[Screening of small molecule inhibitors of IL-15Rα using molecular docking and surface plasmon resonance technology].

The study aims to explore the active molecules of traditional Chinese medicine that specifically bind to interleukin-15 receptor α (IL-15Rα) using molecular docking and surface plasmon resonance (SPR) technology. AutoDock molecular docking software was used to perform simulated docking of more than 3 000 compounds from 48 traditional Chinese medicines at IL-15Rα and screen the specific binding compounds. Then Biocore T200 biomolecular interaction analysis system of SPR was used to confirm the binding specificity of the selected target compounds. Finally, the biological effects of the target compounds on IL-15Rα were verified by cell biological experiments. The results showed that neoprzewaquinone A (Neo) possessed the highest specific binding affinity among the active molecules from traditional Chinese medicine, and the dissociation constant (KD) value was (0.62 ± 0.20) µmol/L. The results of cell experiment showed that Neo significantly inhibited the proliferation of Mo7e cells induced by IL-15, and the IC50 was 1.075 µmol/L, approximately 1/120 of the IC50 of Cefazolin (IL-15 specific antagonist). These results suggest that Neo is a specific inhibitor of IL-15Rα and may be a potential active drug for the treatment of diseases related to the dysfunction of the IL-15Rα signaling.

Protective Effects of Shi-Zhen-An-Shen Decoction on the Cognitive Impairment in MK801-Induced Schizophrenia Model.

BACKGROUND: Cognitive dysfunction is a core feature of schizophrenia that strongly correlates to the patients' difficulties in independent living and occupational functioning. Synaptic dysfunction may result in cognitive and behavioral changes similar to what have been identified in schizophrenia. Shi-Zhen-An-Shen Decoction (SZASD) is the empirical formula of traditional Chinese medicine adopted in treating psychiatric symptoms, especially the cognitive impairment in schizophrenia patients, with proven efficacy in the long term of clinical practice in Beijing Anding Hospital, Capital Medical University. However, the mechanisms of SZASD on the cognitive improvement in schizophrenia is still unclear. Here, we aim to investigate the underlying mechanisms of the impact of SZASD on the cognitive impairment in MK801-induced schizophrenia-like rats. METHODS: Six rat groups (n = 12 per group) were subjected to different treatments for 14 days. All the six groups were injected intraperitoneally with a given volume of 0.9% saline and MK801 (0.2 mg/kg) for consecutive 14 days for modelling. And the rats in the SZASD-treated groups and the clozapine-treated group were given SZASD (low, middle, and high doses) or clozapine, respectively, by intragastric administration. Then, we performed behavioral tests after the treatments, and the rats were sacrificed on the 19th day for biological analysis. RESULTS: Behavioral tests indicated that SZASD mitigated the aberrant motor activity and improved schizophrenia-like rats' spatial reference memory and sensory gating ability. Furthermore, SZASD significantly increased the expressions of PSD95, BDNF, and synapsin I in the hippocampus of MK801-induced schizophrenia-like rats. CONCLUSIONS: Our findings suggest that SZASD may ameliorate cognitive impairment by restoring the levels of synaptic proteins in the hippocampus.

Shi-Zhen-An-Shen Decoction, a Herbal Medicine That Reverses Cuprizone-Induced Demyelination and Behavioral Deficits in Mice Independent of the Neuregulin-1 Pathway.

