Tingxu Yan

Schisandra chinensis produces the antidepressant-like effects in repeated corticosterone-induced mice via the BDNF/TrkB/CREB signaling pathway

The present study aimed to examine the antidepressant-like effects and the possible mechanisms of Schisandra chinensis on depressive-like behavior induced by repeated corticosterone injections in mice. Here we evaluated the effect of an ethanol extract of the dried fruit of S. chinensis (EESC) on BDNF/TrkB/CREB signaling in the hippocampus and the prefrontal cortex. Three weeks of corticosterone injections in mice resulted in depressive-like behavior, as indicated by the significant decrease in sucrose consumption and increase the immobility time in the forced swim test, but without any influence on the locomotor activity. Further, there was a significant increase in serum corticosterone level and a significant downregulation of BDNF/TrkB/CREB signaling pathway in the hippocampus and prefrontal cortex in CORT-treated mice. Treatment of mice with EESC (600mg/kg) significantly ameliorated all the behavioral and biochemical changes induced by corticosterone. Moreover, pharmacological inhibition of BDNF signaling by K252a abolished entirely the antidepressant-like effect triggered by chronic EESC treatment. These results suggest that EESC produces an antidepressant-like effect in CORT-induced depression in mice, which is possibly mediated, at least in part, by rectifying the stress-based hypothalamic-pituitary-adrenal (HPA) axis dysfunction paradigm and upregulation of BDNF/TrkB/CREB signaling pathway.

Schisantherin B ameliorates Aβ1-42-induced cognitive decline via restoration of GLT-1 in a mouse model of Alzheimer's disease.

Accumulation of amyloid beta (Aβ) peptide and hyperphosphorylated tau protein has been proposed to play roles in neural destruction which induce Alzheimers disease (AD) progresses, glutamate transporter type 1 (GLT-1) and Glycogen synthase kinase3β (GSK3β) may be the pathological links between Aβ and tau pathology. Schisantherin B (STB) is one bioactive of lignans isolated from Schisandra chinensis (Turcz.) Baill which has been commonly used as a traditional herbal medicine for thousands of years. This paper was designed to investigate the effects of STB on improving the cognitive function and neurodegeneration in the mouse model of Alzheimers disease induced by Aβ1-42, and its possible mechanism were Glutamate transporter GLT-1, tau and GSK3β. It was found that successive intracerebroventricular (ICV) administration of STB (0.15mg/kg) for 5days significantly attenuated Aβ1-42-induced learning and memory impairment as measured by the Locomotor activity test, Y-maze test and Morris water maze test. Furthermore, STB at a dose of 0.15mg/kg restored the activities of GLT-1 and GSK3β while decreasing the levels of hyperphosphorylated tau protein in the hippocampus and cerebral cortex. The results suggested that STB might protect against cognitive deficits and neurodegeneration induced by Aβ1-42 in mice by regulating the GLT-1 restoration as well as the capacity of GSK3β.

Brain-derived Neurotrophic Factor Signaling Mediates the Antidepressant-like Effect of the Total Flavonoids of Alpiniae Oxyphyllae Fructus in Chronic Unpredictable Mild Stress Mice

The present study verified the antidepressant‐like effects of the total flavonoids of Alpinia oxyphylla Miq. (AOF) using the chronic unpredictable mild stresses paradigm and explored the mechanism that underlies antidepressant‐like effects of AOF in mice. Previous research has shown that tropomyosin‐related kinase B (TrkB) receptor‐mediated extracellular regulated protein kinases (ERK) signaling pathways participate in depression pathophysiology. Therefore, we aimed to explore whether AOF improved depression‐like behaviors by increasing activity of ERK pathways mediated by TrkB. Results showed that AOF significantly reduced the immobility time in the forced swimming test and increased the sucrose preference in sucrose preference test. In addition, decreased phosphorylated cyclic adenosine monophosphate response element‐binding protein (pCREB)/CREB, pERK/ERK, and pTrkB/TrkB levels in the hippocampus induced by chronic unpredictable mild stresses were reversed by intragastric administration of AOF. Results suggested that AOF increased pCREB/CREB, pERK/ERK, and pTrkB/TrkB levels by acting on the TrkB receptor. To verify this hypothesis, mice were pretreated with the TrkB inhibitor K252a (or 0.1% dimethyl sulfoxide, intraperitoneally, 2 weeks), before the intragastric administration of AOF. This resulted in an absence of antidepressant‐like effects, as well as no activation of pERK/pCREB/BDNF signaling pathways. Results demonstrated that AOF might exert antidepressant‐like effects by targeting TrkB receptor‐mediated pERK/pCREB/BDNF signal systems, which could help to identify the AOF receptor. Copyright

