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Aim: To evaluate the effectiveness of yokukansan, a traditional Japanese medicine, as treatment for nocturia due to sleep disorders. Methods: In this study, we included patients diagnosed with nocturia due to sleep disorders, evaluated using the Pittsburgh Sleep Quality Index (PSQI). Participants received 2.5 g of yokukansan, three times daily, for 12 weeks. We evaluated the changes in the overactive bladder (OAB) symptom score (OABSS), hours of undisturbed sleep (HUS), and PSQI score. In addition, patients were categorized based on the severity of their sleep disorders, and we divided patients into two groups according to whether the severity of the disorder was downgraded after treatment: the improved and unchanged groups. Results: Among 35 patients with a mean ± standard deviation age of 73.2 ± 10.5 years, yokukansan administration was associated with significant improvements in nighttime urinary frequency (from 3.8 ± 2.1 to 2.1 ± 1.9), total OABSS score (from 4.9 ± 1.8 to 2.9 ± 1.9), OABSS urgency score (from 1.3 ± 1.0 to 0.7 ± 0.9), HUS (from 2.2 ± 0.6 to 3.5 ± 1.1 h), and global PSQI score (from 11.9 ± 3.1 to 10.0 ± 1.4; all p < 0.001). In addition, significant improvements were noted in both the improved and unchanged groups in terms of the total OABSS, nocturia, and urgency scores. Furthermore, yokukansan treatment was related to improved global PSQI scores in both groups (improved group: from 10.8 ± 0.7 to 8.6 ± 0.5, p = 0.001; unchanged group: from 12.3 ± 3.4 to 10.4 ± 1.3, p = 0.004). Conclusion: Yokukansan may effectively ameliorate nocturia due to sleep disorders. [ABSTRACT FROM AUTHOR]

Background: Diabetic neuropathic pain is a known complication of diabetes mellitus (DM) and results from the complex interaction of various factors affecting the nervous system. Yokuansan (YKS) is a versatile traditional Japanese herbal medicine with a wide range of applications, especially in pain management and neurological manifestations. YKS has analgesic properties for nerve damage and is a potential treatment for DM-induced neuropathic pain, especially in patients with diabetic neuropathy. Thus, we examined the anti-allodynic effect of YKS on DM-induced neuropathic pain. Methods: All experiments were performed on 6-week-old male Sprague–Dawley rats. DM and diabetic neuropathy were induced in rats with streptozotocin. Mechanical allodynia was assessed using dynamic plantar esthesiometry. Additionally, we conducted an immunological assessment of microglia cell changes in the spinal cord and an experiment to clarify the involvement of serotonin. Results: Diabetes significantly reduced withdrawal thresholds in rats during the initial two weeks of the experiment, which stabilized thereafter. However, this effect was not investigated in the control group. We assessed, using the dynamic plantar test, the anti-allodynic effects of orally administered YKS (1 g/kg). Daily YKS administration significantly increased the withdrawal threshold in DM animals. Additionally, oral YKS reduced the expression of Ibal-1-positive microglia. To elucidate the mechanism of action of YKS, we explored the involvement of serotonin (5-hydroxytryptamine [5-HT]) receptors in mediating its effects. Intrathecal administration of 5-HT receptor antagonists (WAY-100635, ketanserin, and ondansetron) inhibited the protective effects of YKS. Conclusions: YKS exhibited an anti-allodynic effect, suggesting that YKS may activate 5-HT receptors in the spinal cord, thereby alleviating diabetic neuropathic pain. [ABSTRACT FROM AUTHOR]

Abstract Background Yokukansan is a traditional Japanese herbal medicine that is widely administered to individuals of various age groups as an effective drug for anxiety, with few side‐effects. While animal studies have yielded promising results concerning yokukansan's potential in treating anxiety disorders, comprehensive validation has remained incomplete. Moreover, most of the clinical investigations regarding yokukansan have primarily focused on Japanese subjects, and its impact on non‐Asian ethnicities remains unverified. Case Presentation We present the case of a 17‐year‐old Caucasian female with panic disorder (PD). Following her relocation to Japan, she experienced panic attacks due to environmental changes, which subsequently prompted her to visit to our clinic. Various medical examinations revealed no abnormalities, which ruled out the possibility of any physical illness other than PD. Significantly, the administration of yokukansan resulted in a notable reduction in panic attacks, as well as in anticipatory anxiety, accompanied by discernible enhancements in psychosocial functioning and overall quality of life. Furthermore, it is imperative to underscore the fact that no noteworthy adverse events took place. Conclusion Panic attacks and profound anxiety in a Caucasian patient with PD were successfully treated with the use of yokukansan. This case study suggests that yokukansan may be effective in treating PD in Caucasians as well as in Asians. However, to substantiate this preliminary observation, further investigations are required.

Abstract Background Yokukansan, a traditional Japanese medicine (Kampo), has been widely used to treat neurosis, dementia, and chronic pain. Previous in vitro studies have suggested that Yokukansan acts as a partial agonist of the 5-HT1A receptor, resulting in amelioration of chronic pain through inhibition of nociceptive neuronal activity. However, its effectiveness for treating postoperative pain remains unknown, although its analgesic mechanism of action has been suggested to involve serotonin and glutamatergic neurotransmission. This study aimed to investigate the effect of Yokukansan on postoperative pain in an animal model. Methods A mouse model of postoperative pain was created by plantar incision, and Yokukansan was administered orally the day after paw incision. Pain thresholds for mechanical and heat stimuli were examined in a behavioral experiment. In addition, to clarify the involvement of the serotonergic nervous system, we examined the analgesic effects of Yokukansan in mice that were serotonin-depleted by para-chlorophenylalanine (PCPA) treatment and intrathecal administration of NAN-190, 5-HT1A receptor antagonist. Results Orally administered Yokukansan increased the pain threshold dose-dependent in postoperative pain model mice. Pretreatment of para-chlorophenylalanine dramatically suppressed serotonin immunoreactivity in the spinal dorsal horn without changing the pain threshold after the paw incision. The analgesic effect of Yokukansan tended to be attenuated by para-chlorophenylalanine pretreatment and significantly attenuated by intrathecal administration of 2.5 µg of NAN-190 compared to that in postoperative pain model mice without para-chlorophenylalanine treatment and NAN-190 administration. Conclusion This study demonstrated that oral administration of Yokukansan has acute analgesic effects in postoperative pain model mice. Behavioral experiments using serotonin-depleted mice and mice intrathecally administered with a 5-HT1A receptor antagonist suggested that Yokukansan acts as an agonist at the 5-HT1A receptor, one of the serotonin receptors, to produce analgesia.

Background: Yokukansan, a traditional Japanese medicine (Kampo), has been widely used to treat neurosis, dementia, and chronic pain. Previous in vitro studies have suggested that Yokukansan acts as a partial agonist of the 5-HT1A receptor, resulting in amelioration of chronic pain through inhibition of nociceptive neuronal activity. However, its effectiveness for treating postoperative pain remains unknown, although its analgesic mechanism of action has been suggested to involve serotonin and glutamatergic neurotransmission. This study aimed to investigate the effect of Yokukansan on postoperative pain in an animal model. Methods: A mouse model of postoperative pain was created by plantar incision, and Yokukansan was administered orally the day after paw incision. Pain thresholds for mechanical and heat stimuli were examined in a behavioral experiment. In addition, to clarify the involvement of the serotonergic nervous system, we examined the analgesic effects of Yokukansan in mice that were serotonin-depleted by para-chlorophenylalanine (PCPA) treatment and intrathecal administration of NAN-190, 5-HT1A receptor antagonist. Results: Orally administered Yokukansan increased the pain threshold dose-dependent in postoperative pain model mice. Pretreatment of para-chlorophenylalanine dramatically suppressed serotonin immunoreactivity in the spinal dorsal horn without changing the pain threshold after the paw incision. The analgesic effect of Yokukansan tended to be attenuated by para-chlorophenylalanine pretreatment and significantly attenuated by intrathecal administration of 2.5 µg of NAN-190 compared to that in postoperative pain model mice without para-chlorophenylalanine treatment and NAN-190 administration. Conclusion: This study demonstrated that oral administration of Yokukansan has acute analgesic effects in postoperative pain model mice. Behavioral experiments using serotonin-depleted mice and mice intrathecally administered with a 5-HT1A receptor antagonist suggested that Yokukansan acts as an agonist at the 5-HT1A receptor, one of the serotonin receptors, to produce analgesia. [ABSTRACT FROM AUTHOR]

