Paeonol, the active component of Cynanchum paniculatum, ameliorated schizophrenia-like behaviors by regulating the PI3K-Akt-GSK3ß-NF-κB signalling pathway in MK-801-treated mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Cynanchum paniculatum (Bunge) Kitag. ex H. Hara (Asclepiadaceae) have been traditionally used in East Asia as analgesic or antiviral agents. Interestingly, some Chinese and Korean traditional medicinal books reported that the use of C. paniculatum in the treatment of psychotic symptoms, such as hallucinations and delusions. AIM OF THE STUDY: In this study, we aimed to investigate whether C. paniculatum could improve sensorimotor gating disruption in mice with MK-801-induced schizophrenia-like behaviors. We also aimed to identify the active component of C. paniculatum that could potentially serve as a treatment for schizophrenia and found that paeonol, the major constituent compound of C. paniculatum, showed potential as a treatment for schizophrenia. MATERIALS AND METHODS: To assess the effect of paeonol on mice with MK-801-induced schizophrenia-like behaviors, we carried out a series of behavioral tests related with symptoms of schizophrenia. In addition, we utilized Western blotting and ELISA techniques to investigate the antipsychotic actions of paeonol. RESULT: C. paniculatum extract (100 or 300 mg/kg) and paenol (10 or 30 mg/kg) significantly reversed MK-801-induced prepulse deficits in acoustic startle response test. In addition, paeonol (10 or 30 mg/kg) attenuated social novelty preference and novel object recognition memory on MK-801-induced schizophrenia-like behaviour in mice. Furthermore, the phosphorylation levels of PI3K, Akt, GSK3ß and NF-κB, as well as related pro-inflammatory cytokine, such as IL-1ß and TNF-α, were significantly reversed by the administration of paeonol (10 or 30 mg/kg) in the prefrontal cortex of MK-801-treated mice. CONCLUSIONS: Collectively, these data show that paeonol can potentially be used as an agent for treating sensorimotor gating deficits, negative symptoms, and cognitive deficits, such as those observed in schizophrenia with few adverse effects.

Anti-Inflammatory Effects of the LK5 Herbal Complex on LPS- and IL-4/IL-13-Stimulated HaCaT Cells and a DNCB-Induced Animal Model of Atopic Dermatitis in BALB/c Mice.

Atopic dermatitis (AD) is a chronic inflammatory skin disease influenced by a complex interplay of genetic and environmental factors. The activation of the JAK-STAT pathway increases the expression of inflammatory cytokines such as IL-4 and IL-13, further deteriorating AD. Therefore, for the treatment of AD, the JAK-STAT pathway is emerging as a significant target, alongside inflammatory cytokines. This study investigates the potential therapeutic effects of a novel herbal complex, LK5, composed of Scutellaria baicalensis, Liriope platyphylla, Sophora flavescens, Dictammus dasycarpus, and Phellodendron schneider, known for their anti-inflammatory and immune-modulating properties. We examined the anti-inflammatory and anti-AD effects of the LK5 herbal complex in HaCaT cells stimulated by LPS and IL-4/IL-13, as well as in a mouse model of AD induced by DNCB. In HaCaT cells stimulated with LPS or IL-4/IL-13, the LK5 herbal complex demonstrated anti-inflammatory effects by inhibiting the expression of inflammatory cytokines including TNF-α, IL-6, and IL-1ß, and downregulating the phosphorylation of STAT proteins. In a murine AD-like model induced by DNCB, administration of the LK5 herbal complex significantly ameliorated clinical symptoms, including dermatitis, ear thickness, and TEWL. Histological analysis revealed a reduction in epidermal thickness and mast cell infiltration. The LK5 herbal complex also inhibited pruritus induced by compound 48/80. Furthermore, the LK5 herbal complex treatment significantly decreased the levels of inflammatory cytokines such as TSLP, IL-6, and IgE in plasma and ear tissue of AD-induced mice. These findings suggest that the LK5 herbal complex may modulate the immune response and alleviate AD symptoms by inhibiting STAT pathways.

The effects of the ethanol extract of Cordia myxa leaves on the cognitive function in mice.

