Brain health

Neurological disorders have become increasingly prevalent in the in the past few decades. Ranging from anxiety and depression to neurodegenerative diseases like Parkinson's or Alzheimer's, neurological impairments are arising as some of the most concerning consequence of modern lifestyles, making brain health a critical focus for nutraceutical applications.

At the same time, emerging research is pointing towards potent natural compounds as potential solutions to prevent and mitigate an large array of these neurological conditions. And Korean ginseng's ginsenosides, through their role in modulating key biochemical pathways related to inflammation, neurotransmitter balance, and neuronal health, could be one of them.

Neuroinflammation is a complex biological process that plays a vital role in protecting our nervous system. However, when this process becomes chronic, it can lead to a host of health issues, from mood imbalance to neurological disorders [1-2].

Multiple ginsenosides have been shown to have potent anti-inflammatory properties and neuroprotective effects. They are known to modulate the production and release of cytokines, which play a crucial role in the development of neuroinflammatory responses. Those effects are possible three main pathways:

Inhibition of NF-kappaB

Rare ginsenosides like Rh2 [3], Rk1 [4] and Rg3 [5], as well as some classical ones like Rd [6], Rg1 [7] and Rb1 [8], can modulate the activation of the NF-κB pathway, a signaling pathway involved in the production of pro-inflammatory cytokines. By inhibiting this physiological process, ginsenosides can reduce excessive neuroinflammation and its associated symptoms.

Activation of Nrf2

Rare ginsenosides like Rh2[9-10], Rk3[11] and Rk1[12], can activate the Nrf2 pathway, which plays a key role in the cellular defense system against oxidative stress and inflammation. Activation of this mechanism can enhance antioxidant and anti-inflammatory mechanisms, further reducing the harmful effects of chronic neuroinflammation [13-17].

Stimulation of BDNF

Rare ginsenosides like Rk1[18], Rh2[19], Rg3[20] and its classical precursor (Rb1[21]) can increase the expression of brain-derived neurotrophic factor (BDNF), a protein that promotes the growth and survival of neurons. BDNF has been found to play a crucial role in learning, memory, and neuroplasticity, and its decreased expression has been associated with several neurological disorders, including depression and Alzheimer's disease. By increasing BDNF expression, ginsenosides can promote brain health and cognitive function.

Conclusion

Neuroinflammation is at the heart of brain health, and ginsenosides have been shown to have potent anti-inflammatory and neuroprotective effects that can improve brain function and reduce the risk of developing these disorders. The existing evidence suggests that this natural compound could be a promising phytonutrient for promoting overall brain health and preventing neurodegenerative issues.

Serotonin is a neurotransmitter that plays a critical role in regulating mood, cognition, and behavior. It is synthesized from the amino acid tryptophan, which is exclusively obtained from our diet. However, tryptophan metabolism can be disrupted in a number of ways, leading to imbalance in serotonin levels that can contributes to several health issues.

Ginsenosides have been found to modulate serotonin balance by targeting several key pathways of tryptophan metabolism, avoiding disruption of serotonin supply :

Inhibition of Kynurenin pathway

Rare ginsenoside Rg3[22] and its classical precursor (Rb1[23]) have been reported to limit the activation of the kynurenine pathway and to inhibit its key enzyme: IDO. The Kynurenine pathway is a complex physiological process that has been implicated in a range of physiological processes, including inflammation and brain functions. By limiting excessive activation of the kynurenine pathway, Rg3 limits the risk of neuroinflammation and the overconsumption of tryptophan, allowing this amino-acid to be used for serotonin production instead of kynurenine production.

Activation of AhR pathway

Multiple ginsenosides have been identified as activators of the AhR pathway [24-26]. In addition, ginsenoside Rg1 was reported to increase the production of Indole derivatives by the gut microbiota [27], leading to an increased activation of the AhR pathway.

The AhR pathway is activated by a range of ligands including tryptophan metabolites. Once activated, the AhR pathway regulates gene expression and modulates a range of cellular processes, including inflammation, oxidative stress, and cellular metabolism.

Conclusion

By modulating tryptophan metabolism through the inhibition of Kynurenin pathway, ginsenosides are able to support serotoninergic balance, while supporting in the same time the immune system aspect of tryptophan metabolism through AhR activation.

GABAergic pathways are related to the network of neurons that utilize the neurotransmitter gamma-aminobutyric acid (GABA) and inhibit or reduce the activity of other neurons in the brain. Those pathways play a critical role in regulating a wide range of physiological and behavioral processes, including mood, anxiety, and stress. The GABAergic support is particularly important for mental health and well-being because it helps to prevent overstimulation of the nervous system, which can lead to feelings of anxiety and distress. This kind of support is usually considered to be at the core of a grounding effect, leading to a sense of being grounded in the present moment and avoid excessive nervosity.

