The purpose of the current research was to develop synergistic nutraceutical combinations in vitro as a potential preventative medicine for Alzheimer’s disease. Docosahexaenoic acid (DHA), luteolin, and urolithin A were among the compounds of interest. The cells’ viability and cytotoxicity assays MTS and LDH were used to see how well individual substances or two-compound combinations prevented Ab1-42 induced toxicity in human neuroblastoma BE(2)-M17 cells.
Alzheimer’s disease (AD) is the most prevalent form of dementia across the world. The traditional AD brain includes extracellular amyloid-b protein clumps, or senile plaques, and intracellular neurofibrillary tangles composed of hyperphosphorylated Tau molecules. For some proposed therapies for AD, there has been limited success in clinical trials, therefore attention has turned to alternative treatments such as food supplements. As a result, nutraceuticals have become intriguing candidates due to their potential neuroprotective effects.
Our research results indicate that a synergistic combination of three compounds (D5L5U5) was the most effective at inhibiting Ab1-42-induced toxicity. This discovery could potentially have significant implications for preventive and co-treatment strategies against Alzheimer’s Disease, hence warranting further investigation into its mechanism of action as well as providing an opportunity to develop advanced functional foods in this regard.
Introduction
Plants are a remarkable source of bioactive compounds, known as phytochemicals. As they defend themselves against attacks from insects and other organisms, these chemicals demonstrate the immense potential to combat disease in humans through their ability to modulate molecular targets within our bodies. Traditional medicines relying on mixtures of herbs have been practiced for centuries throughout parts of Asia such as China, Sri Lanka, and India; today we increasingly tap into this resource by employing herbal remedies derived from plants with powerful natural healing capabilities.
Advances in technology have significantly impacted modern medicine, allowing for a deeper understanding of diseases and drug interactions. Combination drug therapies are an increasingly popular solution to various medical conditions as they optimize therapeutic efficacy while minimizing toxicity effects and the likelihood of resistance. Furthermore, natural compounds offer exciting potential when seeking treatments that existing monotherapies cannot provide enough support with due to their lack of discovery or approval status by organizations such as the FDA.
Alzheimer’s Disease (AD) is a devastating neurodegenerative disorder that has become the second leading cause of death in Australia. Characterized by deposits of amyloid-b protein aggregates known as senile plaques and intracellular hyperphosphorylated tau tangles, AD can be attributed to the normal metabolic processing of Amyloid Precursor Protein (APP). Of these proteins found within the classical AD brain, 90% are composed primarily of Ab1-40 and Ab1-42 peptides – with Ab 1-.42 being identified as particularly toxic.
In the past 16 years, pharmaceutical research has been largely unsuccessful in developing safe and effective drugs for Alzheimer’s Disease (AD). Despite 136 clinical trials conducted up to February 2020 with 121 studied medications, only recently approved Aducanumab can claim success. Unfortunately, its approval is mired by controversy due to unresolved efficacy issues as well as instances of overall failure from similar studies in recent memory.
In light of the inadequacy of available drugs and their adverse effects, combination therapies are being considered for Alzheimer’s disease (AD). Recent evidence suggests that this approach may be more effective than monotherapies. For example, researchers discovered a drug mixture composed of two approved compounds – acamprosate and baclofen – to offer synergistic protection against toxic Ab oligomers in both rat cortical neurons as well as human brain-derived microvascular endothelial cells. Furthermore, cognitive deficits were significantly alleviated when tested on acute Ab25-35 peptide injection mouse models and mutant APP transgenic mice.
Multiple drug combinations have been analyzed through several clinical trials and studies to determine their potential as treatments for Alzheimer’s Disease. Notable examples of these include Memantine, an N-methyl-D-aspartate receptor antagonist combined with Acetyl Cholinesterase inhibitors such as Rivastigmine, Donepezil, or Galantamine.
