Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, synaptic dysfunction, and cholinergic signaling deficits. Paeonol (2-hydroxy-4-methoxyacetophenone), a phenolic compound derived from Paeonia suffruticosa, has well-documented neuroprotective activity, but potential cognitive benefits and the underlying mechanisms have not been widely examined. Here, we investigated the potential of paeonol to improve cognitive function in scopolamine- and Aβ1-42 oligomer-induced mouse models of AD. Paeonol significantly improved the performance of both models in the Y-maze, novel object recognition, and passive avoidance tests, particularly at 10 mg/kg. Western blotting of excised brain tissue revealed that paeonol treatment reversed scopolamine- and Aβ1-42 oligomer-induced suppression of hippocampal PKA and cAMP response element-binding (CREB) phosphorylation and concomitantly enhanced brain-derived neurotrophic factor (BDNF) expression. Notably, paeonol also reversed scopolamine- and Aβ1-42-induced downregulation of Takeda G-protein-coupled receptor 5 (TGR5), an upstream regulator of the PKA-CREB-BDNF pathway, and molecular docking simulations predicted a possible paeonol-TGR5 interaction. Moreover, paeonol suppressed scopolamine-induced elevation of acetylcholinesterase activity with efficacy comparable to the clinical inhibitor donepezil. These findings support the potential of paeonol as a naturally sourced multitarget therapeutic agent for AD.

Abnormal accumulation of amyloid β (Aβ), which may result from excessive production or impaired clearance, is one of the pathomechanisms of Alzheimer's disease (AD). Plasmin is one of the important proteases involved in the Aβ clearance system. In this study, we investigated whether swertisin can regulate plasmin activity and reduce Aβ pathology. First, we examined whether swertisin regulated plasmin activity, mature brain-derived neurotrophic factor (mBDNF) levels, and plasminogen activator inhibitor-1 (PAI-1) activity in vitro. Next, we assessed the effect of swertisin on memory impairments in an Aβ-injected AD-like mouse model and in 5XFAD mice. To evaluate the involvement of plasmin in the effect of swertisin in the Aβ-injected AD-like mouse model, we used 6-aminocaproic acid (6-AA), a plasmin inhibitor. Additionally, we measured plasmin activity and mBDNF levels in the hippocampus of Aβ-injected AD-like mice and 5XFAD mice. Swertisin increased plasmin activity and mBDNF levels in hippocampal slices from both normal and 5XFAD mice. Moreover, swertisin ameliorated Aβ-induced synaptic long-term potentiation (LTP) deficits in hippocampal slices. Swertisin also mitigated memory impairments induced by ventricular injection of Aβ, and this effect was blocked by 6-AA. Furthermore, swertisin improved learning and memory in 5XFAD mice while reducing Aβ deposition and neuroinflammation. This study demonstrates that swertisin ameliorates AD-like pathology by regulating plasmin activity. Plasmin activated by swertisin may cleave Aβ aggregates and increase mBDNF levels, thereby protecting the brain from Aβ toxicity. Swertisin may represent an effective therapeutic strategy for AD patients.

Cognitive dysfunction has become a major health issue in the global aging society. For treating cognitive dysfunction or dementia, several small molecules or innovative drugs, including a monoclonal antibody against the amyloid β protein, have been prescribed. However, their adverse effects require the exploration of alternative treatments. Artemisia argyi (Asteraceae) has been used as traditional medicine for gastrointestinal disorders and inflammation. Recent reports suggest it has potential neuroprotective effects; however, evidence regarding its cognitive benefits and underlying mechanisms remains limited. We examined the memory-enhancing effects of an ethanolic extract of A. argyi (EAA) (10, 30, or 100 mg/kg, once per each behavioral test) in a mouse model of scopolamine-induced cognitive dysfunction and explored its mode of action on memory-related signaling pathways. Memory-related performance was assessed using the Y-maze, novel object recognition, Morris water maze, and passive avoidance tests. Next, Western blotting was used to evaluate changes in signaling molecules, such as CaMKII, ERK, CREB, and brain-derived neurotrophic factor (BDNF) in the hippocampus. EAA administration significantly improved cognitive performance across all tests. It restored the phosphorylation levels of CaMKII, ERK, and CREB, respectively, as well as the expression level of BDNF, after 12 h of treatment. Moreover, it enhanced long-term potentiation without altering basal synaptic transmission within the hippocampus. In summary, EAA facilitated cognitive enhancement during a cholinergic impaired state, attributable to its influence on synaptic plasticity and activation of the CaMKII-ERK-CREB-BDNF signaling cascade.

