Science Behind Neuromodin™
Neuromodin™:
A uniquely formulated natural extract blend
Neuromodin™ is a proprietary, highly bioavailable form of Japanese Knotweed extract, a concentrated source of therapeutic plant compounds, which may offer important anti-inflammatory, antioxidant, and neuroprotective benefits.
THE SCIENCE
Emodin is a natural anthraquinone compound that can be isolated from various sources including buckthorn, rhubarb, and Japanese Knotweed (Polygonum cuspidatum). It has been used in the herbs of traditional Chinese medicine for centuries. Research studies have suggested that emodin has powerful anti-inflammatory and anti-oxidant properties, and can act as a neuroprotective agent to prevent neurotoxicity, neuroinflammation, and oxidative stress-induced neuronal loss, which have been implicated in diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and cerebral ischemia. It also has anti-proliferative properties that may offer potential as an anticancer agent.
There are several proposed mechanisms of action for emodin and safety/tolerability data published in animal models.
By itself, emodin is poorly bioavailable (1), which has limited its therapeutic potential. Often, large doses of the compound have been studied in animals to observe its beneficial effects.
Neuromodin™ is a proprietary formulation of Japanese Knotweed extract, an important source of emodin, which has been especially formulated to enhance bioavailability and facilitate administration.
MECHANISMS
Several studies have shown that emodin modulates intracellular signaling pathways that increase or decrease the production of proteins known to protect cells from stress. It has been hypothesized that the benefits exhibited by emodin are the result of the compound’s effect on these signaling pathways. The graphic below summarizes many of these proposed mechanisms of emodin.
Two possible mechanisms of emodin have been particularly well studied, and may be responsible for some of the compound’s effects as a neuroprotective agent:
ANTIPURINERGIC AGENT (2,3,4): Emodin is a potent and selective antagonist of the P2X7 purine receptor. It may be through this mechanism that the compound derives its effects in reducing neuroinflammation, neuronal apoptosis, and oxidative stress. The pharmaceutical agent, suramin, is a non-selective antipurinergic agent that has been studied as a potential treatment for autism spectrum disorder, and proposed for other important health conditions where chronic cellular inflammation is believed to play a role (2,5).
NRF2 ACTIVATOR (6,7,8): Emodin activates nuclear factor erythroid 2–related factor 2 (NRF2), which leads to a reduction in oxidative stress, inflammation, and mitochondrial dysfunction.
NEUROPROTECTIVE EFFECTS
Emodin has been studied in several in vitro and in vivo animal models of neurologic disease. Notably, emodin has shown to be neuroprotective in various models of Alzheimer’s disease, Parkinson’s disease, and cerebral ischemia (7,8,9,10,11,12,13).
Reduced Neuronal Oxidative Stress
Emodin significantly enhanced cell viability, reduced cell apoptosis and LDH release. Simultaneously, emodin down-regulated H2O2-induced inflammatory factors, including IL-6, NO, and TNF-α, and alleviated H2O2-induced oxidative stress and mitochondrial dysfunction in SH-SY5Y cells (Li et al. 2020) (12).
Reduced Neuronal Cell Death
Emodin was shown to inhibit cerebral ischemia-reperfusion-induced neurological deficit, and reduce the progression of ischemic stroke, neuronal cell death, and cerebral edema. The protective effects of emodin were mediated by the downregulation of connexin 43 (Cx43) and aquaporin 4 (AQP4) (Li et al. 2018) (9).
Reduced Neuroinflammation
Emodin activates AMPK/Nrf2 signaling, which exerts neuroprotective effects. Emodin effectively inhibited the production of pro-inflammatory cytokines and has been used as a natural anti-neuroinflammatory agent. (Park et al. 2017) (8).
STUDY IN MOUSE MODEL OF AUTISM
A highly bioavailable form of emodin was studied in a genetic mouse model of autism (i.e. the FMR-1 knockout mouse). These mice exhibit cognitive and behavioral deficits that are similar to those seen in humans with autism. In this study, the genetically altered mice that were treated with emodin exhibited dramatic improvements in spatial learning, short term and retained memory, similar to the wild type (i.e. the genetically unaltered) mice. In addition, the genetically altered mice treated with emodin exhibited increased social activity, reduced anxiety, and a greater willingness to explore their environment, also similar to that seen in the wild type mice.
This work was sponsored by the pharmaceutical company, PaxMedica, Inc., which has a patent pending on the use of emodin in the treatment of neurodevelopmental conditions (14).