BACKGROUND: Cordia myxa L. (Boraginaceae) is widely distributed in tropical regions and it's fruits, leaves and stem bark have been utilized in folk medicine for treating trypanosomiasis caused by Trypanosoma cruzi. A population-based study showed that T. cruzi infection is associated with cognitive impairments. Therefore, if C. myxa has ameliorating activities on cognitive function, it would be useful for both T. cruzi infection and cognitive impairments. METHODS: In this study, we evaluated the effects of an ethanol extract of leaves of C. myxa (ELCM) on memory impairments and sensorimotor gating deficits in mice. The phosphorylation level of protein was observed by the Western blot analysis. RESULTS: The administration of ELCM significantly attenuated scopolamine-induced cognitive dysfunction in mice, as measured by passive avoidance test and novel object recognition test. Additionally, in the acoustic startle response test, we observed that the administration of ELCM ameliorated MK-801-induced prepulse inhibition deficits. We found that these behavioral outcomes were related with increased levels of phosphorylation phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt) and glycogen synthase kinase 3 beta (GSK-3ß) in the cortex and extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB) in the hippocampus by western blot analysis. CONCLUSIONS: These results suggest that ELCM would be a potential candidate for treating cognitive dysfunction and sensorimotor gating deficits observed in individuals with neurodegenerative diseases.

4-Methoxycinnamic acid attenuates schizophrenia-like behaviors induced by MK-801 in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Scrophularia buergeriana has been used for traditional medicine as an agent for reducing heat in the blood and for nourishing kidney 'Yin'. Therefore, S. buergeriana might be a potential treatment for mental illness, especially schizophrenia, which may be attenuated by supplying kidney Yin and reducing blood heat. In a pilot study, we found that S. buergeriana alleviated sensorimotor gating dysfunction induced by MK-801. AIM OF THE STUDY: In the present study, we attempted to reveal the active component(s) of S. buergeriana as a candidate for treating sensorimotor gating dysfunction, and we identified 4-methoxycinnamic acid. We explored whether 4-methoxycinnamic acid could affect schizophrenia-like behaviors induced by hypofunction of the glutamatergic neurotransmitter system. MATERIALS AND METHODS: Mice were treated with 4-methoxycinnamic acid (3, 10, or 30 mg/kg, i.g.) under MK-801-induced schizophrenia-like conditions. The effect of 4-methoxycinnamic acid on schizophrenia-like behaviors were explored using several behavioral tasks. We also used Western blotting to investigate which signaling pathway(s) is involved in the pharmacological activities of 4-methoxycinnamic acid. RESULTS: 4-Methoxycinnamic acid ameliorated MK-801-induced prepulse inhibition deficits, social interaction disorders and cognitive impairment by regulating the phosphorylation levels of PI3K, Akt and GSK-3ß signaling in the prefrontal cortex. And there were no adverse effects in terms of catalepsy and motor coordination impairments. CONCLUSION: Collectively, 4-methoxycinnamic acid would be a potential candidate for treating schizophrenia with fewer adverse effects, especially the negative symptoms and cognitive dysfunctions.

Dracocephalum moldavica Ethanol Extract Suppresses LPS-Induced Inflammatory Responses through Inhibition of the JNK/ERK/NF-κB Signaling Pathway and IL-6 Production in RAW 264.7 Macrophages and in Endotoxic-Treated Mice.

The excessive synthesis of interleukin-6 (IL-6) is related to cytokine storm in COVID-19 patients. Moreover, blocking IL-6 has been suggested as a treatment strategy for inflammatory diseases such as sepsis. Sepsis is a severe systemic inflammatory response syndrome with high mortality. In the present study, we investigated the anti-inflammatory and anti-septic effects and the underlying mechanisms of Dracocephalum moldavica ethanol extract (DMEE) on lipopolysaccharide (LPS)-induced inflammatory stimulation in RAW 264.7 macrophages along with septic mouse models. We found that DMEE suppressed the release of inflammatory mediators NO and PGE2 and inhibited both the mRNA and protein expression levels of iNOS and COX-2, respectively. In addition, DMEE reduced the release of proinflammatory cytokines, mainly IL-6 and IL-1ß, in RAW 264.7 cells by inhibiting the phosphorylation of JNK, ERK and p65. Furthermore, treatment with DMEE increased the survival rate and decreased the level of IL-6 in plasma in LPS-induced septic shock mice. Our findings suggest that DMEE elicits an anti-inflammatory effect in LPS-stimulated RAW 264.7 macrophages and an anti-septic effect on septic mouse model through the inhibition of the ERK/JNK/NF-κB signaling cascades and production of IL-6.

