Objective: The etiology of diabetes associated cognitive decline is multifactorial and involves insulin receptor down regulation, neuronal apoptosis and glutamatergic neurotransmission. The study was designed to evaluate the impact of tocotrienol oil cognitive function and neuroinflammatory cascade in streptozotocin-induced diabetes. Research design and-method: Streptozotocin-induced diabetic rats were treated with tocotrienol for 10 weeks. Morris water maze Was used for behavioral assessment of memory. Cytoplasmic and nuclear fractions of cerebral cortex and hippocampus were prepared for the quantification of acetylcholinesterase activity, oxidative-nitrosative stress. tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1 beta), NF kappa beta and caspase-3. Results: After 10 weeks of streptozotocin injection, the rats produced significant increase in transfer latency which Was Coupled with enhanced acetylcholinesterase activity, increased oxidative-nitrosative stress, TNF-alpha, caspase-3 activity and active p65 subunit of NF kappa beta in different regions of diabetic rat brain. Interestingly. co-administration of tocotrienol significantly and dose-dependently prevented behavioral, biochemical and molecular changes associated with diabetes. Moreover, diabetic rats treated with insulin-tocotrienol combination produced more, pronounced effect Oil molecular parameters as compared to their per se groups. Conclusions: Collectively, the data reveal that activation of NF kappa beta signaling pathway is associated with diabetes induced cognitive impairment and point towards the therapeutic potential of tocotrienol in diabetic encephalopathy. (C) 2008 Elsevier Inc. All rights reserved.