Post-traumatic stress disorder (PTSD) is a mental illness that can occur in individuals who have experienced trauma. Sinapic acid has been reported to be effective for anxiety as a GABAA receptor agonist, and has been reported to improve cognitive impairment by modulating the GABA/glutamate ratio, but there are no reports associated with PTSD. In the present study, we investigated the effects of sinapic acid in a mouse model of PTSD induced by a single prolonged stress (SPS) protocol.We examined the therapeutic effects of sinapic acid on emotional and cognitive impairment in the SPS mouse model. We also explored the effects of sinapic acid on fear memory extinction. Western blot was employed to investigate how sinapic acid exerts its pharmacological activities.Sinapic acid ameliorated PTSD-like behaviors in a SPS mouse model. Notably, in the case of cognitive dysfunction, paroxetine failed to improve, but sinapic acid restored cognitive function. Additionally, sinapic acid did not increase locomotor behavior, while paroxetine increased. Furthermore, sinapic acid normalized the overactivated GluN2B-containing NMDA receptor signaling pathway in the amygdala and the hypothalamus. The mitigation of fear memory deficits by sinapic acid was exerted by sub-effective dose of GluN2B-containing NMDA receptor antagonist and abolished by GABAA receptor antagonist.Our findings suggest that sinapic acid could serve as a potential therapeutic agent for PTSD by balancing excitatory and inhibitory neurotransmitter systems due to its action on GluN2B-containing NMDA receptors and GABAA receptors.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, synaptic dysfunction, and cholinergic signaling deficits. Paeonol (2-hydroxy-4-methoxyacetophenone), a phenolic compound derived from Paeonia suffruticosa, has well-documented neuroprotective activity, but potential cognitive benefits and the underlying mechanisms have not been widely examined. Here, we investigated the potential of paeonol to improve cognitive function in scopolamine- and A(31-42 oligomer-induced mouse models of AD. Paeonol significantly improved the performance of both models in the Y-maze, novel object recognition, and passive avoidance tests, particularly at 10 mg/kg. Western blotting of excised brain tissue revealed that paeonol treatment reversed scopolamine- and A(31-42 oligomer-induced suppression of hippocampal PKA and cAMP response element-binding (CREB) phosphorylation and concomitantly enhanced brain-derived neurotrophic factor (BDNF) expression. Notably, paeonol also reversed scopolamine- and A(31-42-induced downregulation of Takeda G-protein-coupled receptor 5 (TGR5), an upstream regulator of the PKA-CREB-BDNF pathway, and molecular docking simulations predicted a possible paeonol-TGR5 interaction. Moreover, paeonol suppressed scopolamine-induced elevation of acetylcholinesterase activity with efficacy comparable to the clinical inhibitor donepezil. These findings support the potential of paeonol as a naturally sourced multitarget therapeutic agent for AD.