Objectives: Managing perioperative anxiety improves postoperative recovery significantly by reducing postoperative pain. However, little is known about association between preoperative anxiety and postoperative pain in oral surgical procedures. In the present study, we examined the effect between preoperative anxiety and postoperative pain in mandibular third molar extraction and the anxiolytic effect of Yokukansan (YKS) during the perioperative period. Materials and methods: We conducted a prospective cohort study from September 2021 to May 2022. For patients with a complaint of insomnia on the day before surgery, 2.5 g per package of YKS was administered before sleep on the day before surgery. Twelve patients were administered YKS, and 23 patients were not (non‐YKS). Results: Perioperative anxiety was assessed by the Hospital Anxiety and Depression Scale (HADS) and amylase in saliva, and perioperative pain was assessed by the Numerical Rating Scale (NRS) and the total number of times pain medication. There were no significant differences in HADS and amylase in saliva between the YKS and non‐YKS. The median postoperative NRS was 5 for YKS and 7 for non‐YKS. The maximum use of pain medication was 16 in YKS and 24 in non‐YKS. Although no significant difference was observed in the anxiolytic effects and the improvement of postoperative pain during the perioperative period of mandibular third molar extraction between patients who took YKS and those who did not, NRS and the maximum use of pain medication were less in the YKS patients. Conclusions: Therefore, YKS may be useful for managing postoperative pain through the preoperative anxiolytic effect in oral surgical procedures. [ABSTRACT FROM AUTHOR]

Refractory peripheral neuropathy can occur as a side effect in 60–70% of patients receiving Paclitaxel (PTX). Yokukansan (YKS) is a Japanese herbal medicine reported to have analgesic properties for entrapment nerve injuries. Therefore, we investigated the anti-allodynic effect of Yokukansan on Paclitaxel-induced neuropathic pain. All experiments used 6-week-old male Sprague Dawley rats. Mechanical allodynia was evaluated using a dynamic plantar aesthesiometer. A mobile touch-stimulator unit applied progressively increasing force to the mid-plantar region of the hind paw in a vertical direction until the animal withdrew its paw. This was carried out before the Paclitaxel administration and during the first, second, third, and fourth weeks. Using a rat model of PTX-induced neuropathic pain (PTX rat), we injected PTX (intraperitoneally, 2 mg/kg) five times every 2 days. Using the dynamic plantar test, we evaluated the anti-allodynic effect of YKS (orally administered, 1 g/kg). YKS administration on a daily basis significantly enhanced the withdrawal threshold in PTX rats and reduced the expression level of activated microglia immunostaining with Iba1, a specific marker for microglia. The intrathecal administration of WAY-100635 (5-hydroxytryptamine [5-HT]1A receptor antagonist) and Ketanserin (5-HT2A/2C receptor antagonist) inhibited the protective effects of YKS. YKS exhibited an anti-allodynic effect in a rodent model of PTX-induced neuropathic pain by reducing the sensitivity to pain stimuli. These results suggest that Yokukansan may activate 5-HT receptors in the spinal cord, mediating Paclitaxel-induced neuropathic pain. [ABSTRACT FROM AUTHOR]

Background: Canine atopic dermatitis (CAD) is caused by skin barrier dysfunction due to allergen exposure. Excessive glutamate release in the skin is associated with delayed skin barrier function recovery and epidermal thickening and lichenification. Treatment with Yokukansan (YKS), a traditional Japanese medicine, reduces dermatitis severity and scratching behavior in NC/Nga mice by decreasing epidermal glutamate levels. However, the association between canine keratinocytes and glutamate and the mechanism by which YKS inhibits glutamate release from keratinocytes remains unknown. Aim: We aimed to investigate glutamate release from canine progenitor epidermal keratinocytes (CPEKs) and the inhibitory effect of YKS on this release. We also explored the underlying mechanism of YKS to enable its application in CAD treatment. Methods: Glutamate produced from CPEKs in the medium at 24 h was measured. The measurement conditions varied in terms of cell density and YKS concentration. CPEKs were treated with a glutamate receptor antagonist (MK-801), a glutamate transporter antagonist (THA), and a glutamate dehydrogenase inhibitor (epigallocatechin gallate; EGCG), and the inhibitory effect of YKS, YKS + THA, MK-801, and EGCG on this release was determined. MK-801 and glutamate dehydrogenase inhibitor were tested alone, and THA was tested in combination with YKS. Finally, glutamine incorporated into CPEKs at 24 h was measured using radioisotope labeling. Results: CPEKs released glutamate in a cell density-dependent manner, inhibited by YKS in a concentration-dependent manner. Moreover, YKS reduced the intracellular uptake of radioisotope-labeled glutamine in a concentration-dependent manner. No involvement of glutamate receptor antagonism or activation of glutamate transporters was found, as suggested by previous studies. Additionally, EGCG could inhibit glutamate release from CPEKs. Conclusion: Our findings indicated that glutamate release from CPEKs could be effectively inhibited by YKS, suggesting the utility of YKS in maintaining skin barrier function during CAD. Additionally, CPEKs are appropriate for analyzing the mechanism of YKS. However, we found that the mechanism of action of YKS differs from that reported in previous studies, suggesting that it may have had a similar effect to EGCG in this study. Further research is warranted to understand the exact mechanism and clinical efficacy in treating CAD. [Open Vet J 2024; 14(2.000): 683-691]

Background: The source of yokukansan (YKS) is thought to be Baoying‐Jinjiang (Hoeikinkyōroku in Japanese) by Xue Ji. YKS was originally designed for children and indicated for spasms, clenching of teeth, digestive dysfunction due to mental instability, and insomnia. Key Findings: YKS formula consists of seven types of crude drugs. Clinical studies have revealed that YKS exerts physiological effects including the treatment of behavioral and psychiatric symptoms of dementia (BPSD), preoperative sedation and anxiety, and postoperative delirium. A meta‐analysis showed that YKS could improve BPSD and daily living activities; however, no improvement in cognitive function was observed. Preclinical studies have also reported that YKS modulates neuronal pathways in the central nervous system, including the serotonergic, glutamatergic, GABAergic, and other neurotransmitter pathways. The incidence of adverse events associated with YKS was 5.17%, with the major adverse effect being pseudoaldosteronism. Routine blood sampling is considered for hypokalemia prevention. Conclusion: YKS is useful for BPSD and perioperative mental instability. The modulation of the serotonergic and glutamatergic neural pathways is one of mechanisms. Pseudoaldosteronism is one of the side effects. [ABSTRACT FROM AUTHOR]

Dementia is a common neurodegenerative disorder connected to damage to nerve cells in the brain. Although some conventional drugs are available for dementia treatments and are still sanctified for dementia patients, their short- and long-term side effects and other limitations make treating patients more challenging. The authors aimed to explain novel options for treating dementia with natural products and unravel some clinically proven natural products. This article systematically reviewed recent studies that have investigated the role of natural products and their bioactive compounds for dementia. PubMed Central, Scopus, and Google Scholar databases of articles were collected, and abstracts were reviewed for relevance to the subject matter.In this review, we provide mechanistic insights of clinically validated natural products, including like- Yokukansan, Souvenaid, BDW, Hupergene, Bacopa monnier, Omega-3, Tramiprostate and Palmitoylethanolamide with which have therapeutic efficacy against dementia in the management of dementia. As shown by studies, certain natural ingredients could be used to treat and prevent dementia. We strongly believe that the medicinal plants and phytoconstituents alone or in combination with other compounds would be effective treatments against dementia with lesser side effects as compared to currently available treatments. Moreover, these products should be studied further in order to develop novel dementia medications.

