Health & Medicine︱ Jing Liang PNOIARSA/Shutterstock.com Dihydromyricetin shows Jair Ferreira Belafacce/Shutterstock.comFerreira Jair promise as anxiety wikipedia.org/wiki/Ampelopsis_grossedentata disorder treatment ocial isolation can be a cause of insomnia, headaches, dry mouth, and Anxiety disorders are one of stress, as many of us can confirm for SSRIs, erectile dysfunction. In more the most common mental from our experiences of living severe cases of anxiety, benzodiazepines illnesses, and social isolation S through lockdowns. In fact, there is an can be prescribed. Unfortunately, can be a major source of contributing stress. Medications established link between an isolated benzodiazepines come with some Belafacce/Shutterstock.comFerreira Jair to treat these disorders, such as living environment and experiencing significant downsides. They often cause Dihydromyricetin is produced in unique species, including grossedentata (left) and the Japanese raisin tree (Hovenia dulcis, right). benzodiazepines, are available; mental illness. One of the most common drowsiness and make it dangerous to Its functions include protecting these from stress, as well as contributing to the smell and colour of fruit and flowers. however, they come with a range types of mental illnesses are anxiety consume alcohol. Benzodiazepines are of downsides. In a recent study disorders. These include Generalised also addictive and become less effective of DHM is counteracting the harmful stress of social isolation. The effectiveness counterparts, indicating higher levels in mice, Prof Jing Liang’s team Anxiety Disorder (GAD), OCD, panic over time, so they are only suitable for effects of alcohol abuse, in which DHM of DHM was also compared to diazepam, of anxiety. However, isolated mice at the USC School of Pharmacy disorder, PTSD, and phobias. These can short-term use. is supplemented as a hangover cure with a commonly prescribed benzodiazepine. administered DHM for 2 weeks showed in the US discovered that a interfere with day-to-day life and cause the ability to protect against liver diseases. This was done by housing mice in social significant improvements, with the 2-week chemical called dihydromyricetin distress in those who suffer from them. In order to improve the treatment of isolation for 2 or 4 weeks, followed by 2 isolated mice showing results similar could have potential as a new It is estimated that 3.1% of US adults anxiety disorders, it is vital that more WHAT RESEARCH HAS weeks of treatment with DHM, diazepam, to the group-housed mice. DHM had treatment for anxiety disorders. have GAD, 8.7% have phobias, 1% have effective medications with fewer side REVEALED ABOUT DHM or placebo. The behaviour and brains of a little less effect on mice isolated for 4 OCD, 3.5% have PTSD, and 2.7% have effects are developed for long-term use Prof Jing Liang and her team at the USC these mice were compared against each weeks, perhaps due to the extended panic disorder. and treatment. Luckily, new research School of Pharmacy conduct research other, and a control group of mice that isolation inducing more severe anxiety. has suggested that a chemical called on DHM, with results suggesting that it were housed in a group setting. However, this was still more significant WHAT TREATMENTS ARE AVAILABLE dihydromyricetin could be up to the task. could have many useful applications in than the effect of diazepam treatment. FOR ANXIETY DISORDERS? medicine. One paper published by the THE EFFECT OF DHM TREATMENT These findings indicate that DHM helps to As well as psychological treatment, WHAT IS DIHYDROMYRICETIN? team showed that DHM counteracts ON ANXIOUS BEHAVIOUR reduce anxious behaviour, more so than medication is also available to treat Dihydromyricetin, or DHM, is a the effects of alcohol. Within these Mice were assessed for anxious behaviour benzodiazepines. anxiety disorders. Antidepressants can be bioflavonoid. Flavonoids are chemicals investigations, it was identified that in an elevated plus-maze experiment, prescribed, specifically selective serotonin produced by the metabolism of plants, treating rats with DHM reduced alcohol which is a typical examination assay Anxious behaviour was also assessed via reuptake inhibitors (SSRIs) or serotonin with a vast variety of functions. These consumption and intoxication, as for anxiety levels. This involves a an open field test. This assessment also and noradrenaline reuptake inhibitors functions include protecting plants from well as withdrawal symptoms such as cross-shaped platform with two arms tests for anxious aversion to open spaces, (SNRIs). However, these medications stress, as well as contributing to the anxiety and seizure physical strength levels, have side effects, including dizziness, smell and colour of fruit and flowers. As risk. Another study as well as exploratory a natural flavonoid, DHM is