Green tea extract containing enhanced levels of epimerized catechins attenuates scopolamine-induced memory impairment in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Green tea has been used as a traditional medicine to control brain function and digestion. Recent works suggest that drinking green tea could prevent cognitive function impairment. During tea manufacturing processes, such as brewing and sterilization, green tea catechins are epimerized. However, the effects of heat-epimerized catechins on cognitive function are still unknown. To take this advantage, we developed a new green tea extract, high temperature processed-green tea extract (HTP-GTE), which has a similar catechin composition to green tea beverages. AIM OF THE STUDY: This study aimed to investigate the effect of HTP-GTE on scopolamine-induced cognitive dysfunction and neuronal differentiation, and to elucidate its underlying mechanisms of action. MATERIALS AND METHODS: The neuronal differentiation promoting effects of HTP-GTE in SH-SY5Y cells was assessed by evaluating neurite length and the expression level of synaptophysin. The DNA methylation status at the synaptophysin promoter was determined in differentiated SH-SY5Y cells and in the hippocampi of mice. HTP-GTE was administered for 10 days at doses of 30, 100 and 300 mg/kg (p.o.) to mice, and its effects on cognitive functions were measured by Y-maze and passive avoidance tests under scopolamine-induced cholinergic blockade state. RESULTS: HTP-GTE induced neuronal differentiation and neurite outgrowth via the upregulation of synaptophysin gene expression. These beneficial effects of HTP-GTE resulted from reducing DNA methylation levels at the synaptophysin promoter via the suppression of DNMT1 activity. The administration of HTP-GTE ameliorated cognitive impairments in a scopolamine-treated mouse model. CONCLUSIONS: These results suggest that HTP-GTE could alleviate cognitive impairment by regulating synaptophysin expression and DNA methylation levels. Taken together, HTP-GTE would be a promising treatment for the cognitive impairment observed in dysfunction of the cholinergic neurotransmitter system.

Casticin ameliorates scopolamine-induced cognitive dysfunction in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: The fruit of Vitex rotundifolia L. (Verbenaceae) has been used in traditional medicine as sedative or analgesic agent for headache. Recent population-based cohort studies have shown that headache including migraines is a risk factor for dementia. Thus, the fruit of V. rotundifolia may be useful for treating cognitive dysfunction observed in dementia. AIM OF THE STUDY: We had previously found that the ethanolic extract of the fruit of V. rotundifolia ameliorated cognitive dysfunction and isolated casticin as an active compound. In the present study, we studied the effect of casticin on a mouse model of cognitive impairment induced by scopolamine. MATERIALS AND METHODS: Mice were treated with the ethanolic extract of the fruit of V. rotundifolia (EEVR; 30, 100 or 300 mg/kg, p.o.) or casticin (0.3, 1 or 3 mg/kg, p.o.). We examined the effect of casticin or EEVR using the passive avoidance test, the Morris water maze test and the novel object recognition test. Scopolamine (1 mg/kg, i.p.) was used to induce cognitive impairment by blocking cholinergic neurotransmitter system. We investigated the effects of casticin on acetylcholinesterase (AchE) activity and the phosphorylation levels of extracellular signal-regulated kinase (ERK), cAMP response element binding protein (CREB), and the expression levels of brain-derived neurotrophic factor (BDNF). RESULTS: EEVR (100 and 300 mg/kg, p.o.) significantly ameliorated the latency in the passive avoidance test, and casticin (1 and 3 mg/kg, p.o.) also significantly improved the latency in the passive avoidance test, novel object preference in the novel object recognition test, and swimming time in the target quadrant of the Morris water maze test. Casticin also decreased AChE activity in ex vivo analysis and increased the phosphorylation levels of memory-related signaling molecules, such as ERK, CREB and BDNF in the cortex. CONCLUSION: These results suggest that casticin ameliorates cholinergic blockade-induced cognitive impairment, in part, through the inhibition of AChE and the activation of the ERK-CREB-BDNF signaling pathway. Taken together, the results suggest that casticin may be useful for treating the cognitive dysfunction observed during cholinergic impairment.