Protective effects of Alpinae Oxyphyllae Fructus extracts on lipopolysaccharide-induced animal model of Alzheimer's disease

ETHNOPHARMACOLOGICAL RELEVANCE Alpinae Oxyphyllae Fructus (AOF) with warming and tonifying the kidney and spleen, anti-salivation, anti-polyuria and anti-diarrhea functions is the dried ripe fruits of Alpinia oxyphylla Miq. (Zingiberaceae). As a traditional Chinese medicine, its application history is very long. AIMS OF THE STUDY The purpose of our study is to investigate the effects of different solvent extracts from AOF on lipopolysaccharide (LPS)-induced animal model of Alzheimers disease (AD) to elucidate the traditional medical theories with modern pharmacological methods and provide a reference for further clarifying its active components and mechanisms. MATERIALS AND METHODS The method of stepwise screening was adopted in this paper. The animals were divided into 9 groups, including control (CT) group, model (MD) group, donepezil (DPZ) group, total extract (TT) group, petroleum ether extract (PE) group, chloroform extract (CF) group, ethyl acetate extract (EA) group, n-butanol extract (NB) group and water extract (WT) group. The anti-amnesic effects of different solvent extracts from AOF were measured in LPS-induced memory deficits mice by Y maze test and Morris water maze (MWM) test. Hematoxylin eosin (HE) staining was applied to observe pathological changes in hippocampus and cerebral cortex tissue of different groups. Biochemical indicators including ionized calcium-binding adaptor molecule 1 (IBA-1), interleukin beta 1 (IL-1β), Aβ1-42 and hyperphosphorylated tau proteins (p-tau) in hippocampus and cortex after treatment with LPS were measured according to the manufacturers instructions of ELISA kits. HPLC was used to evaluate the major components of different extracts. RESULTS It was found that successive intragastric administration of AOF (360 mg/kg) extracts for 14 days showed different degrees of improvement on LPS-induced AD model as measured by Y-maze test, Morris water maze test, and Histopathological examination. Moreover, the results of ELISA suggested petroleum ether (PE) extracts were worth recommending for inhibiting the high level of IBA-1, IL-1β, Aβ1-42 and p-tau in hippocampus and cortex after treatment with LPS. CONCLUSIONS The present study demonstrated for the first time that AOF attenuated LPS-induced learning and memory impairment, which may be associated with its inhibitory effect on neuroinflammation, amyloids-β (Aβ) deposition and p-tau. This research provided a theoretical basis for elucidating the traditional theory of AOF, and was also the stepping stone to the next step.

Ameliorating effect of Alpinia oxyphylla—Schisandra chinensis herb pair on cognitive impairment in a mouse model of Alzheimer’s disease

