Suppression of NF-κβ signaling pathway by tocotrienol can prevent diabetes associated cognitive deficits

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Abstract

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.

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-α), interleukin-1beta (IL-1β), NFκβ 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-α, IL-1β, caspase-3 activity and active p65 subunit of NFκβ 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 NFκβ signaling pathway is associated with diabetes induced cognitive impairment and point towards the therapeutic potential of tocotrienol in diabetic encephalopathy.

Introduction

Emerging evidence reveals that diabetes adversely affects the central nervous system. Both acute and chronic metabolic and vascular disturbances can impair the functional and structural integrity of the brain in diabetic patients (Jacobson and Weinger, 1998, Gispen and Biessels, 2000, Northam et al., 2006). However, relatively less is known about the slowly developing end-organ damage to the CNS that may present itself by impairment of cognitive functioning. In a perspective population based study of 6370 elderly individuals, patients with diabetes mellitus have an approximate double risk for the development of dementia (Maiese et al., 2007). In animal models with brain/neuronal insulin receptor knockouts, loss of insulin signaling appears to be linked to increased phosphorylation of the microtubule-associated protein tau that occurs during Alzheimer's disease (Maiese et al., 2007). These cerebral complications of both type 1 and type 2 diabetes may be referred to as ‘diabetic encephalopathy’, a concept introduced several decades ago (Reske-Nielsen et al., 1965). Mijnhout et al. (2006) proposed a new term ‘diabetes-associated cognitive decline’ (DACD) to facilitate research into this area and to increase recognition of the disorder.

Hyperglycemia leads to production of advanced glycation end products (AGEs), and they damage target cells by three mechanisms. First, AGEs modify the intracellular proteins; hence their function is altered. Second, AGEs modify extracellular matrix components, which interact abnormally with the receptors for matrix proteins (integrins) on cell. Third, plasma proteins modified by AGE precursors bind to AGE receptors (Brownlee, 2001) on endothelial cells, mesangial cells, microglia and macrophages, inducing receptor-mediated production of reactive oxygen species (ROS). This AGE receptor ligation activates transcription factor NFκβ, leading to pro-inflammatory gene expression (Schmidt et al., 1999). It includes expression of cytokines and growth factors by macrophages and mesangial cells (IL-1β, IGF-1, TNF-α, TGF-β, macrophage-colony-stimulating factor, granulocyte-macrophage-colony-stimulating factor and platelet-derived growth factor) and expression of pro-coagulatory and pro-inflammatory molecules by endothelial cells (thrombomodulin, tissue factor and VCAM-1). The activation of NF κβ pathway by the hyperglycemia also induces apoptosis in neuronal cells (Mastrocola et al., 2005, Somfai et al., 2006).

Tocochromanols encompass a group of compounds with vitamin E activity essential for human nutrition. Structurally, natural vitamin E includes eight chemically distinct molecules: α-, β-, γ- and δ-tocopherol; and α-, β-, γ- and δ-tocotrienol. Thus, tocotrienols may be viewed as being members of the natural vitamin E family not only structurally but also functionally. Palm oil and rice bran oil represent two major nutritional sources of natural tocotrienol. Taken orally, tocotrienols are bioavailable to all vital organs. Tocotrienols are thought to have more potent antioxidant properties than α-tocopherol (Serbinova et al., 1991, Serbinova and Packer, 1994). The unsaturated side chain of tocotrienol allows for more efficient penetration into tissues that have saturated fatty layers such as the brain and liver (Suzuki et al., 1993). Experimental research examining the antioxidant, free radical scavenging effects of tocopherol and tocotrienols revealed that tocotrienols appear superior due to their better distribution in the fatty layers of the cell membrane (Suzuki et al., 1993, Sen et al., 2007).

With this background, the present study was undertaken to investigate the effects of tocotrienol supplementation on diabetes-induced cognitive impairment and modulation of oxidative–nitrosative stress and cellular death cascade mediators in STZ-induced diabetic rats.

Section snippets

Animals

Male Wistar rats (250–280 g), bred in the Central Animal House Facility of Panjab University, Chandigarh (India) were used. The animals were housed under standard laboratory conditions, maintained on a 12 hour light and dark cycle and had free access to food (Hindustan Lever Products, Kolkata, India) and water. The experimental protocols were approved by the Institutional Animal Ethics Committee of the Panjab University, Chandigarh, and conducted according to the Indian National Science Academy

Effect of tocotrienol on body weight, plasma glucose and insulin levels

Ten weeks after streptozotocin injection, plasma glucose levels were highly elevated in diabetic rats (589 ± 7.48 mg/dl) as compared to the control rats (111 ± 5.62 mg/dl). There was a marked decline in the body weights and insulin levels of streptozotocin-treated rats as compared to age matched control rats (Table 1). Chronic tocotrienol treatment (10 weeks) significantly and dose dependently preserved the body weight and plasma glucose levels. The insulin–tocotrienol combination produced marked

Discussion

In human diabetes, chronic hyperglycemia is associated with a high incidence of progressive dementia (Ryan et al., 2003). The potential mechanisms for this not only include direct effects of hypo- or hyperglycemia and hypo- or hyperinsulimia, but also indirect effects via cerebrovascular alterations (Brands et al., 2004, Lobnig et al., 2005). This study analyzed the role of tocotrienol on the behavioral, biochemical and molecular functions of brains of diabetic rats. STZ-induced diabetes

Conflict of interest

There is no actual or potential conflicts of interest including any financial, personal or other relationships with other people or organizations within three years of beginning the work submitted that could inappropriately influence (bias) their work.

Acknowledgements

The Senior Research Fellowship (Anurag Kuhad) of the Indian Council of Medical Research (ICMR), New Delhi, is gratefully acknowledged. We acknowledge the research support facilities extended by the Centre with Potential for Excellence in Biomedical Sciences (CPEBS) of Panjab University.

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