Yokukansan, a Traditional Japanese Medicine, Enhances the L-DOPA-Induced Rotational Response in 6-Hydroxydopamine-Lesioned Rats: Possible Inhibition of COMT

Ishida, Yoshiteru; Ebihara, Kosuke; Tabuchi, Masahiro; Imamura, Saburo; Sekiguchi, Kyoji; Mizoguchi, Kazuo; Kase, Yoshio; Koganemaru, Go; Abe, Hiroshi; Ikarashi, Yasushi

doi:10.1248/bpb.b15-00691

Cited by 9 publications

(12 citation statements)

References 52 publications

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“…The results indicated that there was an interaction between UGS and L-dopa with signs of dyskinetic symptoms; however, there was no effect on the drug's prolonged duration. In previous study, Ishida et al (2016) reported that UGS prolonged the effectiveness of L-dopa via inhibiting COMT. In addition, they evaluated the effectiveness of L-dopa with the AIMs test and showed the prolonged duration of L-dopa when UGS was administered in rats.…”

Section: Discussionmentioning

confidence: 97%

“…Doo et al (2010) revealed the neuroprotective effects of UGS against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridene (MPTP) neurotoxicity via upregulating PI3K/Akt pathway. In addition, it has been reported that UGS inhibits catechol-O-methyltransferase (COMT) to assist dopamine supplementation (Ishida et al, 2016). However, it is unclear whether UGS could support the effects of L-dopa on motor dysfunctions or suppress the hyperkinetic movements accompanied by chronic treatment with L-dopa in a PD mouse model.…”

Section: Introductionmentioning

confidence: 99%

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An Integrative Approach to Treat Parkinson's Disease: Ukgansan Complements L-Dopa by Ameliorating Dopaminergic Neuronal Damage and L-Dopa-Induced Dyskinesia in Mice

Huh

Choi

Sim

et al. 2019

Front. Aging Neurosci.

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Parkinson's disease (PD) is accompanied by motor impairments due to the loss of dopaminergic neurons in the nigrostriatal pathway. Levodopa (L-dopa) has been the gold standard therapy for PD since the 1960s; however, its neurotoxic features accelerate PD progression through auto-oxidation or the induction of dyskinetic movements. Ukgansan (UGS) is a well-known prescription for treating PD in traditional medicines of East Asia, and its anti-PD function has been experimentally evaluated. The present study investigated whether UGS attenuates (1) motor dysfunction and dopaminergic neuronal damage when co-treated with L-dopa and (2) L-dopa-induced dyskinesia (LID) in 6-hydroxydopamine (6-OHDA)-induced PD mice. Although L-dopa was found to reduce motor dysfunctions, it failed to decrease the dopaminergic neuronal damage and increased the expression of dopamine receptor 1 (D1R) and 2 (D2R) in the 6-OHDA-injected mouse striatum. Co-treatment with UGS resulted in normal striatal histology and ameliorated motor impairments. In addition, UGS suppressed the dyskinesia induced by chronic L-dopa treatment while restoring the dopaminergic neurons in the striatum. For the underlying mechanism, UGS reduced the overexpression of D1R-related signaling proteins, such as phosphorylated extracellular signal-regulated kinase, ΔFosB, and c-fos in the striatum. Overall, the results suggest that the effect of UGS could be complementary to L-dopa by ameliorating motor dysfunction, restoring the dopaminergic neurons, and suppressing the dyskinetic movements in PD.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

An Integrative Approach to Treat Parkinson's Disease: Ukgansan Complements L-Dopa by Ameliorating Dopaminergic Neuronal Damage and L-Dopa-Induced Dyskinesia in Mice

Huh

Choi

Sim

et al. 2019

Front. Aging Neurosci.

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“…Unilateral nigrostriatal lesions by microinjecting 6-hydroxydopamine (6-OHDA) into the rat medial forebrain bundle decreased tyrosine hydroxylase immunoreactivity (i.e., dopamine loss) in the striatum, which has been established as an animal model of Parkinson’s disease (Ishida et al, 2016). Repeated intraperitoneal injection of L -3,4-dihydroxyphenylalanine ( L -DOPA) to the 6-OHDA-lesioned rats induced abnormal rotational and axial movements.…”

Section: Brain Regions Responsible For the Psychopharmacological Effementioning

confidence: 99%

“…This might be due to the augmentation of dopamine supplementation via inhibition of catechol- O -methyltransferase in the striatum. GM and corynoxeine, which are alkaloids in Uncaria hook, are suggested to contribute to the inhibitory effects of YKS (Ishida et al, 2016). …”

Section: Brain Regions Responsible For the Psychopharmacological Effementioning

confidence: 99%

Multiple Psychopharmacological Effects of the Traditional Japanese Kampo Medicine Yokukansan, and the Brain Regions it Affects

Mizoguchi

Ikarashi

2017

Front. Pharmacol.

