Effects Of Yokukansan Research Articles

The Japanese Herbal Medicine Yokukansan Exerted Antioxidant and Analgesic Effects in an Experimental Rat Model of Hunner-Type Interstitial Cystitis

Background and Objectives: The Japanese herbal medicine Yokukansan (YKS) has analgesic properties and is used for various pain disorders. The purpose of the present study was to investigate the effects of YKS in Hunner-type interstitial cystitis (HIC) using an experimental rat model of HIC and to explore its antioxidant activity and role as the underlying mechanism of action. Materials and Methods: The antioxidant capacity of YKS was evaluated by determining its hydroxyl radical (·OH) scavenging capacity using electron spin resonance (ESR). Next, the effects of YKS administration were explored using a toll-like receptor-7 agonist-induced rat model of HIC. The von Frey test was performed to assess bladder pain. Three days after HIC induction, the bladder was removed, and the expression of oxidative stress parameters in the bladder wall was investigated (reactive oxygen metabolites (ROMs), ·OH, and 8-hydroxy-2′-deoxyguanosine (8-OhdG)). Results: YKS had a ·OH scavenging capacity according to the ESR study. In the von Frey test, a significant decrease in the withdrawal threshold was observed in the HIC group compared with the control group; however, the decrease was ameliorated by the administration of YKS. Oxidative stress parameters showed increasing tendencies (ROMs test and 8-OHdG) or a significant increase (·OH) in the HIC group compared with the control group; however, the increase was significantly suppressed by the administration of YKS. Conclusions: These findings suggest that YKS is effective against HIC and that its antioxidant activity is involved in the mechanism of action.

Effect of yokukansan on psychiatric symptoms associated with antiepileptic drugs

Effect of yokukansan on psychiatric symptoms associated with antiepileptic drugs

Effect of Yokukansan on sleep disturbance and neuropathic pain in chronic constriction injury using a rat model

Patients with chronic pain develop peripheral neuropathy and experience sleep disturbance. Yokukansan is used to treat insomnia and control neuropathic pain. We studied if Yokukansan affects neuropathic pain and sleep disturbance using a rat model of chronic constriction injury (CCI). Male Wistar rats (4-week age) were divided into the following groups (n = 7, per group): CCI rats fed normal chow (CCI-0); CCI rats fed powdered chow mixed with 1% Yokukansan (CCI-1); CCI rats fed powdered chow mixed with 3% Yokukansan (CCI-3); and sham-operated control rats fed normal chow (SHAM). We examined sleep duration and quality using electroencephalograms and assessed pain using the von Frey and Hargreaves tests. Results were analyzed by one-way analysis of variance and Bonferroni post hoc tests. The CCI-0 group exhibited an increased wake period, decreased non-rapid eye movement (REM) sleep time, and no change in REM sleep time in comparison to the SHAM group. The CCI-1 group exhibited a decreased wake period, increased non-REM sleep time, and no change in REM sleep time compared to the CCI-0 group. The CCI-3 group exhibited increased non-REM sleep time but no changes in wake and REM sleep times compared to the CCI-1 group. The von Frey and Hargreaves test findings revealed an increase in the pain threshold in the CCI-1 group compared to the CCI-0 group. There was no difference in pain threshold between the CCI-1 and CCI-3 groups. In our rat model of CCI, sleep disturbance was reflected. Yokukansan inhibited CCI-induced sleep disturbance.

Effects of Yokukansan on serotonin1A receptor binding in monkey brain

Effects of Yokukansan on serotonin1A receptor binding in monkey brain

Effect of Yokukansan and Yokukansankachimpihange on Aggressive Behavior, 5-HT Receptors and Arginine Vasopressin Expression in Social Isolation-Reared Mice.

The traditional herbal medicines yokukansan (YKS) and yokukansankachimpihange (YKSCH) are prescribed for neurosis, insomnia or night crying and irritability in children. YKSCH comprises YKS and two additional herbs, a chimpi and a hange, and is used to treat digestive function deficiencies. However, the differences between the effects of YKS and YKSCH on brain function are unclear. The present study examined the effects of YKS and YKSCH on aggressive behavior in mice reared under a social isolation (SI) condition. Mice were housed individually for 6 weeks. YKS and YKSCH were administered orally for 2 weeks before aggression tests. SI increased aggressive behavior against naïve mice, and YKS, but not YKSCH, significantly attenuated this aggressive behavior. Because serotonin (5-HT)2A and 5-HT3A receptor antagonists are reported to have anti-aggressive effects, the mRNA levels of these receptors were examined. YKS attenuated the SI-induced increase in 5-HT2A and 5-HT3A receptor mRNA in the amygdala. On the other hand, YKSCH attenuated the SI-induced increase in 5-HT1A receptor mRNA. YKS and YKSCH did not affect 5-HT and its metabolite 5-hydroxyindoleacetic acid content in the amygdala. However, YKSCH increased the mRNA level of arginine vasopressin (AVP), which is a neuropeptide that has been implicated in aggression, in the amygdala. These results suggest that YKS ameliorates aggressive behavior by decreasing 5-HT2A and 5-HT3A receptor expression. The YKSCH-induced increase in AVP may disrupt the anti-aggressive effect of YKS. YKS may be more effective than YKSCH for treating irritability if digestive function deficiencies are not considered.