BACKGROUND:Schizophrenia is a complex neuropsychiatric disorder characterized by impairments in cognition, perception, and social behavior. Current antipsychotic medications primarily target dopaminergic signaling but often exhibit limited efficacy in treating negative and cognitive symptoms. Moreover, long-term antipsychotic therapy is frequently associated with clinically relevant adverse effects, including metabolic syndrome and extrapyramidal symptoms (EPS). Phosphodiesterase 10A (PDE10A) has emerged as a promising non-dopaminergic therapeutic target involved in regulating cyclic nucleotide signaling in the striatum. However, several synthetic PDE10A inhibitors have shown safety and tolerability limitations. This study therefore investigated the antipsychotic-like potential of the ethanol extract of Dracocephalum moldavica (EEDM) and its major flavone glycoside, tilianin, in an MK-801-induced schizophrenia-like mouse model and explored the underlying molecular mechanisms. METHODS:Tilianin content in EEDM was quantified using HPLC, and phytochemical constituents were comprehensively characterized by UHPLC-Q-TOF LC-MS/MS. The inhibitory effect of EEDM and tilianin on PDE10A activity was evaluated using in vitro enzyme assays, supported by molecular docking. Behavioral tests, including the open field test (OFT), acoustic startle response (ASR), novel object recognition, and social interaction test (SIT), were performed in MK-801-induced schizophrenia-like mice. Mechanistic insights were explored through network pharmacology analysis and further validated by analyzing the cAMP/PKA/CREB signaling in the prefrontal cortex using Western blot analysis. RESULTS:HPLC analysis identified tilianin as the major constituent of EEDM, while UHPLC-Q-TOF LC-MS/MS profiling revealed a diverse phytochemical profile comprising multiple flavonoids and phenolic compounds. Molecular docking predicted stable, high-affinity binding of tilianin to the PDE10A catalytic site (docking score: -11.857 kcal/mol), and this prediction was supported by an enzymatic assay showing PDE10A inhibition by both EEDM (IC50 = 346.6 μg/ml) and tilianin (IC50 = 11.25 μg/ml; 25.20 μM). Tilianin ameliorated MK-801-induced hyperlocomotion, rescued prepulse inhibition (PPI) deficits, and reversed impairments in cognitive and social functions. Network pharmacology identified PDE10A, CREB1, ESR1, and MAPK1 as key hubs modulating synaptic plasticity. Furthermore, tilianin restored the disrupted cAMP/PKA/CREB signaling in the prefrontal cortex. CONCLUSION:These findings suggest that tilianin may act as a network-informed modulator associated with PDE10A inhibition and downstream neuroplastic signaling, providing a potential mechanistic basis for addressing the limited efficacy of conventional antipsychotic strategies in schizophrenia.

Although selective serotonin reuptake inhibitors are the primary treatment for post-traumatic stress disorder (PTSD), they do not address all aspects of PTSD, highlighting the need for new therapies. Schizandrin, a lignan compound found in Schisandra chinensis, alleviates cognitive dysfunction, depression-like behaviors, and anxiety, suggesting that it may ameliorate PTSD symptoms. However, to date, no studies have explored the effects of schizandrin on PTSD symptoms. In the present study, we investigated whether schizandrin alleviates PTSD-like symptoms and explored its mechanism of action. We used a single prolonged stress (SPS) mouse model, a well-known animal model for simulating PTSD, to observe anti-PTSD activities. Behavioral experiments to evaluate emotional and cognitive impairments, network pharmacology, molecular docking analysis, and western blotting were performed. Schizandrin (10 mg/kg, p.o.) mitigated anxiety-like behavior as measured by the elevated plus-maze test, alleviated depression-like behavior as evaluated by the tail suspension test, and improved cognitive dysfunction as assessed by the Y-maze test. Furthermore, schizandrin reduced acquired fear memory in the SPS mouse model, as examined using the fear extinction test. Network pharmacology and molecular docking analyses revealed that schizandrin were bound most stably to the 5-HT1A receptor, a key modulator of fear and stress responses. Finally, we found that schizandrin activated 5-HT1A receptors and subsequently normalized the PI3K-Akt-mTOR and PKA-CREB signaling pathways in the amygdala of the SPS mouse model. These findings suggest that schizandrin is a potential therapeutic candidate for alleviating the multifaceted symptoms of PTSD.