Support GABA signal

Some rare ginsenosides, like Rg3[28] and CK[29] , have been reported to increase GABAergic signaling. This increase of GABA signal can be explained by different mechanisms including spontaneous release of GABA, or increase of GABA level.

Increase GABA Receptor expression

Some rare ginsenosides like Rg5 and Rk1 [30] , as well as a their precursor Rb1 [31], were reported to increase the expression of GABA receptors. By doing so, they can increase sensitivity of the GABAergic pathways and therefore support mental balance.

Conclusion

Ginsenosides are able to support GABAergic pathways leading to a grounding effect. Combined with the serotoninergic balance, ginsenosides offer a unique effect that favors mental well-being.

As our understanding of neurological health continues to deepen, it becomes increasingly clear that mitigating neuroinflammation and maintaining neurotransmitter balance is crucial in preserving brain health.

While further research is needed to fully understand their therapeutic potential, Korean ginseng and its bioactive compounds could well offer a natural, comprehensive and multi-target approach for evidence-based natural solutions to promote Brain Health, as show by their promising results on modulating neuroinflammation, supporting serotoninergic balance, and reinforcing GABAergic pathways.

• [1] Marino M, Mele E, Pastorino GMG, Meccariello R, Operto FF, Santoro A, Viggiano A (2022) – “Neuroinflammation: Molecular Mechanisms And Therapeutic Perspectives.” Cent Nerv Syst Agents Med Chem. 2022;22(3):160-174. doi: 10.2174/1871524922666220929153215.
• [2] Lyman M, Lloyd DG, Ji X, Vizcaychipi MP, Ma D. (2014) – “Neuroinflammation: the role and consequences.” Neurosci Res. 2014 Feb;79:1-12. doi: 10.1016/j.neures.2013.10.004. Epub 2013 Oct 19.
• [3] Xu X, Lu YN, Cheng JH, Lan HW, Lu JM, Jin GN, Xu GH, Jin CH, Ma J, Piao HN, Jin X, Piao LX (2022) – “Ginsenoside Rh2 reduces depression in offspring of mice with maternal toxoplasma infection during pregnancy by inhibiting microglial activation via the HMGB1/TLR4/NF-κB signaling pathway.” J Ginseng Res. 2022 Jan;46(1):62-70. doi: 10.1016/j.jgr.2021.04.003. Epub 2021 Apr 28.
• [4] Liu Y, Qu L, Wan S, Li Y, Fan D (2022) – “Ginsenoside Rk1 Prevents UVB Irradiation-Mediated Oxidative Stress, Inflammatory Response, and Collagen Degradation via the PI3K/AKT/NF-κB Pathway In Vitro and In Vivo. » J Agric Food Chem. 2022 Dec 21;70(50):15804-15817. doi: 10.1021/acs.jafc.2c06377. Epub 2022 Dec 6.
• [5] Joo SS, Yoo YM, Ahn BW, Nam SY, Kim YB, Hwang KW, Lee DI (2008) – “Prevention of inflammation-mediated neurotoxicity by Rg3 and its role in microglial activation.” Biol Pharm Bull. 2008 Jul;31(7):1392-6. doi: 10.1248/bpb.31.1392.
• [6] Zhang X, Liu X, Hu G, Zhang G, Zhao G, Shi M (2020) – “Ginsenoside Rd attenuates blood-brain barrier damage by suppressing proteasome-mediated signaling after transient forebrain ischemia.” Neuroreport. 2020 Apr 8;31(6):466-472. doi: 10.1097/WNR.0000000000001426.
• [7] Gao XQ, Du ZR, Yuan LJ, Zhang WD, Chen L, Teng JJ, Wong MS, Xie JX, Chen WF (2019) – “Ginsenoside Rg1 Exerts Anti-inflammatory Effects via G Protein-Coupled Estrogen Receptor in Lipopolysaccharide-Induced Microglia Activation.” Front Neurosci. 2019 Nov 7;13:1168. doi: 10.3389/fnins.2019.01168. eCollection 2019.