Abstract Aim We conducted a 12‐week double‐blind, placebo‐controlled, multicenter study to evaluate the efficacy and safety of yokukansan in patients with schizophrenia. Methods Patients with schizophrenia resistant to antipsychotics whose Positive and Negative Syndrome Scale (PANSS) scores were stable within five points were enrolled and assigned to the yokukansan or placebo group. Fifty‐three of the 61 consenting patients were allocated to the yokukansan (n = 27) and placebo (n = 26) groups. Results The changes in total and positive PANSS scores at 12 weeks were significantly greater in the yokukansan group than in the placebo group. There were no significant changes in other psychiatric symptom rating scores in either group. Adverse reactions were reported in six of 27 patients (22.2%) in the yokukansan group and five of 26 patients (19.2%) in the placebo group, all of which were nonserious. Conclusion Yokukansan is very safe and has clinical potential as a treatment for schizophrenia in combination with Western medicine.

Background Yokukansan, the Chinese Herbal Medicine, may be effective for treating postoperative delirium. However, there is no suff icient evidence supporting this notion. This study aimed to investigate whether yokukansan was effective for preventing delirium after gastrointestinal cancer surgery by the prospective randomized study. Methods This was a double-blind, randomized, controlled trial. Patients aged 75 years or older who underwent surgery between May 2017 and December 2019 were randomized to the yokukansan or anchusan (another Herbal Medicine) group. They received treatments with oral intake of assigned medicine from the day before surgery until postoperative day 3. Then, the incidence of postoperative delirium was compared. A psychiatrist diagnosed patients with postoperative delirium. Results Seventy-seven patients were enrolled in this study, and the full analysis set comprised 68 patients. In total, 25 of 68 (36.8%) patients presented with postoperative delirium. Specifically, 13 (37.1%) patients in the control group and 12 (36.4%) in the yokukansan group were diagnosed with postoperative delirium. However, the results did not differ significantly in both groups. Moreover, there was no remarkable difference in terms of delirium severity, and adverse events correlated with the medications were not observed. Conclusion Yokukansan was ineffective in preventing delirium after gastrointestinal cancer surgery. [ABSTRACT FROM AUTHOR]

• We examines the effect of yokukansan (TJ-54) in patients undergoing surgery. • Our results neither support nor oppose TJ-54 use in patients undergoing surgery. • Further research considering patients and administration period may be conducted. To evaluate the efficacy and safety of Yokukansan (TJ-54) in patients undergoing surgery. Efficacy was assessed by the onset of delirium, delirium rating scales, anxiety evaluated by Hospital Anxiety and Depression Scale-Anxiety (HADS-A) score, and safety was assessed by any reported adverse events. Six studies were included. There were no significant differences between the groups in the onset of delirium (risk ratio 1.15, 95% confidence interval [CI] 0.77–1.72), delirium rating scales (early postoperative period: standardized mean difference [SMD] −0.24, 95% CI −1.11 to 0.63; late postoperative period: SMD −0.06, 95% CI −1.56 to 1.45), HADS-A score (mean difference −0.47, 95% CI −1.90 to 0.96), and any adverse events (risk ratio 1.18, 95% CI 0.35–4.00). The use of TJ-54 in patients undergoing surgery is not an effective strategy for postoperative delirium and anxiety. Further research considering target patients and durations of administration should be conducted. [ABSTRACT FROM AUTHOR]

Refractory peripheral neuropathy can occur as a side effect in 60–70% of patients receiving Paclitaxel (PTX). Yokukansan (YKS) is a Japanese herbal medicine reported to have analgesic properties for entrapment nerve injuries. Therefore, we investigated the anti-allodynic effect of Yokukansan on Paclitaxel-induced neuropathic pain. All experiments used 6-week-old male Sprague Dawley rats. Mechanical allodynia was evaluated using a dynamic plantar aesthesiometer. A mobile touch-stimulator unit applied progressively increasing force to the mid-plantar region of the hind paw in a vertical direction until the animal withdrew its paw. This was carried out before the Paclitaxel administration and during the first, second, third, and fourth weeks. Using a rat model of PTX-induced neuropathic pain (PTX rat), we injected PTX (intraperitoneally, 2 mg/kg) five times every 2 days. Using the dynamic plantar test, we evaluated the anti-allodynic effect of YKS (orally administered, 1 g/kg). YKS administration on a daily basis significantly enhanced the withdrawal threshold in PTX rats and reduced the expression level of activated microglia immunostaining with Iba1, a specific marker for microglia. The intrathecal administration of WAY-100635 (5-hydroxytryptamine [5-HT]1A receptor antagonist) and Ketanserin (5-HT2A/2C receptor antagonist) inhibited the protective effects of YKS. YKS exhibited an anti-allodynic effect in a rodent model of PTX-induced neuropathic pain by reducing the sensitivity to pain stimuli. These results suggest that Yokukansan may activate 5-HT receptors in the spinal cord, mediating Paclitaxel-induced neuropathic pain.

Abstract Aim Yokukansan is a Japanese herbal medicine used in psychiatry to treat behavioral and psychological symptoms of dementia and other psychiatric symptoms. However, the glycyrrhizic acid included in this medicine can cause pseudoaldosteronism and hypokalemia. We aimed to identify the risk factors for hypokalemia due to yokukansan. Methods A retrospective cohort study was conducted on patients previously treated with yokukansan. The risk factors were determined by comparing the hypokalemia group with the non‐hypokalemia group for each parameter. Results This study included 304 patients who received yokukansan treatment between April 2009 and March 2019. We found that 17.4% (n = 53) of the patients experienced yokukansan‐induced hypokalemia. Risk factors detected as significantly different between patients with and without yokukansan‐associated hypokalemia were low serum potassium concentration before yokukansan administration, dose 7.5 g /day or more, and dementia. Hypokalemia occurred earlier in patients with low albumin, low potassium, and dementia. Conclusion It is necessary to pay attention to hypokalemia onset when administering yokukansan at 7.5 g or more to patients with low potassium levels and dementia. Our findings suggest that potassium levels must be checked early after yokukansan administration, especially in patients with low albumin, low potassium, and dementia.

Objective: To clarify the fetal safety of herbal Kampo medicines, including Hange‐koboku‐to, Koso‐san, Nyoshin‐san, Yokukansan, Yokukansan‐kachinpi‐hange, Saiko‐keishikankyo‐to, Keishi‐karyukotu‐borei‐to, and Kanbaku‐taisou‐to, when administered to pregnant women with depression using a large healthcare administrative database. Methods: We extracted data from the JMDC Claims Database (2005–2018) for this retrospective cohort study of pregnant women aged 19 years or older admitted to obstetric clinics or hospitals for delivery. Participants were classified into four groups: those without depression, those diagnosed with depression without medication, those given Kampo medicines for depression, and those given western medicines for depression. Neonatal outcomes (congenital anomalies, low birth weight, and preterm birth) were considered as the safety outcome measures. Results: We identified 179 707 eligible mothers. The adverse outcomes did not differ significantly between participants receiving Kampo medicine and those not diagnosed with depression during pregnancy. The proportion of low‐birth‐weight neonates did not differ significantly between the Kampo medicine and non‐depression groups (adjusted odds ratio [aOR] 1.28; 95% confidence interval [CI] 0.86–1.91), but was significantly higher in the unmedicated depression group (aOR 1.31; 95% CI 1.07–1.61) and western medicine group (aOR 1.47; 95% CI 1.18–1.83). Conclusion: Kampo medicines are safe for treating depression during pregnancy without increasing the incidence of congenital anomalies, low birth weight, or preterm birth. [ABSTRACT FROM AUTHOR]