Although numerous studies have suggested that chronic stress is a major risk factor for major depressive disorder, the process by which stress causes depression is still not fully understood. Previously, we investigated glucocorticoids, which are stress response hormones that activate a synapse-weakening pathway. Therefore, we hypothesized that chronic stress may cause synaptic depression, which could reduce excitability related to emotions. Animals underwent chronic restraint stress (CRS), followed by basal synaptic transmission measurement in hippocampal slices to assess synaptic function. Drugs were infused into the ventral hippocampus via cannulation before behavioral tests, including forced swimming, tail suspension, and sucrose intake tests, which evaluated depressive-like behaviors and anhedonia. The field excitatory postsynaptic potentials (fEPSPs) are reduced by chronic restraint stress (CRS) in the ventral hippocampus. The ventral hippocampi of mice treated with CRS showed low levels of fEPSP after the forced swim test (FST). In the FST and tail suspension test, CRS-induced increases in immobility time were prevented by the acute inhibition of AMPAR internalization by Tat-GluA23y, which also prevented fEPSP reduction. Mice lacking caspase-3 exhibited resilience to CRS-induced increases in immobility time in the FST, as well as changes in the functionality of synaptic AMPAR. Finally, the caspase-3 inhibitor Z-DEVD-FMK rapidly blocked the CRS-induced increase in immobility time in the FST and the CRS-induced decrease in sucrose preference. These findings suggest that chronic stress-related behavioral changes may require caspase-3-dependent alterations in ventral hippocampal synapses.

Aims: Posttraumatic stress disorder (PTSD) is a debilitating neuropsychiatric illness caused by traumatic or lifethreatening events and manifesting as various symptoms, including intrusive re-experiences of trauma, avoidance behaviors, hyperarousal, and negative changes in perception and mood. Main methods: Current monoamine-based medications commonly exhibit limited efficacy and significant side effects, which hamper their clinical utility. To address this unmet need, we explored 4-methoxycinnamic acid (4MCA) as a potential novel treatment for PTSD in a single prolonged stress (SPS)-induced animal model. Key findings: Administration of 4-MCA (3 and 10 mg/kg, p.o.) significantly mitigated anxiety-like behaviors, alleviated depression-like behaviors, and improved cognitive function in an SPS-treated PTSD mouse model. Further, 4-MCA treatment effectively rectified the fear extinction deficits in the fear conditioning test. Molecular analyses revealed that 4-MCA normalized the elevated corticotropin-releasing hormone (CRH) levels as well as the phosphorylation of protein kinase A (PKA) and cAMP response element-binding protein (CREB) in the amygdala, a pivotal region for fear memory formation. Co-administration of 4-MCA and the CRFR1 antagonist antalarmin at subeffective doses facilitated fear memory extinction. Significance: These findings suggest that 4-MCA alleviates SPS-induced PTSD-like behaviors by regulating the CRH-CRFR1-PKA-CREB signaling pathway in the amygdala, and that 4-MCA may be a potential candidate for future PTSD treatment.

Despite the widespread use of monoaminergic antidepressants, their clinical efficacy is often limited by delayed onset and adverse effects. Targeting the α2C adrenoceptor (AR) has emerged as a promising strategy to overcome these limitations. Here, a series of benzoxazole and oxalamide derivatives were designed, synthesized, and biologically evaluated as potential antidepressants targeting α2C AR. Among them, 11e (KMCA-0011), 21b (KMCA-0002), and 21e (KMCA-0028) exhibited the highest binding affinity. Molecular docking studies provided a rationale for the differences in their binding affinities. These compounds demonstrated antagonistic activity by inhibiting ERK phosphorylation without agonistic effects. In a maternal separation (MS) mouse model, all three compounds significantly alleviated depressive-like behaviors, with 11e (KMCA-0011) and 21e (KMCA-0028) showing the most consistent efficacy. Mechanistically, 11e (KMCA-0011) increased hippocampal brain-derived neurotrophic factor (BDNF) levels and restored corticosterone-induced impairments in long-term potentiation (LTP), indicating modulation of synaptic plasticity. Additionally, 11e (KMCA-0011) and 21e (KMCA-0028) displayed favorable ADME profiles, including high plasma stability and minimal CYP inhibition. Given the predicted limited blood-brain barrier (BBB) permeability of 21e (KMCA-0028), these results collectively identify 11e (KMCA-0011) as a promising lead compound that demonstrates robust antidepressant-like activity, likely mediated through α2C AR antagonism and BDNF-dependent neuroplastic mechanisms.

