LAUSR

&NA; Diabetes mellitus (DM) is associated with learning, memory, and cognitive deficits. S‐allyl cysteine (SAC) is the main organosulfur bioactive molecule in aged garlic extract with anti‐diabetic, antioxidant, anti‐inflammatory and nootropic property. This research was conducted to evaluate the efficacy of SAC on alleviation of learning and memory deficits in streptozotocin (STZ)‐diabetic rats and to explore involvement of toll‐like receptor 4 (TLR4), nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2), nuclear factor‐kappa B (NF‐&kgr;B), and heme oxygenase 1 (HO‐1) signaling cascade. Male Wistar rats were divided into control, diabetic, SAC‐treated diabetic, and glibenclamide‐treated diabetic (positive control) groups. SAC was administered at a dose of 150 mg/kg for seven weeks. Treatment of diabetic rats with SAC lowered serum glucose, improved spatial recognition memory in Y maze, discrimination ratio in novel object recognition task, and restored step‐through latency (STL) in passive avoidance paradigm. In addition, SAC reduced acetylcholinesterase activity, lipid peroxidation marker malondialdehyde (MDA) and augmented antioxidant defensive system including superoxide dismutase (SOD), catalase and reduced glutathione (GSH) in hippocampal lysate. Meanwhile, SAC lowered hippocampal NF‐kB, TLR4, and TNF&agr; and prevented reduction of Nrf2 and heme oxygenase‐1 (HO‐1) in diabetic rats. Taken together, chronic SAC treatment could ameliorate cognitive deficits in STZ‐diabetic rats through modulation of Nrf2/NF‐&kgr;B/TLR4/HO‐1, and acetylcholinesterase and attenuation of associated oxidative stress and neuroinflammation.