Suppression of NF-kappabeta signaling pathway by tocotrienol can prevent diabetes associated cognitive deficits.
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 on cognitive function and neuroinflammatory cascade in streptozotocin-induced diabetes.


METHODS
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-1beta), NFkappabeta 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, IL-1beta, caspase-3 activity and active p65 subunit of NFkappabeta 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 on molecular parameters as compared to their per se groups.


CONCLUSIONS
Collectively, the data reveal that activation of NFkappabeta signaling pathway is associated with diabetes induced cognitive impairment and point towards the therapeutic potential of tocotrienol in diabetic encephalopathy.
Kuhad
Anurag
A
Pharmacology Research Laboratory, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study, Panjab University, Chandigarh-160 014, India.
Bishnoi
Mahendra
M
Tiwari
Vinod
V
Chopra
Kanwaljit
K
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003072:Cognition Disorders / Q000150:complications / Q000517:prevention & control*; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D007328:Insulin / Q000097:blood; D015227:Lipid Peroxidation / Q000187:drug effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013311:Streptozocin; D024508:Tocotrienols / Q000494:pharmacology*
D001786:Blood Glucose; D007328:Insulin; D016328:NF-kappa B; D024508:Tocotrienols; D013311:Streptozocin