BACKGROUND:It has not been known that pellitorine, an active ingredient of Piper sarmentosum Roxb. with therapeutic effects against epilepsy and anxiety disorders, has the neurological effects. Our study aimed to investigate the therapeutic potential of pellitorine in addressing chronic restraint stress (CRS)-associated cognitive deficits. METHODS:The CRS mouse model was treated with pellitorine and subjected to depression-like behavior assessments. Neuronal survival was evaluated through histological and Nissl staining. Immunoblotting assays were conducted to examine the expression levels of signaling pathway proteins. Immunofluorescent staining, flow cytometry, and RNA sequencing were utilized to further elucidate the pathological and molecular changes in pellitorine-treated CRS mice. RESULTS:Behavioral experiments demonstrated that pellitorine treatment significantly alleviated depression-like behaviors and improved cognitive function in CRS mice. Histological analysis revealed a marked reduction in neuronal loss following pellitorine administration. Transcriptomic profiling indicated that pellitorine suppressed ferroptosis-associated signaling pathways and neuroinflammation. Notably, the expression of anti-ferroptosis factors, including GPX4, DHODH, and FSP1, was decreased in CRS mice but restored by pellitorine treatment. In addition, pellitorine prevented neuronal loss, preserved the expression of neuroprotective molecules such as BDNF, Nrf2, HO-1, phosphorylated-CREB, and phosphorylated-ERK1/2, and reduced the protein levels of inflammation-related markers including NLRP3, HMGB1, and NF-κB. Immunofluorescent staining and flow cytometry analyses further showed that pellitorine treatment reduced the number of activated microglia, as indicated by decreased Iba-1+, TREM2+, CD86+, and CX3CR1+ cell populations in the hippocampus. Importantly, pellitorine did not exhibit any observable neurotoxic effects in healthy control mice. CONCLUSIONS:Our findings demonstrate that pellitorine protects against CRS-induced cognitive deficits, neural inflammation, and ferroptosis, highlighting its promise as a therapeutic agent for mental health issues.

Post-traumatic stress disorder (PTSD) is a severe mental illness characterized by increased arousal, intrusion, avoidance, and negative cognitive alterations following exposure to fatal stresses or psychological trauma. In this study, we explored the ameliorating effects of spinosin on PTSD-like behaviors in PTSD model mice induced by single prolonged stress (SPS). A single dose of spinosin (3 mg/kg, p.o.) ameliorated PTSD-like behaviors as assessed using the elevated plus-maze test, marble burying test, Y-maze test, tail suspension test, and fear extinction test. Furthermore, we discovered that spinosin promotes fear extinction through 5-HT1A receptor activation. We also verified that spinosin normalizes the increased phosphorylation levels of PKA and CREB, which are downstream signaling pathways of the 5-HT1A receptor, in the amygdala of mice modeling PTSD. Our findings suggest that spinosin could be an effective treatment for PTSD via 5-HT1A receptor activation, addressing the limitations of current PTSD medications.

