How Traditional Chinese Medicines are being explored in modern Western medicine A focus on some CNS applications Acorus sp. One TCM herb, Acorus sp. has a long history of use in formulas for treating mental conditions. An analysis of TCM formulas used for cognitive health found Acorus sp. to be one of the most commonly used herbs in such [1]. There are several Acorus sp. utilised including A. calamus, A. gramineus and A tatarinowii While asarones [2], simple phenylpropenes, are normally considered the main actives, other constituents play a role, including in modulation of the serotonin transporter, SERT [3]. While toxicity has been an issue hindering their utilisation particularly with regard to hepatic toxicity, perhaps the most intriguing property of asarones are in their ability to induce a broad range of neurotrophic factors [4], including BDNF, NGF, CNTF and GDNF where they may prove to be useful in treating diverse neurological conditions as a neurorestorative, having antidepressant, anxiolytic, anti-Alzheimer, and anti-Parkinson effects 1 More recently, efforts to specifically target their bioactivity towards the CNS to reduce undesirable aspects of toxicity have been explored [5, 6]. Some evidence supporting use in dementias has been noted [7]. Acorus gramineus displays a broad range of pharmacological activities: It contains β-asarone, α-asarone and other phenylpropenes as well as lignans, along with aporphine-type alkaloids with the essential oil having NMDA receptor antagonist-like action and possibly increases NE, DA and 5-HT, also decreasing the activity of acetylcholinesterase. A water extract demonstrated specific binding to striatal dopamine D1 and D2 receptors and competed with [3H]muscimol for specific binding to the GABA binding site of cortex GABAA receptor [1] Li, Yan, Zhang, Xi-Le, Huang, Yan-Ran, Zheng, Yan-Yan, Zheng, Guo-Qing, Zhang, Li-Ping, Extracts or Active Components from Acorus gramineus Aiton for Cognitive Function Impairment: Preclinical Evidence and Possible Mechanisms, Oxidative Medicine and Cellular 2 Longevity, 2020, 6752876, 33 pages, 2020. https://doi.org/10.1155/2020/6752876 [2] Lam KYC, Huang Y, Yao P, Wang H, Dong TTX, Zhou Z, Tsim KWK. Comparative Study of Different Acorus Species in Potentiating Neuronal Differentiation in Cultured PC12 Cells. Phytother Res. 2017 Nov;31(11):1757-1764. https://doi.org/10.1002/ptr.5904 [3] Zhang FH, Wang ZM, Liu YT, Huang JS, Liang S, Wu HH, Xu YT. Bioactivities of serotonin transporter mediate antidepressant effects of Acorus tatarinowii Schott. J Ethnopharmacol. 2019 Sep 15;241:111967. https://doi.org/10.1016/j.jep.2019.111967 [4] Balakrishnan, R.; Cho, D.-Y.; Kim, I.-S.; Seol, S.-H.; Choi, D.-K. Molecular Mechanisms and Therapeutic Potential of α- and β-Asarone in the Treatment of Neurological Disorders. Antioxidants 2022, 11, 281. https://doi.org/10.3390/antiox11020281 [5] Lu, J., Fu, T., Qian, Y., Zhang, Q., Zhu, H., Pan, L., Zhang, M. (2014). Distribution of α- asarone in brain following three different routes of administration in rats. European Journal of Pharmaceutical Sciences, 63, 63–70. . https://doi.org/10.3390/10.1016/j.ejps.2014.06.006 [6] Pan L, Zhou J, Ju F, Zhu H. Intranasal delivery of α-asarone to the brain with lactoferrin- modified mPEG-PLA nanoparticles prepared by premix membrane emulsification. Drug Deliv Transl Res. 2018 Feb;8(1):83-96. doi: https://doi.org/10.1007/s13346-017-0438-8 [7] Dong, Haiying; Wu, Shuqin; Hu, Nan; Xing, Guihua (2018) Efficacy of tenuigenin and β- asarone as augmentations for memantine in the treatment of Alzheimer’s disease https://doi.org/10.1097/WNR.0000000000000952 Gardenia jasminoides Gardenia jasminoides showed a significant rapid acting antidepressant effect. The antidepressant response started at 2 hours after administration - similar to ketamine, it may have a great clinical potential for treating patients with depression. It's used in Yueju pill, a traditional Chinese medicine formulated to treat syndromes of mood disorders. Yueju has been shown to promote a fast-onset antidepressant effect clinically and in preclinical studies. The medical need for rapid antidepressant actions without the limitations of ketamine has lead to a research interest in Gardenia/Yueju which has been characterised using a number of