Alzheimers disease (AD) is the most common cause of dementia. In our previous study, we found both Alpinia oxyphylla and Schisandra chinensis can improve the cognitive function of AD. To investigate whether the Alpinia oxyphylla - Schisandra chinensis herb pair (ASHP) has ameliorating effect on cognitive impairment, we used scopolamine to induce learning and memory impairments, as a mouse model of AD. Subsequently, we carried out Y-maze test and Morris water maze test to observe the behavior of mice. Finally, the level of Acetylcholine (Ach) and muscarinic receptor (M1) receptors, the activity of choline acetyltransferase (ChAT) and acetyl cholinesterase (AChE) were measured by commercial assay kits and ELISA kit. And we used hematoxylin-eosin (HE) staining to check the changes in cortex and the CA1 region of hippocampus. ASHP significantly protected against learning and memory impairments induced by scopolamine in Y-maze test and Morris water maze test. Besides, ASHP was able to increase the level of ACh and M1 receptors, and decrease the activity of AChE, but did not significantly affect the activity of ChAT. In addition, from the results of histopathological examination, we speculated ASHP may have neuroprotective effects. This study provided an experimental basis for further study of Alpinia oxyphylla - Schisandra chinensis herb pair in AD therapy.

Protective Effects of Puerarin against Aβ 1-42-Induced Learning and Memory Impairments in Mice.

Puerarin is a major isoflavone glycoside from the root of Pueraria lobata. It has been reported that puerarin can protect neurons from oxidative stress-induced apoptosis. Emerging evidence suggests that oxidative damage is associated with Aβ-induced neuronal death. In the current study, we evaluated the effect of puerarin on Alzheimers disease induced by Aβ and explored the potential mechanisms underlying this effect. We found that the escape latency of the Morris water maze was decreased in groups treated with puerarin compared to the model group (p < 0.01). In addition, there were significant differences between treated groups and the model group mice in a Y-maze test (p < 0.01). Furthermore, puerarin recovered the levels of brain-derived neurotrophic factor, phosphorylated tau, malondialdehyde, acetylcholine esterase, glycogen synthase kinase-3beta, and the activity of superoxide dismutase to some extent in the hippocampus and cerebral cortex. Shrinkage of nuclei and swollen and eccentrically dispersed neuronal bodies were observed in the hippocampus of Aβ-treated mice. These data demonstrate that puerarin might protect against cognitive deficits, oxidative stress, and neurodegeneration induced by Aβ1-42.

Antidepressant-like effects and cognitive enhancement of Schisandra chinensis in chronic unpredictable mild stress mice and its related mechanism

The aim of this study was to evaluate whether Schisandra chinensis extract (SCE) administration influences chronic unpredictable mild stress (CUMS)-induced depression and cognitive impairment, and explores underlying mechanisms. Sucrose preference test (SPT) and forced swimming test (FST) were used for assessing depressive symptoms, and Y-maze, Morris water maze were used for evaluating cognition processes. The results showed that CUMS (4 weeks) was effective in producing both depression and memory deficits in mice. Additionally, CUMS exposure significantly decreased brain derived neurotrophic factor (BDNF) levels in hippocampus as indicated by ELISA, immunohistochemistry and immunofluorescence assays, accompanied by down-regulated tyrosine kinase receptor B (TrkB)/cAMP-response element binding protein (CREB)/extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3 kinase (PI3K)/ protein kinase B (AKT)/ glycogen synthase kinase-3β (GSK-3β) signaling pathways. Chronic administration of SCE (600 or 1200 mg/kg, i.g.) significantly prevented all these CUMS-induced behavioral and biochemical alterations. It suggested that SCE could improve the depression-like emotional status and associated cognitive deficits in CUMS mice, which might be mediated by regulation of BDNF levels in hippocampus, as well as up-regulating of TrkB/CREB/ERK and PI3K/AKT/GSK-3β pathways.