ETHNOPHARMACOLOGICAL RELEVANCE:Cheonwangbosim-dan (CWBSD) as a traditional herbal medicine prescription has been used for cognitive dysfunction in terms of heart blood deficiency, however, there were few researches for cognitive dysfunction and its mode of action. AIM OF THE STUDY:This study was aimed to examine the effects of CWBSD on hypocholinergic-induced memory impaired mice and unveil its mechanism of action on cognitive function. MATERIALS AND METHODS:The standardized CWBSD was used in the present study. Several behavioral tests, including Y-maze task, the Morris water maze task (MWM), novel object recognition test (NORT) and passive avoidance test (PAT), were employed with administration of CWBSD (150, 500 or 1500 mg/kg) in scopolamine-treated mice. After behavioral tests, the mice were sacrificed and the Western blot analysis and electrophysiological analysis were conducted to investigate the mechanism of CWBSD on ameliorating cognitive function. RESULTS:The administration of CWBSD improved cognitive functions measured by the Y-maze task, MWM, NORT and PAT in scopolamine-induced cognitive impaired mice. This memory improvement effect was associated with the activation of protein kinase C zeta (PKCζ)/calcium-calmodulin-dependent protein kinase Ⅱ (CaMKⅡ)-extracellular signal-regulated kinase (ERK)-cAMP response element-binding protein (CREB)-brain-derived neurotropic factor (BDNF) pathway via N-methyl-D-aspartate receptor subtype 2B (NR2B), and the activation of this pathway increased long-term potentiation in the brain of mice. CONCLUSION:The administration of CWBSD could ameliorate spatial memory, recognition memory and long-term memory, and such ameliorating activities would be derived from the activation of NMDA receptor-associated pathway with increase of LTP in the brain. These results suggests that CWBSD would be a candidate for a new dementia treatment.

ETHNOPHARMACOLOGICAL RELEVANCE:Cheonwangbosimdan (CWBSD), a herbal medicine traditionally used for anxiety, insomnia, depression, and heart palpitations, has been reported to have anti-anxiety, antidepressant, cognitive improvement, and neuroprotective effects.AIM OF THE STUDY:The purpose of this study was to determine if CWBSD could affect post-traumatic stress disorder (PTSD)-like behaviors because it has prioritized clinical use over mechanism study.MATERIALS AND METHODS:A single prolonged stress (SPS) mouse model, a well-established animal model of PTSD, was used to investigate whether standardized CWBSD could mitigate PTSD-like behaviors through robust behavioral tests, including the elevated plus-maze test and marble burying test for measuring anxiety-like behaviors, the splash test, forced swimming test, and tail suspension test for evaluating depression-like behaviors, and the Y-maze test and novel object recognition test for assessing cognitive function. Additionally, a fear extinction test was employed to determine whether CWBSD might reverse fear memory extinction deficits. Amygdala tissue was isolated from SPS-treated mouse brain and subjected to Western blotting or quantitative PCR to explore mechanisms by which CWBSD could mitigate PTSD-like behaviors.RESULTS:CWBSD ameliorated emotional impairments and cognitive dysfunction in an SPS-induced PTSD-like mouse model. It also mitigated deficits in abnormal fear memory extinction. Protein expression levels of N-methyl-D-aspartate (NMDA) receptor subunit 2B (GluN2B) and phosphorylation levels of Ca2+/calmodulin-dependent protein kinase II in the amygdala were increased in SPS model mice and normalized by CWBSD. Additionally, co-administration of CWBSD and GluN2B-containing NMDA receptor antagonist, ifenprodil, at each sub-effective dose promoted fear memory extinction.CONCLUSIONS:CWBSD can alleviate SPS-induced PTSD-like behaviors by normalizing GluN2B-containing NMDA receptor activity in the amygdala. Therefore, CWBSD could be a promising candidate for PTSD treatment with fewer adverse effects and better efficacy than existing therapies.