"Yokukansan (...)" is one of Japanese Kampo prescriptions, which has been clinically treated for the patients with behavioral and psychological symptoms of dementia, as wells as neuropathic pain symptoms. This study investigated the effect of yokukansan on the nociceptive response to 0.5% formalin. Oral administration of Yokukansan significantly inhibited 0.5% formalin-induced nociceptive responses in mice. Intraperitoneal pretreatment with naloxone hydrochloride, an opioid receptor antagonist significantly antagonized the antinociceptive effects of Yokukansan. We also examined the possible involvement of spinal extracellular signal-regulated protein kinase (ERK) in Yokukansan-induced antinociception. In western blotting analysis, oral administration of Yokukansan resulted in a significant blockade of spinal ERK activation induced by 0.5% formalin. Naloxone hydrochloride significantly reversed the blockage of spinal ERK activation induced by Yokukansan. These results suggest that oral administration of Yokukansan-induced antinociceptive effect and blockage of spinal ERK activation may be triggered by activation of opioid receptors. [ABSTRACT FROM AUTHOR]

Neuroinflammation is associated with the development of hypoactive delirium, which results in poor clinical outcomes. Drugs effective against hypoactive sur have not yet been established. Yokukansan has an anti-neuroinflammatory effect, making it potentially effective against hypoactive delirium. This study aimed to examine the effect of Yokukansan on the pentobarbital-induced loss of righting reflex duration extended with lipopolysaccharide (LPS)-induced neuroinflammation and diazepam-induced gamma-aminobutyric acid receptor stimulation in a mouse model. The active ingredients in Yokukansan and its anti-neuroinflammatory effect on the hippocampus were also investigated. Furthermore, we examined the in vitro anti-inflammatory effects of Yokukansan on LPS-stimulated BV2 cells, a murine microglial cell line. Findings revealed that treatment with Yokukansan significantly decreased the duration of pentobarbital-induced loss of righting reflex by attenuating the LPS-induced increase in interleukin-6 and tumor necrosis factor-alpha levels in the hippocampus. Moreover, treatment with Yokukansan significantly decreased the number of ionized calcium-binding adapter molecule-1-positive cells in the hippocampal dentate gyrus after 24 h of LPS administration. In addition, glycyrrhizic acid, an active ingredient in Yokukansan, partially decreased the duration of pentobarbital-induced loss of righting reflex. Treatment with Yokukansan also suppressed the expression of inducible nitric oxide, interleukin-6, and tumor necrosis factor mRNA in LPS-stimulated BV2 cells. Thus, these findings suggest that Yokukansan and glycyrrhizic acid may be effective therapeutic agents for treating neuroinflammation-induced hypoactive delirium. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Opioids, such as morphine, are used in clinical settings for the management of acute and chronic pain. However, long-term use of morphine leads to antinociceptive tolerance and hypersensitivity. The cellular and molecular mechanisms of morphine tolerance seem to be quite complex, with suggestions including internalization of the μ-opioid receptor (MOR), neuroinflammation with activation of microglia and astrocytes, and changes in synaptic function in the central nervous system. Yokukansan (YKS), a traditional Kampo medicine consisting of seven herbs, has been used to treat emotional instability, neurosis, and insomnia. Interestingly, recent studies have begun to reveal the inhibitory effect of YKS on the development of morphine tolerance. In the present study, we determined the effect of YKS on morphine tolerance formation and its mechanisms in a rat model, focusing on the synapses between primary sensory neurons and spinal dorsal horn secondary neurons. We found that morphine tolerance formation was significantly inhibited by YKS (0.3 or 1.0 g/kg/day) preadministration for 7 days. Repeated administration of morphine (10 mg/kg/day) increased the expression of presynaptic proteins, including synaptotagmin I, in the spinal cord, which was suppressed by YKS. Furthermore, these changes in presynaptic protein expression were more pronounced at isolectin B4 (IB4)-positive excitatory synapses around the lamina II of the dorsal horn. These results suggest that YKS suppresses the development of morphine tolerance by inhibiting the enhancement of presynaptic function of dorsal root ganglia neurons projecting to spinal dorsal horn neurons caused by continuous morphine administration. [ABSTRACT FROM AUTHOR]

Background/Aims Herbal medicine is an important complementary therapy for functional dyspepsia (FD). However, its effect against gastric hypersensitivity in patients with FD has rarely been evaluated. Yokukansan (YKS), a traditional Japanese herbal medicine, is effective against neuropathic and inflammatory pain. This study aims to use a maternal separation (MS) stress-induced FD model to investigate the effects of YKS against gastric hypersensitivity, gastric motility, and duodenal micro-inflammation. Methods The MS stress model was established by separating newborn Sprague-Dawley rats from their mothers for 2 hours a day from postnatal days 1 to 10. At the age of 7-8 weeks, the rats were treated with YKS at a dose of 5 mL/kg (1 g/kg) for 7 consecutive days. After YKS treatment, electromyographic activity in the acromiotrapezius muscle by gastric distention and the gastric-emptying rate were assessed. Immunohistochemical analysis of eosinophils in the duodenum and phosphorylated extracellular signal-regulated kinase (p-ERK) 1/2 in the spinal cord was performed. Results YKS treatment suppressed MS stress-induced gastric hypersensitivity and decreased the elevated levels of p-ERK1/2 in the spinal cord. In the gastroduodenal tract, YKS inhibited eosinophil-associated micro-inflammation but did not improve gastric dysmotility. Conclusions YKS treatment improved gastric hypersensitivity by alleviating eosinophil-associated micro-inflammation in the gastroduodenal tract. This treatment may be considered an effective therapeutic option for epigastric pain and micro-inflammation in patients with FD. [ABSTRACT FROM AUTHOR]

Opioids, such as morphine, are used in clinical settings for the management of acute and chronic pain. However, long-term use of morphine leads to antinociceptive tolerance and hypersensitivity. The cellular and molecular mechanisms of morphine tolerance seem to be quite complex, with suggestions including internalization of the μ-opioid receptor (MOR), neuroinflammation with activation of microglia and astrocytes, and changes in synaptic function in the central nervous system. Yokukansan (YKS), a traditional Kampo medicine consisting of seven herbs, has been used to treat emotional instability, neurosis, and insomnia. Interestingly, recent studies have begun to reveal the inhibitory effect of YKS on the development of morphine tolerance. In the present study, we determined the effect of YKS on morphine tolerance formation and its mechanisms in a rat model, focusing on the synapses between primary sensory neurons and spinal dorsal horn secondary neurons. We found that morphine tolerance formation was significantly inhibited by YKS (0.3 or 1.0 g/kg/day) preadministration for 7 days. Repeated administration of morphine (10 mg/kg/day) increased the expression of presynaptic proteins, including synaptotagmin I, in the spinal cord, which was suppressed by YKS. Furthermore, these changes in presynaptic protein expression were more pronounced at isolectin B4 (IB4)-positive excitatory synapses around the lamina II of the dorsal horn. These results suggest that YKS suppresses the development of morphine tolerance by inhibiting the enhancement of presynaptic function of dorsal root ganglia neurons projecting to spinal dorsal horn neurons caused by continuous morphine administration.