Shi-Zhen-An-Shen decoction (SZASD), a Chinese herbal medicine that is a liquor extracted from plants by boiling, has been reported to be effective in treating schizophrenia. However, the mechanism is unclear. Abnormal demyelination has been implicated in schizophrenia. The aim of this study was to investigate the effect of SZASD on myelin in demyelinated mice exhibiting schizophrenia-like behaviors. Sixty male C57BL/6 mice were randomly divided into six groups (n = 10 per group): (1) control group, (2) cuprizone (CPZ, a copper chelator that induced demyelination, 0.2% w/w)+saline, (3) CPZ+low-dose SZASD (8.65 g·kg-1·d-1), (4) CPZ+medium-dose SZASD (17.29 g·kg-1·d-1), (5) CPZ+high-dose SZASD (25.94 g·kg-1·d-1), and (6) CPZ+quetiapine (QTP, an atypical antipsychotic that served as a positive treatment control, 10 mg·kg-1·d-1). Mice in groups 2-6 were treated with CPZ added to rodent chow for six weeks to induce demyelination. During the last two weeks, these mice were given an oral gavage of sterile saline, SZASD, or quetiapine. Behavioral tests and brain analyses were conducted after the last treatment. The brain expression of myelin basic protein (MBP) and neuregulin-1 (NRG-1) was assessed using immunohistochemistry and Western blots. CPZ induced significant schizophrenia-like behaviors in the mice, including reduced nest-building activity and sensory gating deficits. Hyperlocomotor activity was accompanied by significant reductions in MBP expression in the corpus callosum, hippocampus, and cerebral cortex. However, both QTP and SZASD significantly reversed the schizophrenia-like behaviors and demyelination in CPZ-fed mice. The QTP and medium-dose SZASD resulted in better therapeutic effects compared to the low and high SZASD doses. Reduced NRG-1 expression was observed in CPZ-fed mice compared with controls, but neither QTP nor SZASD showed significant influence on NRG-1 expression in the hippocampus. Together, SZASD showed a therapeutic effect on demyelinated mice, and the improvement of demyelination might not be through the NRG-1 pathway.

The Role of Group II Metabotropic Glutamate Receptors in the Striatum in Electroacupuncture Treatment of Parkinsonian Rats.

AIMS: Glutamatergic transmission may play a critical role in the pathogenesis of Parkinson's disease (PD). Electroacupuncture (EA) has been demonstrated to effectively alleviate PD symptoms. In this study, a potential glutamate-dependent mechanism underlying the therapeutic action of EA was investigated. METHODS: The effects of EA stimulation on motor behaviors, dopamine contents, glutamate release, and group II metabotropic glutamate receptor (mGluR2/3) expression in unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats were examined. RESULTS: Unilateral 6-OHDA lesions of the nigrostriatal system caused a marked increase in glutamate content in the ipsilateral cortex and striatum. mGluR2/3 protein expression and mGluR3 mRNA expression were reduced in the striatum. Noticeably, prolonged EA stimulation at 100 Hz significantly reversed these changes in the striatal glutamate system. Behaviorally, EA improved the motor deficits induced by 6-OHDA lesions. Intrastriatal infusion of an mGluR2/3 antagonist APICA blocked the improving effect of EA. CONCLUSIONS: These data collectively demonstrate that the group II mGluR-mediated glutamatergic transmission in the striatum is sensitive to dopamine depletion and may serve as a substrate of EA for mediating the therapeutic effect of EA in a rat model of PD.

Serum brain-derived neurotrophic factor levels associate with cognitive improvement in patients with schizophrenia treated with electroacupuncture.

Accumulating evidence supports that acupuncture has been successfully used for the treatment of neurological disorders to improve cognitive function. This study was set to evaluate the efficacy of electroacupuncture (EA, using two acupoints: Baihui and Shenting) on clinical symptoms, cognitive function and brain-derived neurotrophic factor (BDNF) levels in patients with schizophrenia. Sixty-one inpatients diagnosed schizophrenia with DSM-IV criteria were recruited. The participants were randomly divided into an experimental group (n=30) and a control group (n=31). The patients were evaluated using the Positive and Negative Symptom Scale (PANSS), the Wisconsin Card Sorting Test (WCST) and Wechsler Memory Scale (WMS) at baseline and after EA treatment. There were no significant differences in the PANSS scores and serum BDNF levels between the experimental group and the control group, either at baseline or at the end of the 4-week study period. However, the EA treatment appeared to have significant benefits on memory and moderate benefits on executive functions and problem solving. Significant positive correlation was observed between the increase of BDNF levels and memory improvement after EA treatment. Our results indicated that EA treatment could improve cognitive function, and the cognitive benefits positively associate with serum BDNF levels in patients with schizophrenia.

Inhibition of glutamate and acetylcholine release in behavioral improvement induced by electroacupuncture in parkinsonian rats.