With treatments for Alzheimer’s Disease proving ineffective, the concept of prevention is becoming increasingly prominent. This complex disorder may have multiple pathways to avoid or delay its onset – including a focus on reducing risk through diet and exercise alterations as well as lifestyle modifications. It’s time we look at potential preventive measures that could make all the difference in fighting this devastating condition.
The Mediterranean diet (MeDi) is an effective lifestyle modulation that can reduce the risk of Alzheimer’s disease. It involves a variety of nutritionally-rich foods such as vegetables, fruits, unsaturated fatty acids from olive oil, fish, and low intakes of dairy products like cheese or yogurt along with moderate portions of chicken and red wine for optimal cognitive performance in AD patients.
Pomegranates are a rich source of polyphenols, containing powerful compounds such as ellagitannins and flavonoids. Punicalagin is the most abundant compound found in pomegranate juice; although its bioavailability is low, it can be converted by the gut microbiota into urolithin A (UA), which has significantly greater uptake. Studies conducted on mice have demonstrated that UA derived from pomegranate consumption reduces levels of soluble Ab42 up to 50%, ultimately reducing amyloid deposition in the hippocampus – making this fruit an attractive potential element for fighting against Alzheimer’s disease (AD).
Luteolin, a prominent flavone compound found in pomegranate peel, has shown great potential as an anti-inflammatory and antioxidant agent. Furthermore, it inhibits BACE1 by manipulating the NF-kB signaling pathway, which reduces Tau hyperphosphorylation mediated by zinc exposure to SH-SY5Y cells. In addition to this beneficial effect on neural health demonstrated in murine cortical neurons exposed to Ab25–35 peptide toxicity model, research is currently underway regarding luteolin’s ability to inhibit nonfibrillar forms of amyloid β (Ab) proteins such as Ab1–42 toxicities.
A recent study conducted in mice with the human APP K670N-M671L (APPsw) transgenic mouse model explored the potential benefits of Omega-3 polyunsaturated fatty acids, specifically docosahexaenoic acid (DHA). DHA treatment resulted in reduced levels of Ab40 and Ab42 proteins as well as a decrease in amyloid plaque burden. Several studies also found that DHA inhibited BACE1 activity while simultaneously increasing alpha-secretase activity – contributing to an overall better understanding of marine food sources like fish and algae’s ability to combat Alzheimer’s disease.
DHA has shown the potential to reduce Ab release, inhibit the formation of toxic Ab1-42 fibrils, and decrease soluble oligomer levels in vitro. Similarly, promising results have been observed for DHA’s effects on rats with an artificially induced abundance of Aβ infusions. Nevertheless, further research is required before its efficacy can be confirmed as a safe remedy against amyloidogenic processing disorders like Alzheimer’s Disease.
Recent evidence has indicated that a combination of food-derived compounds, such as EGCG, DHA, and α-lipoic acid powder may be key in fighting Alzheimer’s Disease. The potential beneficial effect was demonstrated on Tg2576 transgenic mice; however further research is needed to examine the effectiveness of multiple target nutraceutical compounds against AD.
This study aimed to explore the potential of combining DHA, LUT, and UA in nutraceutical combinations effectively targeting Alzheimer’s Disease (AD). The compounds were screened for their ability to inhibit Ab1-42 toxicity before being combined with each other. Combination Index calculations through CompuSyn software identified synergism as well as possible antagonistic effects between single compounds, providing a powerful tool for evaluating drug combination action against AD.
The detailed MATERIALS AND METHODS, Statistical Analysis, results, and conclusions are in the literature, please check it out in the end.
References:
Jayatunga, D. P. W., Hone, E., Fernando, W. M. A. D. B., Garg, M. L., Verdile, G., & Martins, R. N. (2022). A Synergistic Combination of DHA, Luteolin, and Urolithin A Against Alzheimer’s Disease. In Frontiers in Aging Neuroscience (Vol. 14). Frontiers Media SA. https://doi.org/10.3389/fnagi.2022.780602