Kampo medicine has been practiced as traditional medicine (TM) in Japan. Kampo medicine uses Kampo formulae that are composed of multiple crude drugs to make Kampo formulae. In Japan, Kampo formulae are commonly used instead of or combined with Western medicines. If drug therapy that follows the guidelines for neuropathic pain does not work or cannot be taken due to side effects, various Kampo formulae are considered as the next line of treatment. Since Kampo formulae are composed of two or more kinds of natural crude drugs, and their extracts contain many ingredients with pharmacological effects, one Kampo formula usually has multiple effects. Therefore, when selecting a formula, we consider symptoms other than pain. This review outlines the Kampo formulae that are frequently used for pain treatment and their crude drugs and the basic usage of each component. In recent years, Yokukansan (YKS) has become one of the most used Kampo formulae for pain treatment with an increasing body of baseline research available. We outline the known and possible mechanisms by which YKS exerts its pharmacologic benefits as an example of Kampo formulae's potency and holistic healing properties. [ABSTRACT FROM AUTHOR]

The traditional Japanese (Kampo) medicines yokukansan (YKS) and yokukansankachimpihange (YKSCH) have similar formulas and the same indications. In animals or cultured cells, the neuropharmacological actions of YKS are sometimes more beneficial than those of YKSCH. Since both drugs are used to treat sleep disorders in Japan, we examined the ameliorative effects of YKS and YKSCH on circadian rhythm disturbance and compared their efficacy using a mouse model of circadian rhythm disruption. Ramelteon was used as the positive control. Ramelteon treatment significantly reversed decreased running wheel activity during the advanced dark phase, indicating facilitation of circadian adaptation. YKS treatment also reversed the activity in the early period of drug treatment; however, it was not statistically significant. YKSCH treatment significantly reversed the decreased activity during the advanced dark phase. Plasma melatonin (MT) levels were significantly increased in the YKSCH but not in the YKS group. The ameliorative effect of YKSCH on rhythm disruption was significantly inhibited by coadministration of the MT2 receptor antagonist. Therefore, the therapeutic effect of YKSCH on circadian rhythm disruption would be attributable, to elevated endogenous MT levels. Taken together, YKS and YKSCH have different pharmacological properties and may be more precisely prescribed depending on patients' psychological symptoms.

ObjectiveThe impact of the 2018 Japan Floods on prescriptions of Yokukansan was evaluated.MethodsThis was a retrospective cohort study based on the National Database of Health Insurance Claims which covers all the prescriptions issued in Japan. Participants were patients aged 65 or older who received any medical care at medical institutions located in the three most-severely affected prefectures between 1 year before and after the disaster. We analyzed the number of new prescriptions of Yokukansan and other Kampo drugs among those who had not been prescribed any Kampo for 1 year before the disaster. Kaplan-Meier analysis and a Cox proportional hazards model were used to evaluate the risk of the disaster for a new prescription.ResultsSubjects comprised 1,372,417 people (including 12,787 victims, 0.93%). The hazard ratio (HR) of the disaster for Yokukansan prescriptions was 1.49 [95% confidence intervals (CI): 1.25–1.78], and 1.54 (95% CI: 1.29–1.84) in the crude and age-sex adjusted model, respectively. The HR of the disaster for prescription of other Kampo drugs in the crude and adjusted model was 1.33 (95% CI: 1.27–1.39), and 1.32 (95% CI: 1.27–1.38), respectively. The magnitude of increase of victims prescribed Yokukansan (31.4%) was statistically higher than for those prescribed other Kampo drugs (19.3%) (p < 0.001).ConclusionThe disaster increased prescriptions of both Yokukansan and other Kampo drugs among elderly victims. The increase was more remarkable in Yokukansan than other Kampo drugs. Clinicians and policymakers should be aware of the increased need for Yokukansan in times of natural disaster.

Kampo medicine has been practiced as traditional medicine (TM) in Japan. Kampo medicine uses Kampo formulae that are composed of multiple crude drugs to make Kampo formulae. In Japan, Kampo formulae are commonly used instead of or combined with Western medicines. If drug therapy that follows the guidelines for neuropathic pain does not work or cannot be taken due to side effects, various Kampo formulae are considered as the next line of treatment. Since Kampo formulae are composed of two or more kinds of natural crude drugs, and their extracts contain many ingredients with pharmacological effects, one Kampo formula usually has multiple effects. Therefore, when selecting a formula, we consider symptoms other than pain. This review outlines the Kampo formulae that are frequently used for pain treatment and their crude drugs and the basic usage of each component. In recent years, Yokukansan (YKS) has become one of the most used Kampo formulae for pain treatment with an increasing body of baseline research available. We outline the known and possible mechanisms by which YKS exerts its pharmacologic benefits as an example of Kampo formulae’s potency and holistic healing properties.

Background: Yokukansan is a traditional Japanese herbal medicine that is widely administered to individuals of various age groups as an effective drug for anxiety, with few side-effects. While animal studies have yielded promising results concerning yokukansan 's potential in treating anxiety disorders, comprehensive validation has remained incomplete. Moreover, most of the clinical investigations regarding yokukansan have primarily focused on Japanese subjects, and its impact on non-Asian ethnicities remains unverified., Case Presentation: We present the case of a 17-year-old Caucasian female with panic disorder (PD). Following her relocation to Japan, she experienced panic attacks due to environmental changes, which subsequently prompted her to visit to our clinic. Various medical examinations revealed no abnormalities, which ruled out the possibility of any physical illness other than PD. Significantly, the administration of yokukansan resulted in a notable reduction in panic attacks, as well as in anticipatory anxiety, accompanied by discernible enhancements in psychosocial functioning and overall quality of life. Furthermore, it is imperative to underscore the fact that no noteworthy adverse events took place., Conclusion: Panic attacks and profound anxiety in a Caucasian patient with PD were successfully treated with the use of yokukansan . This case study suggests that yokukansan may be effective in treating PD in Caucasians as well as in Asians. However, to substantiate this preliminary observation, further investigations are required., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Psychiatry and Clinical Neurosciences Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Objective: Irritability is an emotional stress symptom that causes or exacerbates dizziness. Antidepressants may be helpful for some conditions that are accompanied by irritability; however, they do not completely inhibit irritability. Yokukansan (YKS), a traditional Japanese herbal medicine, has been used for neurosis, insomnia, and children's irritability and night crying. The study investigated the efficacy of YKS in nystagmus in patients with chronic dizziness and irritability.Methods: Twenty-two cases with chronic dizziness and irritability were reviewed retrospectively. The patients were divided into two groups: control patients (0-7 days of treatment) and YKS-treated patients (YKS cases; >7 days of treatment). Dizziness before and during (after, in the controls) YKS treatment was evaluated by scoring the nystagmus intensity on a 5-point scale. The average scores were calculated within a maximum of 6 months before and during or after treatment. The normalized scores were also calculated. The optimal treatment regimen was calculated via receiver operating characteristic (ROC) curve analysis.Results: There were six control cases (1 male, 5 females; mean age: 59.5 years). There were 16 YKS cases (3 males, 13 females; mean age: 61.8 years). While the group mean nystagmus intensity scores significantly decreased from 1.18 to 0.73 in the YKS cases, it did not change in the control cases. The group mean of the normalized nystagmus intensity scores during treatment was 0.73 in the YKS cases. The results of the ROC curve analysis indicated the optimal cut-off period of the YKS treatment was 10 days.Conclusion: The oral administration of YKS for more than 10 days was optimal. The treatments with YKS could be a good option for the treatments of vertigo. [ABSTRACT FROM AUTHOR]

Oxaliplatin is a platinum-based anti-cancer drug used in the treatment of advanced metastatic colorectal cancer. Paclitaxel is also used for the treatment of solid tumors and ovarian and breast cancers. However, these agents causes severe acute and chronic peripheral neuropathies. "Yokukansan (抑肝散)" is one of Japanese Kampo prescriptions, which has been clinically treated for the patients with of behavioral and psychological symptoms of dementia, as wells as neuropathic pain symptoms. In this study, we investigated how the attenuation of mechanical allodynia by Yokukansan in mice model treated with oxaliplatin and paclitaxel in vivo. Oxaliplatin (3 mg/kg) was administered intraperitoneal (i.p.) for one day or Pacltaxel (2 mg/kg) was administered i.p. for 5 days to mice, which peaked at day 7 (oxaliplatin) day 10 (paclitaxel) after injection and subsided almost completely by day 28. Peripheral neuropathy of this anti-cancer drugs was 100% expressed when administered to mice. In this study, we sought to determine whether oral administration of Yokukansan could reduce the induction of mechanical allodynia by oxaliplatin and paclitaxel in mice. Oral administration of Yokukansan significantly inhibited in oxaliplatin and paclitaxel-induced mechanical allodynia. In comparison, diclofonac sodium, nonsteroidal antiinflammatory drug, had no effect on oxaliplatin and paclitaxel -induced mechanical allodynia. These results indicated that oxaliplatin and paclitaxel administration induces mechanical allodynia, and that yokukansan administration might be an efiective therapeutic agent for the side-efiects such as neuropathic pain caused by oxaliplatin and paclitaxel in cancer chemotherapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract Background Preoperative 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. Methods This 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. Discussion This 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 registration UMIN Clinical Trials Registry (UMIN-CTR), UMIN000027561. Registered on 31 May 2017.