Yokukansan Alleviates Cancer Pain by Suppressing Matrix Metalloproteinase-9 in a Mouse Bone Metastasis Model.

Bone cancer pain control is difficult because it includes various characteristics of pain such as nociceptic and neuropathic pain. In this study, we investigated the effect of yokukansan (YKS), one of the traditional Japanese herbal medicines, on cancer pain in mouse bone metastasis model. Oral administration of YKS significantly alleviated pain behavior measured by quantitative body weight bearing. Furthermore, the pain behavior was also significantly alleviated by intrathecal and intraperitoneal administration of matrix metalloproteinase- (MMP-) 9 inhibitor, but not of MMP-2 inhibitor. MMP-9 expression was significantly elevated in the bone tissue on day 3 after carcinoma cell injection and in the ipsilateral spinal cord on day 7, which was suppressed by YKS administration. Taken together, these results suggest that YKS alleviates cancer pain via suppressing MMP-9 expression in bone metastasis model in mice.

Effect of Yokukansan in agitation

Effect of Yokukansan in agitation

Yokukansan for perioperative psychiatric symptoms in cancer patients undergoing high invasive surgery. J-SUPPORT 1605 (ProD Study): study protocol for a randomized controlled trial

BackgroundPreoperative anxiety and postoperative delirium affect both short- and long-term prognoses in patients with cancer; therefore, these conditions require early prevention and treatment. However, no standard preventive or therapeutic methods have been established for them. Yokukansan, a Japanese herbal medicine for the treatment of insomnia and anxiety, causes relatively few adverse drug reactions and effectively improves the behavioral and psychological symptoms of dementia. Thus, it is expected to be useful for treating and/or preventing perioperative psychiatric symptoms in patients with cancer. The objective of this study is to clarify the therapeutic effect of Yokukansan for preoperative anxiety and its preventive effect on postoperative delirium in cancer patients, as well as to confirm its safety profile.MethodsThis study is a randomized, double-blind, placebo-controlled study in cancer patients scheduled to undergo tumor resection. Patients who provide consent are randomly allocated to receive oral administration of Yokukansan or placebo, and study drug administration is continued for 4 days or longer prior to surgery. We defined two primary endpoints, change in preoperative anxiety and incidence of postoperative delirium. Secondary endpoints are severity score of postoperative delirium, duration of postoperative delirium, amount of benzodiazepines used prior to surgery, amount of antipsychotic agents used after surgery, and number of postoperative hospitalization days. We plan to complete the analysis on March 31, 2021. The target number of registered patients is 110 per group, or 220 in total.DiscussionThis study is the first randomized, double-blind, placebo-controlled study intended to clarify the effects of a Japanese herbal medicine, Yokukansan, in the prevention and treatment of perioperative psychiatric symptoms in patients with cancer. The trial was initiated on August 14, 2017, with 195 subjects randomized by October 5, 2018.Trial registrationUMIN Clinical Trials Registry (UMIN-CTR), UMIN000027561. Registered on 31 May 2017.

Yokukansan and Yokukansankachimpihange Ameliorate Aggressive Behaviors in Rats with Cholinergic Degeneration in the Nucleus Basalis of Meynert.

