Dietary and donepezil modulation of mTOR signaling and neuroinflammation in the brain

Somewhat ironically, as the world slowly rids itself of the suffering caused by food scarcity, obesity is simultaneously becoming a major concern for many segments of the global population. The effects of obesity brought on by a High Fat Diet (HFD) are numerous; it has been linked to diabetes, heart disease and several different forms of cancer. Additionally, obesity has also been linked to the development of several brain related pathologies. For example, obesity has been determined to be one of the most significant factors in the development of dementia-related neurodegenerative disorders. This is largely because an HFD, according to studies conducted on mice, can increase neuroinflammation and oxidative stress, decrease cognitive function, and decrease levels of anti-oxidant enzymes in the brain. HFD has also been shown to impair BBB integrity, bring about hippocampal inflammation, and alter synaptic plasticity. Several causes have been identified to link HFD and neurodegeneration, such as the activation of the mammalian target of rapamycin (mTOR) pathway, which leads to neural inflammation, as well as increased levels of acetylcholinesterase (AChE). From this, researchers have approached the treatment of neural disorders such as dementia and Alzheimer's Disease (AD) by using AChE inhibitors and have developed several effective therapies. One of these, which is also one of the only approved treatments available, is the use of Donepezil. Donepezil has been shown to inhibit cholinesterase activity, thus increasing the acetylcholine (ACh) levels for cholinergic transmission, but the mechanisms of action are still unclear and the effects of Donepezil on HFD-induced neural conditions have not been studied; a study conducted by Dasuri et al. at the Pennington Biomedical Research Center at Louisiana State University sought to understand this effect.

Two groups of mice were studied; one group was administered an HFD and another a low-fat diet (LFD). Within each group Donepezil administration was either present or absent. From there, researchers measured a variety of different factors that would indicate the onset of neurodegenerative disorders, such as AChE levels. To do this, they used the Amplite Colorimetric Acetylcholinesterase Assay Kit. Using DTNB in the kit to quantify the thiolcholine produced from the hydrolysis of acetylthiolcholine by AChE and demonstrating results in the form of clear, bright fluorescence, researchers were able to accurately track AChE activity to determine the effectiveness of Donepezil.

Their findings showed that Donepezil was, in fact, effective in warding off mTOR signaling and reducing AChE activity that was seen in the group of mice given the HFD. This indicates that Donepezil can be an effective treatment for neurodegeneration resulting from HFD-induced obesity. The results of this study are profound, as they allow yet another group of people to receive treatment from damaging brain disorders. The validity of these conclusions comes from the reliability of the results obtained; the robustness of the readings coming from the Amplite Colorimetric Acetylcholinesterase Assay Kit give researchers full confidence in what they are studying, allowing them to proceed with critical tests like these and make breakthroughs for treatments that stand to improve the lives of many individuals.

References

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1. Dasuri, Kalavathi, et al. "Dietary and donepezil modulation of mTOR signaling and neuroinflammation in the brain." Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 1862.2 (2016): 274-283.