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.

Yasuaki Kanada, Ayami Katayama, Hideshi Ikemoto, Kana Takahashi, Mana Tsukada, Akio Nakamura, Shogo Ishino, Tadashi Hisamitsu, Masataka Sunagawa Department of Physiology, School of Medicine, Showa University, Shinagawa-ku, Tokyo, Japan Objectives: Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder with symptoms of abnormal defecation and abdominal discomfort. Psychological factors are well known to be involved in onset and exacerbation of IBS. A few studies have reported effectiveness of traditional herbal (Kampo) medicines in IBS treatment. Yokukansan (YKS) has been shown to have anti-stress and anxiolytic effects. We investigated the effect of YKS on defecation induced by stress and involvement of oxytocin (OT), a peptide hormone produced by the hypothalamus, in order to elucidate the mechanism of YKS action. Methods and results: Male Wistar rats were divided into four groups; control, YKS (300 mg/kg PO)-treated non-stress (YKS), acute stress (Stress), and YKS (300 mg/kg PO)-treated acute stress (Stress+YKS) groups. Rats in the Stress and Stress+YKS groups were exposed to a 15-min psychological stress procedure involving novel environmental stress. Levels of plasma OT in the YKS group were significantly higher compared with those in the Control group (P < 0.05), and OT levels in the Stress+YKS group were remarkably higher than those in the other groups (P < 0.01). Next, rats were divided into four groups; Stress, Stress+YKS, Atosiban (OT receptor antagonist; 1 mg/kg IP)-treated Stress+YKS (Stress+YKS+B), and OT (0.04 mg/kg IP)-treated acute stress (Stress+OT) groups. Rats were exposed to acute stress as in the previous experiment, and defecation during the stress load was measured. Administration of YKS or OT significantly inhibited defecation; however, administration of Atosiban partially abolished the inhibitory effect of YKS. Finally, direct action of YKS on motility of isolated colon was assessed. YKS (1 mg/mL, 5 mg/mL) did not inhibit spontaneous contraction. Conclusion: These results suggested that YKS influences stress-induced defecation and that increased OT secretion may be a mechanism underlying this phenomenon. Keywords: Yokukansan, oxytocin, irritable bowel syndrome, acute stress, corticosterone, Kampo medicine

Aim: Rapid eye movement sleep behaviour disorder (RBD) is characterized by abnormal behaviours accordant with nightmares during rapid eye movement sleep and is considered a prodromal marker of dementia with Lewy body. Most common in the elderly population, RBD is generally treated with clonazepam (CZP), a long‐term acting benzodiazepine antiepileptic. As such, alternative drugs for RBD are urgently needed to minimize the adverse effects peculiar to benzodiazepines. The efficacy of yokukansan (YKS), a traditional Japanese herbal medicine, on RBD was initially reported by Shinno et al. in 2008. However, no study has compared YKS with CZP. Therefore, this study aimed to clarify the possibility of using YKS as an alternative to CZP. Methods: This was a retrospective cohort study conducted at Jikei University Affiliated Hospital. The subjects were selected from 36 outpatients who had been diagnosed with RBD based on the International Classification of Sleep Disorders, third edition. Of the 23 who met the inclusion criteria but not the exclusion criteria, 11 were treated with YKS monotherapy, and 12 were treated with CZP monotherapy. The primary outcome was the total score on the Japanese version of the Rapid Eye Movement Sleep Behaviour Disorder Questionnaire (RBDQ‐JP), and the secondary outcomes were the scores from the eight‐item Short‐Form Health Survey and factors 1 and 2 of the RBDQ‐JP. Results: The mean total RBDQ‐JP score significantly improved from 52.5 to 21.7 (P = 0.002) after treatment with YKS (mean dosage: 3.0 g/day), which was similar to the change after CZP treatment (from 43.8 to 21.3). On RBDQ‐JP factor 1 (dream content), the mean score on five of six items significantly improved after treatment with YKS. There was no significant change in Short‐Form Health Survey scores after treatment with either drug. Potassium concentrations were within the normal range in patients treated with YKS. Conclusions: The present results suggest that a small amount of YKS may be an alternative to CZP for RBD, without remarkable adverse events. Further study is needed to prospectively clarify the efficacy and safety of YKS in more detail. [ABSTRACT FROM AUTHOR]

Recently, the herbal medicine Ukgansan (Yigansan in China, Yokukansan in Japan) was reported to be effective in the management of movement disorders. We report the case of a 62-year-old woman with herpes simplex encephalitis exhibiting atypical abnormal movements in the chronic stage. While controlling the abnormal movements with haloperidol, an antipsychotic agent, we prescribed Ukgansan-gami, an extract of a variant of Ukgansan, at a dose of 12 g/day to prevent the recurrence of abnormal movements and allow for the discontinuation of haloperidol. The patient was successfully treated with Ukgansan-gami, with no further recurrence of symptoms, making the use of haloperidol no longer necessary. The potential mechanism of action of Ukgansan involves the inhibition of nervous system hyperexcitability through the suppression of glutamate sodium channels, as well as attenuation of hypermotility through serotonin regulation. The present case suggests that herbal medicine therapy was likely to be an alternative to antipsychotics. [ABSTRACT FROM AUTHOR]

1. Yokukansankachimpihange (YKSCH), a Kampo formulation combining Citrus unshiu peel (CUP) and Pinellia tuber (PT) with yokukansan (YKS), has been recently used to treat the behavioral and psychological symptoms of dementia. Several flavonoids derived from CUP and PT reportedly exhibit psychopharmacological activity, but it remains unclear whether these flavonoids reach the brain after oral administration of YKSCH. 2. In this study, we first measured eight target flavonoids in the plasma and brain in rats orally administered YKSCH. Among these flavonoids, hesperidin, narirutin, nobiletin, and heptamethoxyflavone (HMF) were detected in the plasma, and nobiletin and HMF were detected in the brain. 3. Next, to clarify whether CUP and PT affect the pharmacokinetics of YKS ingredients in YKSCH, the plasma pharmacokinetics of geissoschizine methyl ether (GM) as a representative active ingredient in YKS was examined in rats orally administered YKSCH or YKS. There was no significant difference between the two groups, inferring that the pharmacokinetics of GM may not be affected by the two additional crude drugs. 4. Taken together, this study suggests that the CUP-derived flavonoids nobiletin and HMF may be responsible for the psychopharmacological effects of YKSCH in addition to YKS ingredients. [ABSTRACT FROM AUTHOR]

Background: Cognitive dysfunction is often accompanied by behavioral and psychological symptoms of dementia (BPSD) in patients with Alzheimer's disease and other forms of senile dementia. BPSD include agitation, aggression, and hallucinations. BPSD have a serious effect on the quality of life of dementia patients and their caregivers, but effective drug therapy for BPSD has not been identified as yet. Typical and atypical antipsychotics that are used for the treatment of BPSD are known to cause a variety of extrapyramidal adverse events. Yokukansan (YKS, Yi‐gan san in Chinese) is a Japanese traditional herbal (kampo) medicine that is used to alleviate night‐crying and irritation in children, as well as to treat neurosis and insomnia. It is currently also used to treat BPSD. Methods: In this review, we summarize the pharmacological effects of YKS in the context of BPSD. Conclusion: YKS is expected to be useful in treating and/or preventing BPSD. [ABSTRACT FROM AUTHOR]