• [8] Zhu J, Jiang Y, Wu L, Lu T, Xu G, Liu X (2012) – “Suppression of local inflammation contributes to the neuroprotective effect of ginsenoside Rb1 in rats with cerebral ischemia.” Neuroscience. 2012 Jan 27;202:342-51. doi: 10.1016/j.neuroscience.2011.11.070. Epub 2011 Dec 6.
• [9] Wu J, Wang S, Zhao W, Li M, Li S (2023) – « Ginsenoside Rh2 inhibits CBP/p300-mediated FOXO3a acetylation and epilepsy-induced oxidative damage via the FOXO3a-KEAP1-NRF2 pathway. » Eur J Pharmacol. 2023 Feb 5;940:175391. doi: 10.1016/j.ejphar.2022.175391. Epub 2022 Nov 15.
• [10] Fan ZX, Yang CJ, Li YH, Yang J, Huang CX (2022) – « Ginsenoside Rh2 attenuates myocardial ischaemia‑reperfusion injury by regulating the Nrf2/HO‑1/NLRP3 signalling pathway. » Exp Ther Med. 2022 Nov 29;25(1):35. doi: 10.3892/etm.2022.11734. eCollection 2023 Jan.
• [11] She L, Xiong L, Li L, Zhang J, Sun J, Wu H, Ren J, Wang W, Zhao X, Liang G (2023) – « Ginsenoside Rk3 ameliorates Aβ-induced neurotoxicity in APP/PS1 model mice via AMPK signaling pathway. » Biomed Pharmacother. 2023 Feb;158:114192. doi: 10.1016/j.biopha.2022.114192. Epub 2022 Dec 30.
• [12] Xiong J, Yang J, Yan K, Guo J (2021) – « Ginsenoside Rk1 protects human melanocytes from H2O2‑induced oxidative injury via regulation of the PI3K/AKT/Nrf2/HO‑1 pathway. » Mol Med Rep. 2021 Nov;24(5):821. doi: 10.3892/mmr.2021.12462. Epub 2021 Sep 24.
• [13] Yao Y, Hu S, Zhang C, Zhou Q, Wang H, Yang Y, Liu C, Ding H (2022) – “Ginsenoside Rd attenuates cerebral ischemia/reperfusion injury by exerting an anti-pyroptotic effect via the miR-139-5p/FoxO1/Keap1/Nrf2 axis.” Int Immunopharmacol. 2022 Apr;105:108582. doi: 10.1016/j.intimp.2022.108582. Epub 2022 Feb 3.
• [14] Li J, Gao W, Zhao Z, Li Y, Yang L, Wei W, Ren F, Li Y, Yu Y, Duan W, Li J, Dai B, Guo R (2022) – « Ginsenoside Rg1 Reduced Microglial Activation and Mitochondrial Dysfunction to Alleviate Depression-Like Behaviour Via the GAS5/EZH2/SOCS3/NRF2 Axis. » Mol Neurobiol. 2022 May;59(5):2855-2873. doi: 10.1007/s12035-022-02740-7. Epub 2022 Mar 1.
• [15] Zhang Z, Yang K, Mao R, Zhong D, Xu Z, Xu J, Xiong M (2022) – « Ginsenoside Rg1 inhibits oxidative stress and inflammation in rats with spinal cord injury via Nrf2/HO-1 signaling pathway. » Neuroreport. 2022 Jan 19;33(2):81-89. doi: 10.1097/WNR.0000000000001757.
• [16] Shi Y, Miao W, Teng J, Zhang L (2028) – « Ginsenoside Rb1 Protects the Brain from Damage Induced by Epileptic Seizure via Nrf2/ARE Signaling. » Cell Physiol Biochem. 2018;45(1):212-225. doi: 10.1159/000486768. Epub 2018 Jan 22.
• [17] Ashrafizadeh M, Ahmadi Z, Yaribeygi H, Sathyapalan T, Jamialahmadi T, Sahebkar A (2021) – “The Effects of Ginsenosides on the Nrf2 Signaling Pathway.” Adv Exp Med Biol. 2021;1328:307-322. doi: 10.1007/978-3-030-73234-9_20.
• [18] Li Z, Zhao L, Chen J, Liu C, Li S, Hua M, Qu D, Shao Z, Sun Y (2020) – “Ginsenoside Rk1 alleviates LPS-induced depression-like behavior in mice by promoting BDNF and suppressing the neuroinflammatory response.” Biochem Biophys Res Commun. 2020 Oct 1;530(4):658-664. doi: 10.1016/j.bbrc.2020.07.098. Epub 2020 Aug 5.
• [19] Lv J, Lu C, Jiang N, Wang H, Huang H, Chen Y, Li Y, Liu X (2021) – “Protective effect of ginsenoside Rh2 on scopolamine-induced memory deficits through regulation of cholinergic transmission, oxidative stress and the ERK-CREB-BDNF signaling pathway.” Phytother Res. 2021 Jan;35(1):337-345. doi: 10.1002/ptr.6804. Epub 2020 Aug 4.