Schisandrin rescues depressive-like behaviors induced by chronic unpredictable mild stress via GDNF/ERK1/2/ROS and PI3K/AKT/NOX signaling pathways in mice

The current study aimed to prove the antidepressant-like effects and the probable mechanisms of Schisandrin on depression, which induced by chronic unpredictable mild stress (CUMS) in mice. Four weeks of CUMS exposure resulted in depressive-like behavior, as indicated by the significant decrease in sucrose consumption and increase the immobility time in the forced swim test, but without any influence on the locomotor activity. Further, there were significant downregulations of GDNF/ERK1/2/ROS and PI3K/AKT/NOX signaling pathways in the hippocampus and prefrontal cortex in depressed mice. Treatment of mice with Schisandrin (30mg/kg) and Fluoxetine (10mg/kg) significantly ameliorated all the behavioral and biochemical changes induced by CUMS. These results suggest that Schisandrin produces an antidepressant-like effect in CUMS-induced mice, which possibly mediated, at least in part, by rectifying the signaling pathways of GDNF/ERK1/2/ROS and PI3K/AKT/NOX.

Nootkatone, a neuroprotective agent from Alpiniae Oxyphyllae Fructus, improves cognitive impairment in lipopolysaccharide-induced mouse model of Alzheimer's disease

Abstract Neuroinflammatory responses play a crucial role in the pathogenesis of Alzheimers disease (AD). Our previous study demonstrated that petroleum ether extracts from Alpiniae Oxyphyllae Fructus(AOF) could attenuate lipopolysaccharide (LPS)‐induced learning and memory impairment in mice, which could be associated with its inhibitory effect on neuroinflammation. Therefore, our present study is to investigate the potential therapeutic neuroprotective effects of nootkatone (NKT) on an AD mouse model induced by intracerebroventricular injection of LPS. We found that NKT (10 mg/kg) group showed good performance in behavior experiments including Y‐maze test and Morris water maze test. The results of histopathological examination and immunohistochemical analysis showed that LPS induced degeneration of neurons and activation of microglia particularly in hippocampus and NKT (10 mg/kg) reversed these changes. Enzyme linked immunosorbent assay and western blot analysis also demonstrated that the model group had increased expression of IL‐1&bgr;, IL‐6, TNF‐&agr;, NLRP3 and NF‐&kgr;B p65, especially in hippocampus relative to sham‐operated group, and NKT (10 mg/kg) decreased the high expression of these inflammatory cytokines. Collectively, these data indicated that LPS‐induced learning and memory impairments in mice could be improved by NKT, which was associated with attenuating neuroinflammatory responses. Our study indicated that NKT could act as a potential therapeutic agent for the treatment of neuroinflammation and AD. HighlightsEffects of nootkatone (NKT) were studied in mouse model of Alzheimers disease (AD).LPS by intraventricular injection (40 &mgr;g/mouse) could induce mouse model of AD.NKT could significantly improve the ability of learning and memory.The mechanism of action of NKT may be its inhibitory effect on neuroinflammation.

Neuroprotective Effects of Spinosin on Recovery of Learning and Memory in a Mouse Model of Alzheimer's Disease

Previous studies have shown that spinosin was implicated in the modulation of sedation and hypnosis, while its effects on learning and memory deficits were rarely reported. The aim of this study is to investigate the effects of spinosin on the improvement of cognitive impairment in model mice with Alzheimer’s disease (AD) induced by Aβ1–42 and determine the underlying mechanism. Spontaneous locomotion assessment and Morris water maze test were performed to investigate the impact of spinosin on behavioral activities, and the pathological changes were assayed by biochemical analyses and histological assay. After 7 days of intracerebroventricular (ICV) administration of spinosin (100 µg/kg/day), the cognitive impairment of mice induced by Aβ1–42 was significantly attenuated. Moreover, spinosin treatment effectively decreased the level of malondialdehyde (MDA) and Aβ1–42 accumulation in hippocampus. Aβ1–42 induced alterations in the expression of brain derived neurotrophic factor (BDNF) and B-cell lymphoma-2 (Bcl-2), as well as inflammatory response in brain were also reversed by spinosin treatment. These results indicated that the ameliorating effect of spinosin on cognitive impairment might be mediated through the regulation of oxidative stress, inflammatory process, apoptotic program and neurotrophic factor expression, suggesting that spinosin might be beneficial to treat learning and memory deficits in patients with AD via multi-targets.