Chronic stress is widely recognized as a risk factor for the development of major depression and anxiety disorders. Recently, we reported that yokukansan (YKS), a traditional Japanese herbal medicine, alleviated emotional abnormality in stress-maladaptive mice. The aim of the present study was to examine the effect of YKS on the expression of excitatory amino acid transporter (EAAT) 1–4 in the prefrontal cortex and hippocampus in stress-maladaptive mice. Mice were chronically exposed to inadaptable stress, i.e. repeated restraint stress for 240 min/day for 14 days. After the final exposure to stress, brains of mice were rapidly removed and the hippocampus and prefrontal cortex were dissected. Expressions of EAAT1-4 and glial fibrillary acidic protein (GFAP), a marker of astrocytes, in the brain tissues were analyzed by western blotting. Western blot analysis revealed that the expression level of EAAT2 was specifically decreased in the hippocampus of stress-maladaptive mice while there were no changes in the level of GFAP, and this change was inhibited by chronic treatment with YKS. In contrast, no changes were observed in the levels of EAAT1, EAAT3 or EAAT4 in stress-maladaptive mice. These results suggest that YKS may protect against the decrease in hippocampal EAAT2 expression induced by stress maladaptation, and this may contribute, at least in part, to the improvement of emotional abnormality.

Abstract Background Our 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. Methods Three-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. Results In 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. Conclusions These findings suggest that YKS and KST may be useful for the improvement of neurodevelopmental disorders.

Haruto Katahira,1 Masataka Sunagawa,1 Daishi Watanabe,1,2 Yasuaki Kanada,1,3 Ayami Katayama,1 Risa Yamauchi,1 Masashi Takashima,4 Shintaro Ishikawa,1 Tadashi Hisamitsu1 1Department of Physiology, 2Department of Neurology, School of Medicine, Showa University, 3Department of Surgery, Showa University Koto Toyosu Hospital, Tokyo, 4Department of Orthopaedic Surgery, Showa University Fujigaoka Hospital, Kanagawa, Japan Objective: Various stressors induce stress responses through the hypothalamic–pituitary–adrenal and the sympathetic–adrenal–medullary axes, which are regulated, in part, by orexin. For example, secretion of orexin in the hypothalamus is increased in rats exposed to the stress of social isolation for 1 week. In this study, the antistress effects of Kampo medicine Yokukansan (YKS) via the regulation of orexin secretion were investigated using a rat model.Methods and results: The administration of 300 mg/kg per day of YKS to rats for 1 week significantly decreased the plasma orexin levels compared with non-treated rats, whereas the administration of 1,000 mg/kg of YKS had no effect on orexin levels. Therefore, 300 mg/kg of YKS was an effective dose for controlling orexin secretion. Subsequently, rats were divided into group-housed control (Con), individually housed stress (Stress), and individually housed YKS (300 mg/kg)-treated stress (Stress + YKS) groups. After 1 week, a resident–intruder aggression test was performed, and the plasma levels of orexin and corticosterone were measured. In the Stress group, aggressive behavior and the levels of corticosterone and orexin significantly increased compared with the Con group; however, these effects were inhibited in the Stress + YKS group. Further, an orexin receptor antagonist (TCS 1102; 10 mg/kg) was intraperitoneally administered to rats exposed to isolation stress to determine whether orexin was involved in stress responses. Under these conditions, aggressive behavior and the level of corticosterone significantly decreased compared with the Stress group.Conclusion: These results suggest that orexin is involved in the control of stress response and that YKS exerts an antistress effect via the regulation of orexin secretion. Keywords: Yokukansan, orexin, antistress effect, social isolation stress, corticosterone, aggressive behavior

Yokukansan, a traditional Japanese herbal medicine, has been considered to be a novel alternative treatment for several neurological diseases such as neurodegenerative disorders, as well as neurosis, insomnia, and behavioral and psychological symptoms in Alzheimer's disease. Moreover, it has been shown that yokukansan has antidepressant-like and pain-relieving effects in animal models. Recently, several studies have shown that yokukansan has a neuroprotective effect. In this study, we focused on whether or no yokukansan influences cell proliferation related to cell-cycle progression by using B65 neuroblastoma cells derived from monoaminergic neurons. Under treatment with yokukansan, the proliferation rate of B65 neuroblastoma cells significantly increased in a dose-dependent manner. In particular, a proliferative effect was observed after treatment with yokukansan for 48 h and 72 h. Moreover, among seven medicinal herbs that comprise yokukansan, both Bupleuri Radix and Glycyrrhize Radix also enhanced the proliferation of B65 neuroblastoma cells. We assessed the effect of yokukansan on p44/42 mitogen-activated protein kinase (MAPK) phosphorylation in B65 neuroblastoma cells, and found that yokukansan increased p44/42 MAPK phosphorylation after treatment for 48 h. In contrast, neither Bupleuri Radix nor Glycyrrhize Radix altered the level of p44/42 MAPK phosphorylation, although they did increase cell proliferation. Our findings suggest that yokukansan has a cell-proliferative due to both Bupleuri Radix and Glycyrrhize Radix, and this is unrelated to the p44/42 MAPK signaling cascade.

Yokukansan (YKS), a traditional Japanese Kampo medicine, affects neurological and psychiatric disorders. It ameliorates hippocampal neurogenesis in animals. However, its effect on neuronal cell differentiation remains unclear. Therefore, we investigated the effects of YKS on pluripotent P19 embryonic carcinoma cells as neuronal differentiation model cells.Western blotting and immunocytochemistry revealed that 10 μg/mL YKS treatment during embryoid body formation or neuronal differentiation increased the expression of the neuronal stem cell marker, Nestin, by 1.9-fold and 1.7-fold, respectively, and of the mature neuron marker, NeuN, by 1.5-fold and 1.4-fold, respectively.We examined the effect of YKS on intracellular signaling pathways in P19 cells and found significant elevation in phospho-PDK1 and phospho-mTOR expression (1.1-fold and 1.2-fold, respectively). Therefore, we investigated the effect of PDK1 and mTOR inhibitors on the level of neuronal lineage markers. We found that the mTOR inhibitor significantly abolished the YKS effect on the level of neuronal lineage markers.Moreover, to identify the target(s) of YKS, antibody array analysis that simultaneously detects 16 phosphorylated proteins was performed. YKS significantly upregulated 10 phosphorylated proteins including PDK1, Akt, AMPK, PRAS40, mTOR, p70 S6 kinase, GSK-3α, Bad and ERK1/2 under cell proliferation conditions. These results suggest that YKS simultaneously activates multiple signaling pathways.Thus, we concluded that YKS enhances the level of neuronal lineage markers in differentiated P19 cells, however it does not induce neuronal differentiation. Furthermore, mTOR is the predominant mediator of the YKS effect on these cells.