Yokukansan (YKS) and yokukansankachimpihange (YKSCH) are traditional Japanese Kampo medicines. The latter comprises YKS along with the medicinal herbs Citrus unshiu peel and Pinellia tuber. Both of these Kampo medicines are indicated for the treatment of night crying and irritability in children and for neurosis and insomnia in adults. In recent clinical trials, YKS exhibited ameliorative effects on the behavioral and psychological symptoms of dementia, such as aggressiveness, excitement, and irritability. In the present study, we aimed to clarify the involvement of cholinergic degeneration in the nucleus basalis of Meynert (NBM) in the development of aggressiveness in rats. Subsequently, using this animal model, the effects of YKS and YKSCH on aggressiveness were compared and the mechanisms underlying these effects were investigated. L-Glutamic acid (Glu) was injected into the right NBM of rats to induce deterioration of cholinergic neurons. On day 8 after Glu injection, aggressive behaviors were evaluated using resident–intruder tests. After the evaluation, YKS or YKSCH was administered to rats with aggressive behaviors daily for 7 days. In some groups, the 5-HT1A receptor antagonist WAY-100635 was coadministered with YKS or YKSCH over the same period. In other groups, locomotor activity was measured on days 12–14 after Glu injection. On day 15, immunohistochemistry was then performed to examine choline acetyltransferase (ChAT) activities in the NBM. Aggressive behaviors had developed on day 8 after Glu injection and were maintained until day 15. YKS and YKSCH significantly ameliorated the aggressive behaviors. These suppressive effects were entirely abolished following coadministration of WAY-100635. Finally, the number of ChAT-positive cells in the right NBM was significantly reduced on day 15 after Glu injection, and treatment with YKS or YKSCH did not ameliorate these reduced cell numbers. Our results show that unilateral Glu injections into the NBM of rats leads to the development of aggressive behaviors, which is thought to reflect cholinergic degeneration. YKS and YKSCH treatments ameliorated Glu-induced aggressive behaviors, and these effects were suggested to be mediated by 5-HT1A receptor stimulation, but not by improvement of cholinergic degeneration.

Daily administration of yokukansan and keishito prevents social isolation-induced behavioral abnormalities and down-regulation of phosphorylation of neuroplasticity-related signaling molecules in mice

BackgroundOur previous studies demonstrated that post-weaning social isolation (ISO) in mice induces behavior abnormalities such as deficits of sociability- and attention-like behaviors. These deficits can be attenuated by methylphenidate (MPH), a drug used for attention deficit hyperactivity disorder (ADHD), suggesting that ISO mice offer a potential animal model of comorbid developmental disorder with ADHD and autism spectrum disorder symptoms. This study investigated the effects of Kampo formulae, yokukansan (YKS) and keishito (KST), on the neuropsychiatric symptoms of ISO mice to clarify the therapeutic or preventive/delaying potential of these formulae for the treatment of neurodevelopmental disorders.MethodsThree-to-4-week old male ICR mice were socially isolated during an experimental period and YKS and KST (1523.6 and 2031.8 mg/kg, p.o.) was administered starting from week 2 and week 0 after starting ISO for the analysis of their therapeutic and preventive/delaying potentials, respectively. Sociability, attention-related behavior and fear memory were elucidated by a 3 chamber test, a water-finding test and fear conditioning test, respectively. Moreover, the phosphorylation of neuroplasticity-related signaling molecules in mice hippocampus was analyzed using western blotting.ResultsIn a therapeutic procedure, YKS ameliorated ISO-induced impairments of attention-like behavior and context-dependent fear memory, but not of sociability, whereas KST had no beneficial effects in ISO mice. In experiments to analyze the preventive/delaying potentials of these treatments, both YKS and KST improved sociability, attention, and context-dependent fear memory deficits. The improvement of sociability in mice by YKS and KST was not inhibited by a dopamine D1 receptor antagonist, suggesting that YKS and KST improved the ISO-induced sociability deficit by other mechanisms besides activation of the dopaminergic system. On the other hand, the beneficial effects of YKS and KST on attention-like behavior were inhibited by a muscarinic antagonist, suggesting that YKS and KST ameliorated ISO-induced attention-like behavior through a cholinergic mechanism. Moreover, the phosphorylated forms of CaMKII and CREB were down-regulated by ISO stress and restored by YKS and KST administration.ConclusionsThese findings suggest that YKS and KST may be useful for the improvement of neurodevelopmental disorders.

PS28. The effect of Yokukansan, a traditional herbal medicine, on sleep disturbances in elderly patients with neurotic disorders

PS28. The effect of Yokukansan, a traditional herbal medicine, on sleep disturbances in elderly patients with neurotic disorders

PT661. The effect of Yokukansan, a traditional herbal medicine, on sleep disturbances and anxiety symptoms in restless legs syndrome

PT661. The effect of Yokukansan, a traditional herbal medicine, on sleep disturbances and anxiety symptoms in restless legs syndrome

Effects of Yokukansan, a Japanese Kampo Medicine for Symptoms Associated Autism Spectrum Disorder.