Prior evidence shows that acupuncture improves symptoms in both Parkinson's disease (PD) patients and animal models. We examined the effects of high-frequency (100 Hz) electroacupuncture (EA) on behavior in a rat PD model induced by medial forebrain bundle (MFB) transection. Neurotransmitters levels in the striatum were measured using in vivo microdialysis and high performance liquid chromatography (HPLC). High-frequency EA stimulation at Dazhui (GV14) and Baihui (GV20) acupoints decreased rotational behavior induced by apomorphine (APO) and improved motor coordination, protected axotomized dopaminergic neurons from degeneration in the substantia nigra (SN), it did not increase striatal dopamine (DA) levels. However, EA stimulation at acupoints significantly decreased the abnormally elevated glutamate (Glu) and acetylcholine (ACh) levels in the lesioned side of striatum. Moreover, the Glu levels correlated significantly with survival ratios of dopaminergic neurons in the SNc and rotational bahavior. These data suggested that behavioral alleviation with EA stimulation may be associated with modulation of neurotransmitters release, such as Glu and ACh in the striatum, rather than with DA restoration.

[High-frequency electro-acupuncture stimulation modulates intracerebral γ-aminobutyric acid content in rat model of Parkinson's disease].

The purpose of the present study is to observe the effect of electro-acupuncture (EA) stimulation on intracerebral neurotransmitters in a rat model of Parkinson's disease (PD), and explore the possible mechanism. We used 6-hydroxydopamine (6-OHDA) injection in medial forebrain bundle (MFB) in the right brain of Sprague Dawley (SD) rat to establish the parkinsonian rat model, and randomly divided the PD rats into model and 100 Hz EA stimulation groups (n =10 in each group). EA stimulation group received 4 courses of EA stimulation on Baihui (GV-20) and Dazhui (GV-14) acupuncture points. Moreover, ten rats were randomly selected as sham operation group, only receiving normal saline (NS) injection in MFB. Then apomorphine (APO)-induced rotational behavior in different groups was recorded, and the contents of γ-aminobutyric acid (GABA) in the brain were analyzed with high pressure/performance liquid chromatography-electrochemical detection (HPLC-ECD). The results showed that model group exhibited abnormal rotational behavior with APO treatment, suggesting the successful establishment of PD model. Compared with sham operation group, model group showed increased GABA contents in cortex and striatum, as well as decreased GABA content in ventral midbrain, on the lesioned side. EA stimulation could effectively ameliorate the abnormal rotational behavior of PD rat. Compared with the model group, EA stimulation decreased the ratio of GABA content on the lesioned side to that on unlesioned side in the cortex, while increased the ratios in the striatum and cerebellum. However, there was no difference of the ratio in the ventral midbrain among three groups. These results suggest high-frequency EA stimulation significantly improves the abnormal behavior of PD rats, which may exert through enhancing the inhibitory effect of cerebellum-basal ganglia-cortical loop on motor center.

Electro-acupuncture stimulation acts on the basal ganglia output pathway to ameliorate motor impairment in Parkinsonian model rats.

The role of electro-acupuncture (EA) stimulation on motor symptoms in Parkinson's disease (PD) has not been well studied. In a rat hemiparkinsonian model induced by unilateral transection of the medial forebrain bundle (MFB), EA stimulation improved motor impairment in a frequency-dependent manner. Whereas EA stimulation at a low frequency (2 Hz) had no effect, EA stimulation at a high frequency (100 Hz) significantly improved motor coordination. However, neither low nor high EA stimulation could significantly enhance dopamine levels in the striatum. EA stimulation at 100 Hz normalized the MFB lesion-induced increase in midbrain GABA content, but it had no effect on GABA content in the globus pallidus. These results suggest that high-frequency EA stimulation improves motor impairment in MFB-lesioned rats by increasing GABAergic inhibition in the output structure of the basal ganglia.

Electro-acupuncture stimulation improves motor disorders in Parkinsonian rats.

Electro-acupuncture (EA) is believed to be effective for alleviating motor symptoms in patients with Parkinson's disease. In a rat hemiparkinsonian model induced by unilateral transection of the medial forebrain bundle (MFB), the effects of EA stimulation were investigated. EA stimulation at a high frequency (100 Hz) significantly reduced apomorphine-induced rotational behavior. Tyrosine hydroxylase immunohistochemical staining revealed that EA at 100 Hz protected axotomized dopaminergic neurons from degeneration in the substantia nigra (SN). Moreover, high frequency EA reversed the axotomy-induced decrease in substance P content and increase in glutamate decarboxylase-67 (GAD 67) mRNA level in the midbrain; however, it did not affect the axotomy-induced increase in enkephalin content in the globus pallidus. These results suggest that the effects of high frequency EA on motor symptoms of Parkinsonian rats may involve restoration of the homeostasis of dopaminergic transmission in the basal ganglia circuit.