Ethnopharmacological relevance: The Moutan cortex (MC), the root bark of Paeonia suffruticosa Anderws (Paeoniaceae), has been historically employed in traditional herbal medicine for addressing women 's ailments by replenishing kidney Yin. Aim of the study: We aimed to explore if paeonol, an active constituent of MC, could ameliorate neuropsychiatric symptoms, such as anxiety, depression, and cognitive impairments, associated with post -menopausal syndrome (PMS) in an ovariectomized (OVX) mouse model. Materials and methods: The experimental design comprised 6 groups, including a sham group, OVX group, paeonol administration groups (3, 10 or 30 mg/kg, p.o.), and an estradiol (E2) -treated positive control group. Behavioral tests including the open field, novel object recognition, Y -maze, elevated plus -maze, splash, and forced swimming tests were conducted. In addition, we investigated the effets of paeonol on the phosphorylated levels of phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR), as well as on the expression levels of G protein -coupled receptor (GPR30) and brain -derived neurotrophic factor (BDNF) in the prefrontal cortex and hippocampus. Results: Paeonol treatment (10 and 30 mg/kg, p.o.) effectively reversed the cognitive decline in OVX mice, measured by the novel object recognition and Y -maze tests, similar to that in the positive control group. Additionally, it alleviated anxiety- and depressive -like behaviors, as evaluated by the elevated plus -maze test, splash test, and forced swimming test. Paeonol restored GPR30 expression levels in the prefrontal cortex and hippocampus, mirroring the effects of E2 administration. Furthermore, it reversed the reduced expression levels of the PI3K-Akt-mTOR signaling pathway in the prefrontal cortex and hippocampus and increased BDNF expression in the hippocampus of OVX mice. Conclusion: This research suggests that paeonol would be beneficial for alleviating PMS-associated cognitive impairment, anxiety and depression.

Post-traumatic stress disorder (PTSD) is a mental illness that can occur in individuals who have experienced trauma. Current treatments for PTSD, typically serotonin reuptake inhibitors, have limited effectiveness for patients and often cause serious adverse effects. Therefore, a novel class of treatment with better pharmacological profile is necessary. D-Pinitol has been reported to be effective for depression and anxiety disorders, but there are no reports associated with PTSD. In the present study, we investigated the effects of D-pinitol in a mouse model of PTSD induced by a single prolonged stress (SPS) protocol. We examined the therapeutic effects of D-pinitol on emotional and cognitive impairments in the SPS mouse model. We also investigated the effects of D-pinitol on fear memory formation. Mineralocorticoid receptor transactivation assay, Western blot, and quantitative PCR were employed to investigate how D-pinitol exerts its pharmacological activities. D-Pinitol ameliorated PTSD-like behaviors in a SPS mouse model. D-Pinitol also normalized the increased mRNA expression levels and protein levels of the mineralocorticoid receptor in the amygdala. A mineralocorticoid receptor agonist reversed the effects of D-pinitol on fear extinction and recall, and the antagonistic property of D-pinitol against the mineralocorticoid receptor was confirmed in vitro. Our findings suggest that D-pinitol could serve as a potential therapeutic agent for PTSD due to its antagonistic effect on the mineralocorticoid receptor.

An herbal medicinal product consisting of three kinds of herbal materials, Prunella vulgaris L. (Lamiaceae), Clematis chinensis Osbeck (Ranunculaceae) and Trichosanthes kirilowii Max. (Cucurbitaceae) has been prescribed in the clinic for treating rheumatoid arthritis in Korea. In the present study, we investigated the antidepressive effect of this herbal complex extract (HCE) on lipopolysaccharide (LPS)-induced depression-like behavior. The effects of HCE on LPS-induced depressive-like behaviors were evaluated using a forced swimming test (FST) and splash test. In addition, we also evaluated locomotor activity and anxiety-like behaviors using the open field test and elevated plus-maze (EPM) test. Inflammatory cytokines were evaluated in the cortical regions. HCE attenuated anxiety-like behavior in the EPM test and depressive- and anhedonia-like behaviors induced by LPS in the FST and splash test. In addition, LPS-induced increases in the phosphorylation levels of protein kinase B (Akt) and glycogen synthase kinase 3 beta (GSK-3β) and expression levels of proinflammatory factors in the cortex were normalized by HCE. Moreover, decreases in the level of BDNF in the cortex were attenuated by HCE. These results suggest that HCE attenuates inflammation-induced depression-like behaviors through its normalization of Akt-GSK-3β signaling and proinflammatory factors and its upregulation of BDNF in the cortex and that HCE has therapeutic potential for depressive disorders in inflammatory states.