produced showed that DHM DHM treatment was shown behaviour. Distances in unique plant species, including the treatment could be an to be anxiolytic, meaning that it travelled by the mice Japanese raisin tree (Hovenia dulcis) effective medication were measured, with mice and Ampelopsis grossedentata. Both for Alzheimer’s disease. reduced anxiety. housed in isolation found plants are used in East Asian traditional Mice with the disease to travel significantly less teas and remedies, with many treated with DHM were shown to have enclosed in walls, and two open with than their group-housed counterparts. reported health benefits. Teas made reduced memory loss, anxiety, seizure no walls. The mice were placed into the Isolated mice treated with DHM travelled from Ampelopsis grossedentata, risk, and levels of peptides associated maze to observe for anxious behaviour much more than mice with no treatment. known as vine tea or moyeam, are with Alzheimer’s. In both of these determined by an aversion to the open popular in . It is said to help with studies, DHM treatment was shown to arms. Mice with higher levels of anxiety This finding indicates that DHM treatment hyperglycemia, hyperlipidemia, sore be anxiolytic, meaning that it effectively spent more time in the enclosed arms, restores the exploratory and motor activity throats, and colds. In China, Japan, and reduced anxiety. and less anxious mice spent more in the that is otherwise reduced with high Korea, the Japanese raisin tree is often open arms. anxiety behaviour. Diazepam treatment used in traditional . It In their most recent study, the researchers actually lowered the distance travelled by has been historically used as a laxative focused on this effect and set out to test Mice housed in isolation with no the isolated mice. In the open field test, and treatment for parasitic infection. how effective DHM treatment was at treatment spent a lot less time in the when mice spend more time in corners A more recent application for the use reducing anxiety caused by the chronic open arms than their group-housed and are frozen in place, along with a lifted

www.researchoutreach.org www.researchoutreach.org tail, these observations indicate higher Mice were assessed for anxious behaviour in anxiety levels in these animal models. an elevated plus-maze experiment, involving a cross-shaped platform with two arms enclosed These anxiety-like behaviours all increased in walls, and two open with no walls. in untreated isolated mice compared to Behind the Research the group-housed mice. Importantly, the , via Wikimedia Commons via , isolated group treated with DHM showed a reduction in these behaviours. To further Dr Jing Liang

add to this evidence, it was also observed CC BY-SA 3.0 that isolation-induced anxiety also caused E: [email protected] T: +1 323 442 3118 a reduction in the time mice spent rearing W: https://pharmacyschool.usc.edu/directory/?expert=jing.liangphd

other mice and time spent in the center of Samueljohn.de, the open field. Treatment with DHM was found to reverse this behavior, as isolated mice fed DHM showed an increase in Research Objectives Detail these behaviours compared to untreated Prof Liang and her team investigate the utility Address mice. In all of these tests, treatment with of dihydromyricetin (DHM) as a pharmacotherapy for anxiety Dr Jing Liang diazepam did not appear to help the disorders. Professor measured anxious behaviours. Clinical Pharmacology, USC School of Pharmacy, PSC 504 1985 Zonal Ave, Los Angeles, California 90089 THE EFFECT OF DHM TREATMENT References USA ON SIGNALLING IN THE BRAIN The researchers tested the effect Anxiety and Depression Association of America. Facts & Bio of DHM treatment on GABAergic Statistics. Available at: https://adaa.org/about-adaa/press- Dr Jing Liang, a professor at the USC School of Pharmacy, neurotransmission. This is a type of room/facts-statistics (Accessed 11 December 2020) focuses her research on dihydromyricetin, a flavonoid with signalling in the brain that involves the DHM treatment helps to increase multiple pharmacological benefits, as a treatment for Alzheimer’s neurotransmitter GABA, which reduces Hyun, T.K., Eom, S.H., Yu, C.Y., and Roitsch, T. (2010). disease (AD). The theory established by Dr Liang is that impaired neuronal excitability. Prior studies by Prof the effect of GABA receptors, Hovenia dulcis--an Asian traditional herb. Planta medica, gephyrin-GABA pathway is an underlying mechanism and link Liang’s team have indicated that DHM reducing the impairment of GABAergic 76(10), 943–949. between anxiety and AD. modulates GABA receptor function. GABA receptor-mediated currents in transmission from social isolation. Liang, J., López-Valdés, H.E., Martínez-Coria, H., Funding hippocampus cells were measured using Lindemeyer, A.K., Shen, Y., Shao, X.M., and Olsen, R.W. • National Institute of Health