Dracocephalum moldavica attenuates scopolamine-induced cognitive impairment through activation of hippocampal ERK-CREB signaling in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Dracocephalum moldavica (Moldavian balm) has been traditionally used for the treatment of intellectual disabilities, migraines and cardiovascular problems in East Asia. Recent scientific studies have demonstrated the usefulness of this plant to treat neurodegenerative disorders, including Alzheimer's disease. AIM OF THE STUDY: This study aimed to investigate the effects of the ethanolic extract of D. moldavica leaves (EEDM) on scopolamine-induced cognitive impairment in mice and the underlying mechanisms of action. MATERIALS AND METHODS: The behavioral effects of EEDM were examined using the step-through passive avoidance and Morris water maze tasks. To elucidate the underlying mechanism, we tested whether EEDM affects acetylcholinesterase activity and the expression of memory-related signaling molecules including extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB) in the hippocampus. RESULTS: EEDM (25, 50 or 100 mg/kg) significantly ameliorated the scopolamine-induced step-through latency reduction in the passive avoidance task in mice. In the Morris water maze task, EEDM (50 mg/kg) significantly attenuated scopolamine-induced memory impairment. Furthermore, the administration of EEDM increased the phosphorylation levels of ERK and CREB in the hippocampus but did not alter acetylcholinesterase activity. CONCLUSIONS: These findings suggest that EEDM significantly attenuates scopolamine-induced memory impairment in mice and may be a promising therapeutic agent for improving memory impairment.

A botanical drug composed of three herbal materials attenuates the sensorimotor gating deficit and cognitive impairment induced by MK-801 in mice.

OBJECTIVES: A botanical drug derived from the ethanolic extract composed of Clematis chinensis Osbeck (Ranunculaceae), Trichosanthes kirilowii Maximowicz (Cucurbitaceae) and Prunella vulgaris Linné (Lamiaceae) has been used to ameliorate rheumatoid arthritis as an ethical drug in Korea. In our study, we investigated the effect of this herbal complex extract (HCE) on schizophrenia-like behaviours induced by MK-801. METHODS: HCE (30, 100 or 300 mg/kg, p.o) was orally administered to male ICR mice to a schizophrenia-like animal model induced by MK-801. We conducted an acoustic startle response task, an open-field task, a novel object recognition task and a social novelty preference task. KEY FINDINGS: We found that a single administration of HCE (100 or 300 mg/kg) ameliorated MK-801-induced abnormal behaviours including sensorimotor gating deficits and social or object recognition memory deficits. In addition, MK-801-induced increases in phosphorylated Akt and GSK-3ß expression levels in the prefrontal cortex were reversed by HCE (30, 100 or 300 mg/kg). CONCLUSIONS: These results imply that HCE ameliorates MK-801-induced dysfunctions in prepulse inhibition, social interactions and cognitive function, partly by regulating the Akt and GSK-3ß signalling pathways.

Danshensu attenuates scopolamine and amyloid-ß-induced cognitive impairments through the activation of PKA-CREB signaling in mice.

Alzheimer's disease (AD) is an important chronic neurodegenerative disorder and is mainly associated with cognitive dysfunction. At present, bioactive compounds from traditional medicinal plants have received much attention for the enhancement of cognitive function. Danshensu, a phenolic acid isolated from herbal medicines, has various pharmacological activities in the central nervous system, including anxiolytic-like and neuroprotective properties. The present study aimed to investigate the ameliorating effects of danshensu on scopolamine- and amyloid-ß (Aß) protein-induced cognitive impairments in mice. Danshensu (3 and 10 mg/kg, p.o.) effectively ameliorated scopolamine-induced cognitive dysfunction in mice, as measured in passive avoidance and Y-maze tasks. In a mechanistic study, danshensu inhibited monoamine oxidase A (MAO-A) activity but not MAO-B. Additionally, danshensu treatment increased the dopamine level and the phosphorylation levels of protein kinase A (PKA) and cAMP response element binding protein (CREB), in the cortex of the brain. Furthermore, the ameliorating effect of danshensu against scopolamine-induced cognitive impairment was fully blocked by H89, a PKA inhibitor. Finally, danshensu also ameliorated Aß-induced cognitive impairments in an animal model of AD. The results revealed that danshensu treatment significantly improved scopolamine and Aß-induced cognitive impairments in mice by facilitation of dopamine signaling cascade such as PKA and CREB due to MAO-A inhibition. Thus, danshensu could be used as a promising therapeutic agent for preventing and treating AD.