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Yokukansan (YKS), a traditional Japanese Kampo medicine, has indications for use in night crying and irritability in children, as well as neurosis and insomnia. It is currently also used for the remedy of the behavioral and psychological symptoms of dementia (BPSD), such as aggressiveness, agitation, and hallucinations. In parallel with clinical evidence, a significant amount of fundamental researches have been undertaken to clarify the neuropsychopharmacological efficacies of YKS, with approximately 70 articles, including our own, being published to date. Recently, we reviewed the neuropharmacological mechanisms of YKS, including its effects on glutamatergic, serotonergic, and dopaminergic neurotransmission, and pharmacokinetics of the ingredients responsible for the effects. This review is aimed to integrate the information regarding the psychopharmacological effects of YKS with the brain regions known to be affected, to facilitate our understanding of the clinical efficacy of YKS. In this review, we first show that YKS has several effects that act to improve symptoms that are similar to BPSDs, like aggressiveness, hallucinations, anxiety, and sleep disturbance, as well as symptoms like tardive dyskinesia and cognitive deficits. We next provide the evidence showing that YKS can interact with various brain regions, including the cerebral cortex, hippocampus, striatum, and spinal cord, dysfunctions of which are related to psychiatric symptoms, cognitive deficits, abnormal behaviors, and dysesthesia. In addition, the major active ingredients of YKS, geissoschizine methyl ether and 18β-glycyrrhetinic acid, are shown to predominantly bind to the frontal cortex and hippocampus, respectively. Our findings suggest that YKS has multiple psychopharmacological effects, and that these are probably mediated by interactions among several brain regions. In this review, we summarize the available information about the valuable effects of a multicomponent medicine YKS on complex neural networks.

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“…Basic in vivo and in vitro studies illustrated that GM alleviates experimental anxiety, aggressiveness, dementia, allodynia, and vasoconstriction (Watanabe et al, 2003;Matsumoto et al, 2013;Mizoguchi and Ikarashi, 2017;Ikarashi et al, 2018). Multiple actions such as serotonergic (Pengsuparp et al, 2001;Nishi et al, 2012: Ueki et al, 2013, dopaminergic (Ueda et al, 2011;Ishida et al, 2016), and adrenergic neurotransmission (Nakagawa et al, 2012), as well as neuroprotection (Kawakami et al, 2011;Kanno et al, 2014;Sun et al, 2016), are considered as the mechanisms underlying the pharmacological effects of GM (Ikarashi and Mizoguchi, 2016;Ikarashi et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Properties, Pharmacology, and Pharmacokinetics of Active Indole and Oxindole Alkaloids in Uncaria Hook

2021

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Uncaria Hook (UH) is a dry stem with hook of Ucaria plant and is contained in Traditional Japanese and Chinese medicine such as yokukansan, yokukansankachimpihange, chotosan, Gouteng-Baitouweng, and Tianma-Gouteng Yin. UH contains active indole and oxindole alkaloids and has the therapeutic effects on ailments of the cardiovascular and central nervous systems. The recent advances of analytical technology led to reports of detailed pharmacokinetics of UH alkaloids. These observations of pharmacokinetics are extremely important for understanding the treatment’s pharmacological activity, efficacy, and safety. This review describes properties, pharmacology, and the recently accumulated pharmacokinetic findings of UH alkaloids, and discusses challenges and future prospects. UH contains major indole and oxindole alkaloids such as corynoxeine, isocorynoxeine, rhynchophylline, isorhynchophylline, hirsuteine, hirsutine, and geissoschizine methyl ether (GM). These alkaloids exert neuroprotective effects against Alzheimer’s disease, Parkinson’s disease, and depression, and the mechanisms of these effects include anti-oxidant, anti-inflammatory, and neuromodulatory activities. Among the UH alkaloids, GM exhibits comparatively potent pharmacological activity (e.g., agonist activity at 5-HT1A receptors). UH alkaloids are absorbed into the blood circulation and rapidly eliminated when orally administered. UH alkaloids are predominantly metabolized by Cytochrome P450 (CYP) and converted into various metabolites, including oxidized and demethylated forms. Regarding GM metabolism by CYPs, a gender-dependent difference is observed in rats but not in humans. Several alkaloids are detected in the brain after passing through the blood–brain barrier in rats upon orally administered. GM is uniformly distributed in the brain and binds to various channels and receptors such as the 5-HT receptor. By reviewing the pharmacokinetics of UH alkaloids, challenges were found, such as differences in pharmacokinetics between pure drug and crude drug products administration, food-influenced absorption, metabolite excretion profile, and intestinal tissue metabolism of UH alkaloids. This review will provide readers with a better understanding of the pharmacokinetics of UH alkaloids and their future challenges, and will be helpful for further research on UH alkaloids and crude drug products containing UH.

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Yokukansan, a Traditional Japanese Medicine, Enhances the L-DOPA-Induced Rotational Response in 6-Hydroxydopamine-Lesioned Rats: Possible Inhibition of COMT

Cited by 9 publications

References 52 publications

An Integrative Approach to Treat Parkinson's Disease: Ukgansan Complements L-Dopa by Ameliorating Dopaminergic Neuronal Damage and L-Dopa-Induced Dyskinesia in Mice

An Integrative Approach to Treat Parkinson's Disease: Ukgansan Complements L-Dopa by Ameliorating Dopaminergic Neuronal Damage and L-Dopa-Induced Dyskinesia in Mice

Multiple Psychopharmacological Effects of the Traditional Japanese Kampo Medicine Yokukansan, and the Brain Regions it Affects

Properties, Pharmacology, and Pharmacokinetics of Active Indole and Oxindole Alkaloids in Uncaria Hook

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