acute, subacute and chronic behavioural paradigms and clinically [1]. As preclinical findings indicated this plant showed ketamine-like rapid antidepressant effects, and as a polyherbal formal (Yueju) which had antidepressant potency in a relatively rapid manner clinically [2]. Results from an experimental investigation uncovered ketamine-like rapid antidepressant effects - increased BDNF expression, in parallel with its rapid antidepressant efficacy in behavior paradigms and Involvement of normalised NMDA receptor and mTOR-related 3 signaling [3] in rapid antidepressant effects, along with epigenetic DNMT1 activity [4]: acute administration of Yueju rapidly attenuated depression-like symptoms in learned helplessness paradigm and novelty-suppressed feeding test, tasks which normally require chronic treatment of SSRI to exhibit antidepressant efficacy. In a chronic mild stress model that mimics clinical depression, a single administration of Yueju also showed rapid and lasting antidepressant effects similar to ketamine. These findings suggest that Gardenia/Yueju may be potentially used as a rapid antidepressant in the clinical setting. The primary active components of gardenia are iridoid glycosides (mainly geniposide and gardenoside), chlorogenic acid, and ursolic acid. In a water-ethanol commercial extract of the fruits, gardenoside and other iridoids made up 70% of the extract, chlorogenic acid 20%, and ursolic acid 10%. In addition, apocarotenoids like crocins are the yellow pigment seen in the fruit. The yellow pigment causes immediate antidepressant responses, dependent on synthesis of proteins, including synaptic proteins. This was followed by enhanced expression of CREB and BDNF, which likely mediated the persistent antidepressant responses in solution, these have very rapid antidepressant effects in animal models [5] [1] Li Ren, Gang Chen, Rapid antidepressant effects of Yueju: A new look at the function and mechanism of an old herbal medicine, Journal of Ethnopharmacology, Volume 203, 2017,Pages 226-232, https://doi.org/10.1016/j.jep.2017.03.042 [2] Xue W, Zhou X, Yi N, Jiang L, Tao W, Wu R, Wang D, Jiang J, Ge X, Wang Y, Wu H, Chen G. Yueju pill rapidly induces antidepressant-like effects and acutely enhances BDNF expression in mouse brain. Evid Based Complement Alternat Med. 2013;2013:184367. https://doi.org/10.1155%2F2013%2F184367 [3] Tang, J., Xue, W., Xia, B. et al. Involvement of normalized NMDA receptor and mTOR- related signaling in rapid antidepressant effects of Yueju and ketamine on chronically stressed mice. Sci Rep 5, 13573 (2015). https://doi.org/10.1038/srep13573 [4] Ye D, Zhang L, Fan W, Zhang X, Dong E. Genipin normalizes depression-like behavior induced by prenatal stress through inhibiting DNMT1. Epigenetics. 2018;13(3):310-317. https://doi.org/10.1080/15592294.2018.1450033 [5] Wu R, Tao W, Zhang H, Xue W, Zou Z, Wu H, Cai B, Doron R, Chen G. Instant and Persistent Antidepressant Response of Gardenia Yellow Pigment Is Associated with Acute Protein Synthesis and Delayed Upregulation of BDNF Expression in the Hippocampus. ACS Chem Neurosci. 2016 Aug 17;7(8):1068-76. https://doi.org/10.1021/acschemneuro.6b00011 Scutellaria sp. 4 Baikal skullcap root ( Scutellaria baicalensis ) Has a protective effect on neurons with strong antioxidative and anti-inflammatory activities and also exhibits anti-convulsive, anxiolytic, and mild sedative actions. It markedly enhanced cognitive and memory functions in animal models of aging brains and neurodegeneration The main flavonoid in this plant is baicalin which has a diverse range of psychopharmacological properties. It has been proposed as a therapy for dopamine dysregulation disorders and been utilised clinically in the adjunctive treatment of schizophrenia S. baicalensis and it's primary active constituent baicalin has diverse pharmacological properties. In particular, baicalin seems to have promising CNS activity [1]. Antidepressant- and anxiolytic-like properties (the latter mediated through the activation of benzodiazepine binding site of GABAA receptors) Inhibits prolyl oligopeptidase dose-dependently, having potential benefits for schizophrenia, bipolar affective disorder, and related neuropsychiatric diseases [2]. Can potentially be used to treat dopaminergic dysfunction-associated