New Depsides and Neuroactive Phenolic Glucosides from the Flower Buds of Rugosa Rose ( Rosa rugosa).

The flower buds of Rosa rugosa Thunb. have been commonly used as a source of rose oil and as an ingredient in tea in eastern Asia, including China, Japan, and Korea. Repeated chromatography of a hot water extract from the flower buds of R. rugosa led to the isolation and characterization of three new depside glucosides, rosarugosides A-C (1-3), along with three phenolic compounds, one ionone glucoside, four flavonoids, and two tannins having known chemical structures. Linarionoside A and 2-phenylethyl-(6- O-galloyl)-ß-d-glucopyranoside were isolated from R. rugosa for the first time in this study. The structures of the new compounds 1-3 were elucidated by interpreting one- and two-dimensional nuclear magnetic resonance spectroscopic and mass spectrometric data. Among the isolates, a new depside glucoside (1) and two major phenolic glucosides (4 and 5) improved MK-801-induced sensorimotor gating deficits, which were measured via an acoustic startle response test in mice.

Aster glehni Extract Ameliorates Scopolamine-Induced Cognitive Impairment in Mice.

The leaves of Aster glehni Fr. Schm. (Asteraceae) have been used to treat insomnia in Korea. Insomnia is a common adverse effect of therapeutic agents for Alzheimer's disease (AD), and the control of sleep disturbance may prevent dementia. We hypothesized that the leaves of A. glehni can attenuate cognitive dysfunctions observed in AD. We observed the ameliorating effects of the ethanolic extract of leaves of A. glehni (AG-D) on memory dysfunction through the Morris water maze test, the passive avoidance test, and the Y-maze test. We performed acetylcholinesterase (AChE) activity assay and Western blotting to determine the mechanism of action of AG-D. AG-D significantly attenuated memory dysfunction observed in the above behavior studies and inhibited the activity of AChE. AG-D also increased the levels of phosphorylation extracellular signal-regulated kinase (ERK), cAMP response element-binding protein (CREB), phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), and glycogen synthase kinase 3ß (GSK-3ß) and the expression levels of brain-derived neurotrophic factor (BDNF) in the hippocampi. These results suggest that AG-D ameliorates memory impairments by AChE inhibition and activation of ERK-CREB-BDNF and PI3K-Akt-GSK-3ß signaling pathways. Taken together, this study suggests that AG-D could be used as a potential treatment for cognitive dysfunction.

The Ameliorating Effects of Bee Pollen on Scopolamine-Induced Cognitive Impairment in Mice.

Bee pollen consists of floral pollen mixed with bee secretions and nectar. It has been considered as a functional food and has different kinds of biologically active ingredients, such as flavonoids, polyphenols, phytosterols and minerals. However, its function in cognition has yet been investigated. In the present study, we investigated the ameliorating effect of bee pollen against scopolamine-caused cognitive impairment through the passive avoidance test, the Y-maze test and the Morris water maze test. In addition, Western blotting was employed to verify the effects of bee pollen on memory-related signaling molecules in the hippocampus. Bee pollen extract (100 or 300 mg/kg, per os (p.o.)) obviously reversed scopolamine-caused cognitive impairment in the passive avoidance test, ameliorated spontaneous alternation versus the scopolamine-treated group in the Y-maze test and prolonged swimming time in the target zone in the Morris water maze test. In addition, the phosphorylation levels of extracellular signal-regulated kinase (ERK), cAMP response element-binding protein (CREB), protein kinase B (Akt) and glycogen synthase kinase-3ß (GSK-3ß), and the expression levels of brain-derived neurotrophic factor (BDNF) and tissue plasminogen activator (tPA) in the hippocampi, were increased in response to the treatment with bee pollen extract (100 or 300 mg/kg, p.o.). These results indicated that bee pollen ameliorates cognitive impairment induced by cholinergic blockade through the enhancing conversion of proBDNF to mature BDNF by tPA, probably, through the ERK-CREB pathway or Akt-GSK-3ß signaling pathway and would be a useful agent for the treatment of cognitive dysfunction.