Ethnopharmacological relevance: Artemisia annua L. (Asteraceae) has been used as an antipyretic and anti-parasitic drug in traditional medicine for more than 2000 years. It has also been prescribed to treat symptoms caused by deficiency of Yin, which might be observed in menopausal state from the point of view of traditional medicine. Aim of the study: We hypothesized that A. annua might be useful for treating menopausal disorders with less adverse effects than hormone replacement therapy. Thus, the aim of the present study was to investigate effects of A. annua on postmenopausal symptoms of ovariectomized (OVX) mice.Materials and methods: OVX mice were employed as a model for postmenopausal disorders. Mice were treated with a water extract of A. annua (EAA; 30, 100 or 300 mg/kg, p.o.) or 170-estradiol (E2; 0.5 mg/kg, s.c.) for 8 weeks. Open field test (OFT), novel object recognition task (NOR), Y-maze test, elevated plus maze test (EPM), splash test and tail suspension test (TST) were conducted to determine whether EAA could ameliorate postmenopausal symptoms. Phosphorylated levels of extracellular signal-regulated kinase (ERK), protein kinase B (Akt), and glycogen synthase kinase-30 (GSK-30), 0-catenin and expression level of synaptophysin in the cortex and hippocampus were evaluated by Western blot analysis. Results: EAA treatment significantly increased the discrimination index in NOR, decreased the time in closed arm than in open arm in EPM, increased grooming time in splash test, and decreased immobility time in TST, as did E2 treatment. In addition, decreased phosphorylation levels of ERK, Akt, GSK-30, and 0-catenin and expression levels of synaptophysin in the cortex and hippocampus after OVX were reversed by administration of EAA and E2.Conclusion: These results suggest that A. annua can ameliorate postmenopausal symptoms such as cognitive dysfunction, anxiety, anhedonia, and depression by activating ERK, Akt, and GSK-30/0-catenin signaling pathway and hippocampal synaptic plasticity, and that A. annua would be a novel treatment for postmenopausal symptoms.

Alzheimer's disease (AD) is characterized by cognitive impairment. It is common in the elderly. Etiologically, dysfunction of cholinergic neurotransmitter system is prominent in AD. However, disease modifying drug for AD is still unavailable. We hypothesized that krill oil and modified krill oil containing 20 % lysophosphatidylcholine-docosahexaenoic acid (LPC-DHA, LPC20K) could play a crucial role in AD by improving cognitive functions measured by several behavioral tests. We found that LPC20K could ameliorate short-term, long-term, spatial, and object recognition memory under cholinergic hypofunction states. To find the underlying mechanism involved in the effect of LPC20K on cognitive function, we investigated changes of signaling molecules using Western blotting. Expression levels of protein kinase C zeta (PKCζ) and postsynaptic density protein 95 (PSD-95), and phosphorylation levels of extracellular signal-regulated kinase (ERK), Ca2+/calmodulin-dependent protein kinase Ⅱ (CaMKⅡ), and cAMP response element-binding protein (CREB) were significantly increased in LPC20K-administered group compared to those in the memory impairment group. Moreover, the expression levels of BDNF were temporally increased especially 6 or 9 h after administration of LPC20K compared with the control group. These results suggest that LPC20K could ameliorate memory impairment caused by hypocholinergic state by enhancing the expression levels of PKCζ and PSD-95, and phosphorylation levels of ERK, CaMKⅡ and CREB and increasing BDNF expression levels. Therefore, LPC20K could be used as a dietary supplement against cognitive impairment observed in diseases such as AD with a hypocholinergic state.