A neuropsychiatric syndrome, Autism spectrum disorder (ASD) is qualified via impairments in qualitative communication, social interaction, and stereotyped or restricted, repetitive patterns of behavior, interests, or activities. While all ASDs are considered to have qualitative deficits in social relatedness to others, many people with ASDs have other symptoms, including irritability (which includes aggression, self-injurious behavior, and severe tantrums). In order to decrease these behaviors, it is often helpful to make use of behavioral therapy. In addition, due to the intensity and severity of irritability, adjunctive medications are sometimes needed. Although many of the adjunctive medications have been tested and demonstrated to be useful in treating ASD, no clear standardized treatment has emerged. While the adjunctive medications have shown efficacy, the associated side effects have proven to be a barrier to their accepted use. A traditional Japanese medicine, Yokukansan (YKS), is composed of seven kinds of dried herbs and is widely clinically prescribed for treating psychiatric disorders by acting mainly on the glutamatergic and serotonergic nervous systems. YKS may be safe and useful in treating dementia patients' behavioral and psychological symptoms according to indications from recent studies. We introduce in this review, the ameliorative effects of YKS on Asperger's disorder in open-label studies and on ASDs including pervasive developmental disorder not otherwise specified (PDD-NOS). This review will suggest that YKS is well tolerated and effective for the treatment for subjects with ASD who have severe hyperactivity/noncompliance and irritability/agitation. Additionally, the serotonergic, glutamatergic, anti-inflammatory and neurogenesis effects are explored which are thought to be involved in the mechanisms underlying the efficacy of YKS.

Effect of Yokukansan, a Traditional Herbal Prescription, on Sle ep Disturbances in Patients with Alzheimer's Disease

Objective: Evidence of the effects of Yokukansan (YKS), a traditional herbal medicine, on behavioral and psychological symptoms of dementia (BPSD) has accumulated. As well as BPSD, patients with Alzheimer’s disease (AD) demonstrate poorer sleep quality. Specific sleep disorders such as sleep-disordered breathing and periodic limb movement disorder (PLMD) can be prevalent in the elderly. PLMs are generally considered to produce sleep fragmentation by provoking arousals. This study aimed to examine whether YKS alters polysomnography variables in patients with AD. Methods: Seven patients (3 men and 4 women) with probable AD according to the standard criteria were investigated. Participants were treated with YKS for 4 weeks. The Neuropsychiatric Inventory for the assessment of BPSD, the Mini-Mental State Examination (MMSE) for cognitive function, polysomnography for evaluation of sleep structure and Pittsburgh Sleep Quality Index (PSQI) for subjective sleep quality, and Epworth Sleepiness Scale (ESS) were carried out at baseline and at the end of the treatment. The local institutional review boards approved this study. All patients gave written consent according to institutional guidelines and the tenets of the Declaration of Helsinki. Results: Treatment with YKS resulted in a decreased NPI score, a prolonged total sleep time, a shortened sleep latency, an increased sleep efficiency, and decreased periodic limb movement during sleep. YKS also improved subjective evaluations with PSQI and ESS. Conclusions: YKS was effective for BPSD and sleep disturbances in patients with AD. YKS did not induce daytime somnolence, extrapyramidal signs, or an increased apnea-hypopnea index.

Effect of Yokukansan on sleep disturbance in a rat model of cerebrovascular dementia

Aim: Symptoms of dementia are classified into cognitive dysfunction and behavioral and psychological symptoms of dementia, including sleep disturbance. Yokukansan (YKS) is effective for sleep disturbance in patients with dementia, but the mechanisms are still unclear. In this study, we evaluated sleep disturbance in rats with cerebral ischemia. We investigated the effect of YKS on sleep disturbance in cerebral ischemia-treated rats. Methods: Cerebral ischemia was induced by twice occluding both of the common carotid arteries. Wakefulness, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep were classified using electroencephalography and electromyography. mRNA expression of sleep–wakefulness signals were quantified using reverse transcription–polymerase chain reaction. Results: Rats with cerebral ischemia had a higher total wakefulness time and lower total NREM sleep time during the light phase. These changes were ameliorated with 1000 mg/kg YKS for 14 days, but not 3 mg/kg donepezil for 7 days. mRNA expression of the prefrontal cortical prostaglandin (PG) E2 (EP4) receptor and of the PGD2 (DP) receptor was increased by cerebral ischemia. Elevated prefrontal cortical EP4 and DP receptor mRNA expression was reduced by YKS treatment. Conclusion: Rats with cerebral ischemia had NREM sleep disturbance. YKS might reduce this sleep disturbance by preventing neuroinflammation, and this was mediated by the EP4 and DP receptors in the prefrontal cortex.