Dementia is a common neurodegenerative disorder connected to damage to nerve cells in the brain. Although some conventional drugs are available for dementia treatments and are still sanctified for dementia patients, their short- and long-term side effects and other limitations make treating patients more challenging. The authors aimed to explain novel options for treating dementia with natural products and unravel some clinically proven natural products. This article systematically reviewed recent studies that have investigated the role of natural products and their bioactive compounds for dementia. PubMed Central, Scopus, and Google Scholar databases of articles were collected, and abstracts were reviewed for relevance to the subject matter.In this review, we provide mechanistic insights of clinically validated natural products, including like- Yokukansan, Souvenaid, BDW, Hupergene, Bacopa monnier , Omega-3, Tramiprostate and Palmitoylethanolamide with which have therapeutic efficacy against dementia in the management of dementia. As shown by studies, certain natural ingredients could be used to treat and prevent dementia. We strongly believe that the medicinal plants and phytoconstituents alone or in combination with other compounds would be effective treatments against dementia with lesser side effects as compared to currently available treatments. Moreover, these products should be studied further in order to develop novel dementia medications., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

Background: Canine atopic dermatitis (CAD) is caused by skin barrier dysfunction due to allergen exposure. Excessive glutamate release in the skin is associated with delayed skin barrier function recovery and epidermal thickening and lichenification. Treatment with Yokukansan (YKS), a traditional Japanese medicine, reduces dermatitis severity and scratching behavior in NC/Nga mice by decreasing epidermal glutamate levels. However, the association between canine keratinocytes and glutamate and the mechanism by which YKS inhibits glutamate release from keratinocytes remains unknown., Aim: We aimed to investigate glutamate release from canine progenitor epidermal keratinocytes (CPEKs) and the inhibitory effect of YKS on this release. We also explored the underlying mechanism of YKS to enable its application in CAD treatment., Methods: Glutamate produced from CPEKs in the medium at 24 hours was measured. The measurement conditions varied in terms of cell density and YKS concentration. CPEKs were treated with a glutamate receptor antagonist (MK-801), a glutamate transporter antagonist (THA), and a glutamate dehydrogenase inhibitor (epigallocatechin gallate; EGCG), and the inhibitory effect of YKS, YKS + THA, MK-801, and EGCG on this release was determined. MK-801 and glutamate dehydrogenase inhibitor were tested alone, and THA was tested in combination with YKS. Finally, glutamine incorporated into CPEKs at 24 hours was measured using radioisotope labeling., Results: CPEKs released glutamate in a cell density-dependent manner, inhibited by YKS in a concentration-dependent manner. Moreover, YKS reduced the intracellular uptake of radioisotope-labeled glutamine in a concentration-dependent manner. No involvement of glutamate receptor antagonism or activation of glutamate transporters was found, as suggested by previous studies. In addition, EGCG could inhibit glutamate release from CPEKs., Conclusion: Our findings indicated that glutamate release from CPEKs could be effectively inhibited by YKS, suggesting the utility of YKS in maintaining skin barrier function during CAD. In addition, CPEKs are appropriate for analyzing the mechanism of YKS. However, we found that the mechanism of action of YKS differs from that reported in previous studies, suggesting that it may have had a similar effect to EGCG in this study. Further research is warranted to understand the exact mechanism and clinical efficacy in treating CAD., Competing Interests: The authors declare that there is no conflict of interest.

Introduction: Yokukansan (YKS), a Kampo formula used in traditional Japanese medicine, has an analgesic effect, and is used for various pain disorders. This study investigated its analgesic effects on Hunner-type interstitial cystitis (HIC) and its mechanism of action in animal models.   Methods: Rats with toll-like receptor-7 agonist (loxoribine)-induced HIC were used. Eight-week-old female Wistar rats were divided into three groups: control, HIC, and HIC-administered YKS (YKS + HIC). Bladder pain was assessed based on escape behavior using the von Frey test. Three days after HIC induction, the bladder and spinal cord were excised, and the expression of substance P (SP) was examined.   Results: The pain threshold decreased significantly in the HIC group compared to that in the control group, but this decrease was suppressed by further YKS administration. The expression of SP in the bladder wall and spinal cord increased significantly in the HIC group compared to that in the control group; however, this increase was suppressed by YKS administration., Conclusion: SP is involved in the onset of bladder pain via neurokinin 1 receptors in bladder tissue. YKS may be useful for managing HIC-induced pain, and the suppression of SP secretion is one of its mechanisms of action., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Tsunokawa et al.)

The Kampo medicine yokukansan (YKS) has a wide variety of properties such as anxiolytic, anti-inflammatory and analgesic effects, and is also thought to regulate tumor suppression. In this study, we investigated the anti-tumor effect of YKS. We used Lewis lung carcinoma (LLC)-bearing mice that were fed food pellets containing YKS and then performed a fecal microbiota analysis, a microarray analysis for microRNAs (miRNAs) and an in vitro anti-tumor assay. The fecal microbiota analysis revealed that treatment with YKS partly reversed changes in the microbiota composition due to LLC implantation. Furthermore, a miRNA array analysis using blood serum showed that treatment with YKS restored the levels of miR-133a-3p/133b-3p, miR-1a-3p and miR-342-3p following LLC implantation to normal levels. A TargetScan analysis revealed that the epidermal growth factor receptor 1 signaling pathway is one of the major target pathways for these miRNAs. Furthermore, treatment with YKS restored the levels of miR-200b-3p and miR-200c-3p, a recognized mediator of cancer progression and controller of emotion, in the hypothalamus of mice bearing LLC. An in vitro assay revealed that a mixture of pachymic acid, saikosaponins a and d and isoliquiritigenin, which are all contained in YKS, exerted direct and additive anti-tumor effects. The present findings constitute novel evidence that YKS may exert an anti-tumor effect by reversing changes in the fecal microbiota and miRNAs circulating in the blood serum and hypothalamus, and the compounds found in YKS could have direct and additive anti-tumor effects. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to investigate the effects of yokukansan on forebrain ischemia. Because we can measure nitric oxide production and hydroxyl radical metabolism continuously, we investigated the effect of yokukansan on nitric oxide production and hydroxyl radical metabolism in cerebral ischemia and reperfusion.Methods: Yokukansan (300 mg per kg per day) was mixed into feed and given to 16 mice for 10days. Sixteen additional mice received normal feed (control). Nitric oxide production and hydroxyl radical metabolism were continuously monitored using the salicylate trapping method. Forebrain ischemia was producedin all mice by occluding the common carotid artery bilaterally for 10minutes. Levels of the nitric oxide metabolites nitrite and nitrate were determined using the Griess reaction. Survival rates of hippocampal CA1 neurons were calculated and 8-hydroxydeoxyguanosine-immunopositive cells were counted to evaluate the oxidative stress in hippocampal CA1 neurons 72hours after the start of reperfusion.Results: Arterial blood pressure and regional cerebral blood flow were not significantly different between the 2 groups. The level of nitrate was significantly higher in the yokukansan group than in the control group during ischemia and reperfusion. Levels of 2,3- and 2,5-dihydroxybenzoic acid were significantly lower in the yokukansan group than in the control group during ischemia and reperfusion. Although survival rates in the CA1 did not differ significantly, there were fewer 8-hydroxydeoxyguanosine-immunopositive cells in animals that had received yokukansan than in control animals.Conclusions: These data suggest that yokukansan exerts reducing hydroxyl radicals in cerebral ischemic injury. [ABSTRACT FROM AUTHOR]

Background: Preoperative 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.Methods: This 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.Discussion: This 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 Registration: UMIN Clinical Trials Registry (UMIN-CTR), UMIN000027561 . Registered on 31 May 2017. [ABSTRACT FROM AUTHOR]

Background: Fentanyl can induce acute opioid tolerance and postoperative hyperalgesia when administered at a single high dose; thus, this study examined the analgesic efficacy of a combination of fentanyl and Yokukansan (YKS). Methods: Rats were divided into control, formalin-injected (FOR), YKS-treated+FOR (YKS), fentanyl-treated+FOR (FEN), and YKS+FEN+FOR (YKS+FEN) groups. Acute pain was induced via subcutaneous injection of formalin into the paw. The time engaged in pain-related behavior was measured. Results: In the early (0–10 min) and intermediate (10–20 min) phases, pain-related behavior in the YKS+FEN group was significantly inhibited compared with the FOR group. In the late phase (20–60 min), pain-related behavior in the FEN group was the longest and significantly increased compared with the YKS group. We explored the influence on the extracellular signal-regulated kinase (ERK) pathway in the spinal cord, and YKS suppressed the phosphorylated ERK expression, which may be related to the analgesic effect of YKS in the late phase. Conclusions: These findings suggest that YKS could reduce the use of fentanyl and combined use of YKS and fentanyl is considered clinically useful.