CNS diseases (incl. neurodegenerative and ADHD). It's able to protect dopaminergic neurons and modulate brain dopamine levels, thus serving as a potentially effective novel treatment for ADHD [3]. In schizophrenia, addition of baicalin (1.5g/day) to atypical antipsychotics led to greater improvements in both primary and secondary negative symptoms than those treated with antipsychotics alone - seems to have efficacy for predominant negative symptoms and in improving cognitive function [4]. Able to facilitate remyelination in various models of CNS disorders and suppress neuroinflammation [5] Baicalin can: - pass through the blood–brain barrier - stimulate neurogenesis - promote neural differentiation and inhibit neuronal apoptosis - inhibit neuroinflammation and oxidative stress - promote CNS myelin repair Shown to be relatively nontoxic when given orally 5 [1] Sowndhararajan, K.; Deepa, P.; Kim, M.; Park, S.J.; Kim, S. Neuroprotective and Cognitive Enhancement Potentials of Baicalin: A Review. Brain Sci. 2018, 8, 104. https://doi.org/10.3390/brainsci8060104 [2] Teresa Tarragó, Nessim Kichik, Birgit Claasen, Roger Prades, Meritxell Teixidó, Ernest Giralt, Baicalin, a prodrug able to reach the CNS, is a prolyl oligopeptidase inhibitor, Bioorganic & Medicinal Chemistry,Volume 16, Issue 15, 2008, Pages 7516-7524, https://doi.org/10.1016/j.bmc.2008.04.067 [3] Zhou, R., Wang, J., Han, X. et al. Baicalin regulates the dopamine system to control the core symptoms of ADHD. Mol Brain 12, 11 (2019). https://doi.org/10.1186/s13041-019-0428-5 [4] Efficacy and safety of the adjunctive Baicalin in schizophrenia patients with negative symptoms and cognitive impairment: a randomized pilot study https://www.academia.edu/97015688/Efficacy_and_safety_of_the_adjunctive_Baicalin_in_ schizophrenia_patients_with_negative_symptoms_and_cognitive_impairment_a_randomiz ed_pilot_study [5]Ruo-Song Ai et al. Baicalin Promotes CNS Remyelination via PPARγ Signal PathwayMarch 2022 issue 9 (2) Neurology, https://doi.org/10.1212/NXI.0000000000001142 Chinese Cats Claw (Uncaria rhynchophylla ) Rhynchophylline and isorhynchophylline, two main alkaloids, have anti-inflammatory, anti- depression, anti-neurodegenerative, and anti-drug addiction properties It has a neuroprotective effect, antipsychotic properties, confers some anxiety reducing properties, and can reduce social aggression. It has particular been studied with regard to dementias. - the alkaloids in this plant are NMDA receptor inhibitors. While the IC50 values are too high for what is normally found in the brain, it is possible that mild inhibition (less than 20%) may occur with high doses. - geissoschizine methyl ether is a potent agonist of the 5-HT1A receptors while it is inhibitory at the 5-HT2A, 5-HT2C, and 5-HT7 receptors at the same concentration range, with the possibility of being a partial agonist at higher doses. - anxiolytic and enhanced social behaviour Yang W, Ip SP, Liu L, Xian YF, Lin ZX. Uncaria rhynchophylla and its Major Constituents on Central Nervous System: A Review on Their Pharmacological Actions. Curr Vasc Pharmacol. 2020;18(4):346-357. https://doi.org/10.2174/1570161117666190704092841 Jiang S, Borjigin G, Sun J, Li Q, Wang Q, Mu Y, Shi X, Li Q, Wang X, Song X, Wang Z, Yang C. Identification of Uncaria rhynchophylla in the Potential Treatment of Alzheimer's Disease by 6 Integrating Virtual Screening and In Vitro Validation. Int J Mol Sci. 2023 Oct 22;24(20):15457. https://doi.org/10.3390/ijms242015457 Wang C, Zhu MH, Sun N, Shen W, Jiang N, Zhao QS, Zhang YX, Huang Y, Zhou WX. Isorhynchophylline ameliorates stress-induced emotional disorder and cognitive impairment with modulation of NMDA receptors. Front Neurosci. 2022 Dec 15;16:1071068. https://doi.org/10.3389/fnins.2022.1071068 Zeng P, Su HF, Ye CY, Qiu SW, Tian Q. Therapeutic Mechanism and Key Alkaloids of Uncaria rhynchophylla in Alzheimer's Disease From the Perspective of Pathophysiological Processes. Front Pharmacol. 2021 Dec 15;12:806984 https://doi.org/10.3389/fphar.2021.806984 Zeng P, Wang XM, Ye CY, Su HF, Tian Q. The Main Alkaloids in Uncaria rhynchophylla and Their Anti-Alzheimer's Disease Mechanism Determined by a Network Pharmacology Approach. Int J Mol Sci. 2021 Mar 31;22(7):3612. https://doi.org/10.3390/ijms22073612 7