Mother/Offspring Co-administration of the Traditional Herbal Remedy Yokukansan During the Nursing Period Influences Grooming and Cerebellar Serotonin Levels in a Rat Model of Neurodevelopmental Disorders

Neurodevelopmental impairment in the serotonergic system may be involved in autism spectrum disorder. Yokukansan is a traditional herbal remedy for restlessness and agitation in children, and mother-infant co-administration (MICA) to both the child and the nursing mother is one of the recommended treatment approaches. Recent studies have revealed the neuropharmacological properties of Yokukansan (YKS), including its 5-HT1A (serotonin) receptor agonistic effects. We investigated the influence of YKS treatment on behavior in a novel environment and on brain monoamine metabolism during the nursing period in an animal model of neurodevelopmental disorders, prenatally BrdU (5-bromo-2'-deoxyuridine)-treated rats (BrdU-rats). YKS treatment did not influence locomotor activity in BrdU-rats but reduced grooming in open-field tests. YKS treatment without MICA disrupted the correlation between locomotor behaviors and rearing and altered levels of serotonin and its metabolite in the cerebellum. These effects were not observed in the group receiving YKS treatment with MICA. These data indicate a direct pharmacological effect of YKS on the development of grooming behavior and profound effects on cerebellar serotonin metabolism, which is thought to be influenced by nursing conditions.

Promotive Effects of Yokukansan, a Traditional Japanese Medicine, on Proliferation and Differentiation of Cultured Mouse Cortical Oligodendrocytes

Effects of yokukansan, a traditional Japanese medicine, on proliferation and differentiation of oligodendrocytes were examined using purified mouse cortical oligodendrocyte precursor cells (OPCs). OPCs were cultured for four days, and proliferation was evaluated by counting A2B5 (a specific antibody to OPC)-reactive cells on the second day of cell culture. Differentiation from OPC to oligodendrocyte was evaluated by counting O4 (a specific antibody to detect differentiated cells in various stages)-reactive cells on the fourth day of culture. The effects of yokukansan (final concentration: 100 or 200 μg/ml) on proliferation and differentiation were examined by adding it to the medium for four days. Yokukansan increased not only the number of A2B5-positive cells on the second day but also the number of O4-positive cells on the fourth day compared to those in the corresponding controls. A WST-8 assay was used to identify active components from seven components of Uncaria Hook (UH), one of the constituent galenicals of yokukansan. Geissoschizine methyl ether (GM: 0.1 - 3.0 μM) was identified by this screening assay and increased the number of A2B5-positive cells on the second day and O4-positive cells on the fourth day as yokukansan did. These results suggest that yokukansan promotes the proliferation and differentiation of oligodendrocytes, and also that GM contained in UH is one of active components responsible for this effect of yokukansan.

Yokukansan, a traditional Japanese medicine, adjusts glutamate signaling in cultured keratinocytes.

Glutamate plays an important role in skin barrier signaling. In our previous study, Yokukansan (YKS) affected glutamate receptors in NC/Nga mice and was ameliorated in atopic dermatitis lesions. The aim of this study was to assess the effect of YKS on skin and cultured human keratinocytes. Glutamate concentrations in skin of YKS-treated and nontreated NC/Nga mice were measured. Then, glutamate release from cultured keratinocytes was measured, and extracellular glutamate concentrations in YKS-stimulated cultured human keratinocytes were determined. The mRNA expression levels of NMDA receptor 2D (NMDAR2D) and glutamate aspartate transporter (GLAST) were also determined in YKS-stimulated cultured keratinocytes. The glutamate concentrations and dermatitis scores increased in conventional mice, whereas they decreased in YKS-treated mice. Glutamate concentrations in cell supernatants of cultured keratinocytes increased proportionally to the cell density. However, they decreased dose-dependently with YKS. YKS stimulation increased NMDAR2D in a concentration-dependent manner. Conversely, GLAST decreased in response to YKS. Our findings indicate that YKS affects peripheral glutamate signaling in keratinocytes. Glutamine is essential as a transmitter, and dermatitis lesions might produce and release excess glutamate. This study suggests that, in keratinocytes, YKS controls extracellular glutamate concentrations, suppresses N-methyl-D-aspartate (NMDA) receptors, and activates glutamate transport.

『抑肝散の認知症症状に対する薬理学的検証』 認知症モデルに対する抑肝散の治療効果の薬理学的検証

『抑肝散の認知症症状に対する薬理学的検証』 認知症モデルに対する抑肝散の治療効果の薬理学的検証

Effect of yokukansan on memory disturbance in an animal model of cerebrovascular dementia

Effect of yokukansan on memory disturbance in an animal model of cerebrovascular dementia