Learn more about the science behind Neuromodin™ by viewing the webinar video below
SAFETY AND TOLERABILITY
Japanese Knotweed has been used in traditional Chinese medicine for centuries, and there are no reported risks of Japanese Knotweed or piperine in humans.
Emodin Study in Mice (15)
While there have been no published clinical studies on the use of emodin, one study in mice showed the compound to be safe at multiple doses over a 12 week period.
Study Design:
Investigators fed male and female mice a standard diet infused with varying concentrations of emodin over a 12-week period (20 mg/kg, 40 mg/kg, and 80 mg/kg).
Results:
After 12-weeks there were no toxicities observed in the liver, kidneys, or heart.
Conclusion:
Emodin consumption over a 12-week period is safe in mice at concentrations of 20mg/kg, 40mg/kg, and 80mg/kg body weight.
Resveratrol
Resveratrol, another compound that is found in Japanese Knotweed at levels similar to emodin, has been associated with nausea, vomiting, diarrhea, and liver dysfunction in rare instances and in certain patient populations. These adverse effects have typically occurred when the compound has been consumed at high levels over long periods of time (16).
European Regulations
In Europe, there have been historical concerns surrounding the use of hydroxyanthracene derivatives, including emodin and related compounds, in food. A rigorous analysis was commissioned by the European Food Safety Authority (EFSA), where the Panel on Food Additives and Nutrient Sources Added to Food (ANS) published a report in 2018, which concluded that there is some evidence of in vitro genotoxicity with high doses of emodin and aloe emodin (17). As such, the Panel concluded that there is a theoretical safety concern from certain botanical extracts that contain hydroxyanthracene derivatives at high doses. Those with substances considered for risk assessment by the EFSA are derived from specific plants, including Rheum palmatum, Cassia senna, Rhamnus frangula, Rhamnus purshiana, and Aloe barbadensis. Notably, the Panel did not mention Japanese Knotweed (Polygonum cuspidatum) in its risk assessment, and Japanese Knotweed is the supplement source in Neuromodin™.
In addition, in 2022, the same Panel met to review the use of resveratrol as a food supplement. Japanese Knotweed has been well known to be a source of resveratrol and is often used as a supplement for this product as well. In this meeting, the Panel specifically listed Japanese Knotweed as an acceptable source of resveratrol supplementation (18), validating its safety.
The safety concerns around the use of plant extracts containing hydroxyanthracene derivatives stem from the long established use of these extracts as laxatives, which may relate to their historical use at high doses. If you should experience any laxative effects of Neuromodin™, or any other adverse effects, we would encourage you to discontinue use and consult with your physician.
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In summary, we are excited by the science behind Neuromodin™ and believe in its potential as a natural and safe dietary supplement that may provide important benefits in learning, memory, and behavior.
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FUTURE STUDIES
We are committed to advancing the science around the use of Neuromodin™ to further validate its potential benefits in enhancing memory, cognition, and behavior. We plan to conduct clinical trials with Neuromodin™ in the near future, and would welcome your interest and participation. Please Contact Us to join our mailing list and learn more once we launch our trials.
REFERENCES
(1) C.-S. Shia, Y.-C. Hou, S.-Y. Tsai, P.-H. Huieh, Y.-L. Leu, P.-D.L. Chao (2010). Differences in pharmacokinetics and ex vivo antioxidant activity following intravenous and oral administrations of emodin to rats. J. Pharmaceut. Sci., 99 (4), pp. 2185-2195.
(2) Naviaux RK (2017). Antipurinergic therapy for autism-An in-depth review. Mitochondrion. 2018 Nov;43:1-15. doi: 10.1016/j.mito.2017.12.007. Epub 2017 Dec 16. PMID: 29253638
(3) Kong, H., Zhao, H., Chen, T. et al. (2022). Targeted P2X7/NLRP3 signaling pathway against inflammation, apoptosis, and pyroptosis of retinal endothelial cells in diabetic retinopathy. Cell Death Dis 13, 336. https://doi.org/10.1038/s41419-022-04786-w
(4) Pelegrin P (2021). P2X7 receptor and the NLRP3 inflammasome: Partners in crime. Biochem Pharmacol. 2021 May; 187:114385.
doi: 10.1016/j.bcp.2020.114385. Epub 2020 Dec 20. PMID: 33359010.