grants AA017991 (to JL), AA07680 picrotoxin, a central nervous system affected by isolation-induced anxiety. ATP and organisation (arrangement) of GABA (2014). Dihydromyricetin ameliorates behavioral deficits and AA021213 (to RWO), AA022448 (to DLD), R01HL135623-01, stimulant that interacts with GABA is the fuel source of the cell, and previous receptors. The amount of gephyrin was and reverses neuropathology of transgenic mouse models R42DA044788-02 (to XMS) receptors. Compared to group-housed studies have shown that anxious rats have observed to be 40% lower in mice that of Alzheimer’s disease. Neurochemical research, 39(6), • American Foundation for Pharmaceutical Education (AFPE; to JS) mice, 2-week isolated mice had much lower ATP levels in the brain. Isolated had been housed in isolation rather 1171–1181. • Carefree Biotechnology Foundation weaker currents. However, in the isolated mice with no treatment had around a third than in a group. However, isolated mice Panche, A.N., Diwan, A.D., and Chandra, S.R. (2016). mice treated with DHM, the currents were less ATP in their hippocampus cells than treated with DHM had normal levels of Collaborators comparable to group-housed mice. This group-housed mice. Treatment with DHM gephyrin. Treatment with diazepam did Flavonoids: an overview. Journal of Nutritional Science, 5, e47. The researchers would like to acknowledge the USC School indicates that DHM treatment helps to resulted in an increased level of ATP in the not have this effect. Results from other of Pharmacy and Carefree Biotechnology Foundation for Shen, Y., Lindemeyer, A. K., Gonzalez, C., Shao, X. increase the effect of GABA receptors, brains of isolated mice, whereas diazepam studies by Prof Liang’s team also support their support. They would also like to give a special thanks to M., Spigelman, I., Olsen, R. W., and Liang, J. (2012). reducing the impairment of GABAergic treatment had no effect. the conclusion that DHM treatment Dr Richard W. Olsen, a distinguished professor at the UCLA Dihydromyricetin as a novel anti-alcohol intoxication transmission from social isolation. restores gephyrin levels in genetic Department of Molecular and Medical Pharmacology, for his medication. The Journal of neuroscience: the official journal The amount of gephyrin in the mouse Alzheimer’s mice. continued guidance and mentorship. of the Society for Neuroscience, 32(1), 390–401. ATP levels in the hippocampus were also brains was also tested. Gephyrin is a measured to assess whether they were protein that helps with the programming WHAT DO THESE RESULTS MEAN? Silva, J., Shao, A.S., Shen, Y., Davies, D.L., Olsen, R.W., Personal Response This study shows that social isolation The illustration Holschneider, D.P., Shao, X.M. and Liang, J. (2020). depicts a GABAergic contributes to anxious behaviour and Modulation of Hippocampal GABAergic Neurotransmission Based on these results, what future direction synapse in adult rat results in changes in GABAergic signalling and Gephyrin Levels by Dihydromyricetin Improves Anxiety. brain where GABA is of research would best help us understand in the brains of mice. The results show that released exocytotically Frontiers in Pharmacology, 11, 1008. the anxiolytic properties of DHM? and acts upon treatment with DHM can help alleviate Anxiety can be independent or contribute to specific post-synaptic these changes caused by social isolation, Wan, W., Jiang, B., Sun, L., Xu, L., and Xiao, P. (2017). receptors. The signal developing other disorders, such as Alzheimer’s disease more so than benzodiazepine treatment. is terminated by Metabolomics reveals that vine tea (Ampelopsis (AD). We started this study because more than 70% removal of GABA from The researchers also claim that the effect grossedentata) prevents high-fat-diet-induced metabolism of AD patients have anxiety, and this is often the initial the synaptic cleft by of DHM on GABAergic signalling could disorder by improving glucose homeostasis in rats. PloS one, transport of GABA manifestation in early AD. If we can treat anxiety in the early back into the nerve lead to long-term changes in the brain 12(8), e0182830. stages of AD, we can potentially reduce the occurrence and terminal by the plasma circuits associated with anxiety, as well as development of AD. Based on the current results, DHM has membrane GABA the demonstrated short-term alleviation the potential to be an effective new treatment for anxiety transporter (GAT) 1. of anxious behaviour. As a whole, this and even early AD. The next step is to now determine whether DHM has neuroprotective effects and how it is study highlights DHM as having potential contributing to these benefits. to become an effective new treatment for Lise Sofie H. Nissen-Meyer Farrukh Abbas Chaudhry, CC BY 2.5, via Wikimedia Commons anxiety disorders.

www.researchoutreach.org www.researchoutreach.org