and redox pathways may represent a promising multi-target approach for AD and support further evaluation of this combinatorial strategy.