Rakshit_2026_Biomed.Pharmacother_203_119833

Alzheimer's disease (AD) is the most common neurodegenerative disorder and is characterized by progressive cognitive decline, cholinergic dysfunction, oxidative stress, and neuroinflammation. Despite extensive research, effective disease-modifying therapies remain unavailable. 6-Hydroxyflavanone (6-OH-F), a naturally occurring flavonoid with antioxidant and anti-inflammatory properties, has not been investigated in AD. This study evaluated the neuroprotective potential of 6-OH-F against amyloid-beta (Abeta)-induced AD pathology. Network pharmacology was employed to identify potential targets and pathways associated with 6-OH-F in AD. Neuro-2a cells were pretreated with 6-OH-F (12.5-50 microM) before Abeta exposure, followed by assessment of cell viability, reactive oxygen species (ROS), acetylcholinesterase (AChE), NLRP3, TNF-alpha, and IL-1beta levels. AD was induced in mice by intracerebroventricular administration of pre-aggregated Abeta. Animals received 6-OH-F (15, 30, or 60 mg/kg, p.o.) for four weeks. Behavioral, biochemical, molecular, imaging, and histopathological analyses were subsequently performed. Network pharmacology revealed significant overlap between 6-OH-F targets and AD-associated genes, with enrichment of pathways related to neuronal function and inflammation. In vitro, 6-OH-F attenuated Abeta-induced cytotoxicity and reduced ROS, AChE, NLRP3, TNF-alpha, and IL-1beta levels. In vivo, 6-OH-F improved cognitive performance, alleviated oxidative stress and cholinergic dysfunction, and suppressed the expression of TLR4, pNF-kappaB, NLRP3, ASC, caspase-1, GSDMD, pro-inflammatory cytokines, IBA1, and GFAP. Furthermore, it reduced neuronal degeneration, blood-brain barrier disruption, and cerebral hemodynamic abnormalities. 6-OH-F ameliorates Abeta-induced cognitive impairment by attenuating oxidative stress, neuroinflammation, and pyroptotic signaling, potentially through modulation of the TLR4/NF-kappaB/NLRP3 pathway, highlighting its therapeutic potential in Alzheimer's disease.