• [20] Sur B, Lee B (2022) – “Ginsenoside Rg3 modulates spatial memory and fear memory extinction by the HPA axis and BDNF-TrkB pathway in a rat post-traumatic stress disorder.” J Nat Med. 2022 Sep;76(4):821-831. doi: 10.1007/s11418-022-01636-z. Epub 2022 Aug 18.
• [21] Jiang N, Huang H, Zhang Y, Lv J, Wang Q, He Q, Liu X (2021) – “Ginsenoside Rb1 Produces Antidepressant-Like Effects in a Chronic Social Defeat Stress Model of Depression Through the BDNF-Trkb Signaling Pathway.” Front Pharmacol. 2021 Sep 29;12:680903. doi: 10.3389/fphar.2021.680903. eCollection 2021.
• [22] Kang A, Xie T, Zhu D, Shan J, Di L, Zheng X (2017) – “Suppressive Effect of Ginsenoside Rg3 against Lipopolysaccharide-Induced Depression-Like Behavior and Neuroinflammation in Mice.” J Agric Food Chem. 2017 Aug 16;65(32):6861-6869. doi: 10.1021/acs.jafc.7b02386. Epub 2017 Aug 7.
• [23] Liu S, Cheng Y, Chen WZ, Lv JX, Zheng BS, Huang DD, Xia XF, Yu Z (2021) – “Inflammation Disturbed the Tryptophan Catabolites in Hippocampus of Post-operative Fatigue Syndrome Rats via Indoleamine 2,3-Dioxygenas Enzyme and the Improvement Effect of Ginsenoside Rb1.” Front Neurosci. 2021 Aug 26;15:652817. doi: 10.3389/fnins.2021.652817. eCollection 2021.
• [24] Hu Q, He G, Zhao J, Soshilov A, Denison MS, Zhang A, Yin H, Fraccalvieri D, Bonati L, Xie Q, Zhao B.(2013) – “Ginsenosides are novel naturally-occurring aryl hydrocarbon receptor ligands.” PLoS One. 2013 Jun 11;8(6):e66258. doi: 10.1371/journal.pone.0066258. Print 2013.
• [25] Zhang Y, Wang Y, Ma Z, Liang Q, Tang X, Tan H, Xiao C, Gao Y (2017) – “Ginsenoside Rb1 Inhibits Doxorubicin-Triggered H9C2 Cell Apoptosis via Aryl Hydrocarbon Receptor.” Biomol Ther (Seoul). 2017 Mar 1;25(2):202-212. doi: 10.4062/biomolther.2016.066.
• [26] Li H, Gao YH, Song L, Chen TF, Zhang GP, Ye ZG, Gao Y, Huo W (2022) – “Ginsenoside Rg1 protects mice against 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced liver injury by inhibiting CYP1A1 through the aryl hydrocarbon receptor.” J Ethnopharmacol. 2022 Aug 10;294:115394. doi: 10.1016/j.jep.2022.115394. Epub 2022 May 17.
• [27] Cheng H, Liu J, Zhang D, Wang J, Tan Y, Feng W, Peng C (2022) – “Ginsenoside Rg1 Alleviates Acute Ulcerative Colitis by Modulating Gut Microbiota and Microbial Tryptophan Metabolism.” Front Immunol. 2022 May 17;13:817600. doi: 10.3389/fimmu.2022.817600. eCollection 2022.
• [28] Lee BH, Kim HJ, Chung L, Nah SY (2013) – “Ginsenoside Rg₃ regulates GABAA receptor channel activity: involvement of interaction with the γ₂ subunit.” Eur J Pharmacol. 2013 Apr 5;705(1-3):119-25. doi: 10.1016/j.ejphar.2013.02.040. Epub 2013 Mar 13. PMID: 23499684
• [29] Bae MY, Cho JH, Choi IS, Park HM, Lee MG, Kim DH, Jang IS (2010) – “Compound K, a metabolite of ginsenosides, facilitates spontaneous GABA release onto CA3 pyramidal neurons.” J Neurochem. 2010 Aug;114(4):1085-96. doi: 10.1111/j.1471-4159.2010.06833.x. Epub 2010 May 26.
• [30] Shao J , Zheng X , Qu L , Zhang H , Yuan H , Hui J , Mi Y , Ma P , Fan D (2020) – “Ginsenoside Rg5/Rk1 ameliorated sleep via regulating the GABAergic/serotoninergic signaling pathway in a rodent model.” Food Funct. 2020 Feb 26;11(2):1245-1257. doi: 10.1039/c9fo02248a. PMID: 32052003
• [31] Chen H, Shen J, Li H, Zheng X, Kang D, Xu Y, Chen C, Guo H, Xie L, Wang G, Liang Y (2018) – “Ginsenoside Rb1 exerts neuroprotective effects through regulation of Lactobacillus helveticus abundance and GABAA receptor expression.” J Ginseng Res. 2020 Jan;44(1):86-95. doi: 10.1016/j.jgr.2018.09.002. Epub 2018 Sep 19.