(5) Hough et al. (2023). Randomized clinical trial of low dose suramin intravenous infusions for treatment of autism spectrum disorder. Ann Gen Psychiatry. 22: 45. Published online 2023 Nov 6.
doi: 10.1186/s12991-023-00477-8
(6) Ding, Z., Da, H. H., Osama, A., Xi, J., Hou, Y., & Fang, J. (2021). Emodin ameliorates antioxidant capacity and exerts neuroprotective effect via PKM2-mediated Nrf2 transactivation. Food and Chemical Toxicology, 160, 112790. https://doi.org/10.1016/j.fct.2021.112790
(7) Li Z, Bi H, Jiang H, Song J, Meng Q, Zhang Y, Fei X (2021). Neuroprotective effect of emodin against Alzheimer's disease via Nrf2 signaling in U251 cells and APP/PS1 mice. Mol Med Rep. 2021 Feb;23(2):108.
doi: 10.3892/mmr.2020.11747. Epub 2020 Dec 10. PMID: 33300068; PMCID: PMC7723071.
(8) Park, S.Y., Jin, M.L., Ko, M.J. et al. (2016). Anti-neuroinflammatory Effect of Emodin in LPS-Stimulated Microglia: Involvement of AMPK/Nrf2 Activation. Neurochem Res 41, 2981–2992.
https://doi.org/10.1007/s11064-016-2018-6
(9) Y. Li, Q.Q. Xu, C.S. Shan, Y.H. Shi, Y. Wang, G.Q. Zheng (2018). Combined use of emodin and ginsenoside Rb1 exerts synergistic neuroprotection in cerebral ischemia/reperfusion rats. Front. Pharm., 9, p. 943.
(10) Y.P. Sun, J.P. Liu (2015). Blockade of emodin on amyloid-beta 25–35-induced neurotoxicity in AbetaPP/PS1 mice and PC12 cells through activation of the class III phosphatidylinositol 3-kinase/Beclin-1/B-cell lymphoma 2 pathway. Planta Med., 81 (2), pp. 108-115.
(11) S.M. Ahn, H.N. Kim, Y.R. Kim, Y.W. Choi, C.M. Kim, H.K. Shin, B.T. Choi (2016). Emodin from Polygonum multiflorum ameliorates oxidative toxicity in HT22 cells and deficits in photothrombotic ischemia. J Ethnopharmacol, 2016 Jul 21: 188:13-20.
DOI: 10.1016/j.jep.2016.04.058
(12) R. Li, W. Liu, L. Ou, F. Gao, M. Li, L. Wang, P. Wei, F. Miao (2020). Emodin alleviates hydrogen peroxide-induced inflammation and oxidative stress via mitochondrial dysfunction by inhibiting the PI3K/mTOR/GSK3β pathway in neuroblastoma SH-SY5Y cells. BioMed Res. Int., p. 1562915.
(13) S.Y. Park, Y.-W. Choi, G. Park (2018). Nrf2-mediated neuroprotection against oxygen-glucose deprivation/reperfusion injury by emodin via AMPK-dependent inhibition of GSK-3β. J. Pharm. Pharm., 70 (4), pp. 525-535.
(14) Rome Z, Derby M, inventors (2020); PaxMedica Inc., assignee. Administration of antipurinergic compositions for treating nervous system disorders. United States patent application, US 63/104,357. 2020 Oct 22.
(15) Sougiannis AT, Enos RT, VanderVeen BN, Velazquez KT, Kelly B, McDonald S, Cotham W, Chatzistamou I, Nagarkatti M, Fan D, Murphy EA (2021). Safety of natural anthraquinone emodin: an assessment in mice. BMC Pharmacol Toxicol. 2021 Jan 28;22(1):9.
doi: 10.1186/s40360-021-00474-1. PMID: 33509280; PMCID: PMC7845031.
(16) Salehi B, Mishra AP, Nigam M, et al. (2018). Resveratrol: a double-edged sword in health benefits. Biomedicines. 6(3):91.
doi:10.3390/biomedicines6030091
(17) EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS) (2018). Safety of hydroxyanthracene derivatives for use in food. EFSA Journal 2018; 16(1): 5090.
(18) COMMISSION IMPLEMENTING REGULATION (EU) 2022/672. Amending Implementing Regulation (EU) 2017/2470 as regards the specifications of the novel food trans-resveratrol (from microbial source). Official Journal of the European Union. 25 April 2022.
(19) Sharifi-Rad, J., Herrera-Bravo, J., Kamiloglu, S., Petroni, K., Mishra, A. P., Monserrat-Mesquida, M., Sureda, A., Martorell, M., Aidarbekovna, D. S., Yessimsiitova, Z., Ydyrys, A., Hano, C., Calina, D., & Cho, W. C. (2022). Recent advances in the therapeutic potential of emodin for human health. Biomedicine &Amp; Pharmacotherapy, 154, 113555.