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1.
J Ethnopharmacol ; 249: 112407, 2020 Mar 01.
Article in English | MEDLINE | ID: mdl-31751652

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Persicaria orientalis (L.) Spach (internationally accepted and only valid name; synonym: Polygonum orientale L.; family: Polygonaceae), which is named Hongcao in China, is a Chinese herbal medicine that has a wide range of pharmacological effects including treatment to rheumatoid arthritis, coronary heart disease, hernia, carbuncle sore, enhance immunity, antimicrobial, osteogenic and dilated bronchiectasis. AIM OF THIS REVIEW: This review aims to provide systematically organized information on traditional uses of Persicaria orientalis (L.) Spach (P. orientalis) and to critically analyze evidences in phytotherapeutic, botanical, and pharmacological literatures that support its therapeutic potential in treatment to human diseases. Isolation of additional compounds and detailed pharmacological investigations are key areas to investigate. MATERIALS AND METHODS: Relevant information on P. orientalis was collected through published scientific materials (including PubMed, ScienceDirect, Wiley, ACS, CNKI, Scifinder, Springer, Taylor & Francis, Web of Science, Google Scholar, and Baidu Scholar) and other literature sources (e.g., Chinese Pharmacopoeia, 2015 edition, Chinese herbal classic books and PhD and MSc thesis, etc.). RESULTS: Traditional uses were compiled in this review, including classic prescriptions and historical applications. Approximately 70 compounds, mainly including flavonoids, phenolics, lignans, limonoids and steroids, have been isolated and identified from P. orientalis. Among them, flavonoids were main components. Crude extracts and pure compounds isolated from P. orientalis exhibited various pharmacological activities, such as protection against ischemia and hypoxia-induced myocardial cells and hypoxia/reoxygenation cardiomyocyte, increase the blood flow in myocardium, expanding bronchus, anti-inflammatory and analgesic, and antithrombotic effects and so on. CONCLUSIONS: P. orientalis is a valuable source with therapeutic potential on a wide range of diseases especially cardiovascular-system disorders. Though most traditional uses of P. orientalis are supported by in vitro/vivo pharmacological studies, however, there is still a lack of researches on active pharmacodynamic ingredients as well as in-depth and in-vivo mechanistic studies. Therefore, isolation and identification of more active compounds (especially flavonoids), their structure-activity relationship and studies on pharmacodynamic mechanisms by more elaborative in-vivo studies on P. orientalis may be focused on in order to confirm efficacy of reported therapeutic effects of P. orientalis and help explore it's therapeutic potentials. Furthermore, research designs of pharmacological studies based on traditional uses of anti-rheumatoid arthritis through cell lines and animal models should also be considered as key research topics.


Subject(s)
Arthritis, Rheumatoid/drug therapy , Cardiovascular Diseases/drug therapy , Drugs, Chinese Herbal/pharmacology , Medicine, Chinese Traditional/methods , Polygonaceae/chemistry , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/therapeutic use , Ethnopharmacology , Flavonoids/pharmacology , Flavonoids/therapeutic use , Humans
2.
Eur J Med Chem ; 143: 1148-1164, 2018 Jan 01.
Article in English | MEDLINE | ID: mdl-29133048

ABSTRACT

The RET tyrosine kinase is an important therapeutic target for medullary thyroid cancer (MTC), and drug resistance mutations of RET, particularly V804M and V804L, are a main challenge for the current targeted therapy of MTC based on RET inhibitors. In this investigation, we report the structural optimization and structure-activity relationship studies of N-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine derivatives as a new class of RET inhibitors. Among all the obtained kinase inhibitors, 1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-((6,7,8,9-tetrahydropyrimido[5,4-b][1,4]oxazepin-4-yl)amino)phenyl)urea (17d) is a multi-kinase inhibitor and potently inhibits RET and its drug resistance mutants. It showed IC50 (half maximal inhibitory concentration) values of 0.010 µM, 0.015 µM, and 0.009 µM against RET-wild-type, RET-V804M, and RET-V804L, respectively. 17d displayed significant anti-viability potencies against various RET-driving tumor cell lines. In a xenograft mouse model of NIH3T3-RET-C634Y, 17d exhibited potent in vivo anti-tumor activity, and no obvious toxicity was observed. Mechanisms of action were also investigated by Western blot and immunohistochemical assays. Collectively, 17d could be a promising agent for the treatment of MTC, hence deserving a further investigation.


Subject(s)
Amines/pharmacology , Antineoplastic Agents/pharmacology , Drug Resistance, Neoplasm/drug effects , Proto-Oncogene Proteins c-ret/antagonists & inhibitors , Amines/chemical synthesis , Amines/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm/genetics , Drug Screening Assays, Antitumor , Mice , Mice, Inbred NOD , Mice, SCID , Molecular Structure , Mutation , NIH 3T3 Cells , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Proto-Oncogene Proteins c-ret/genetics , Proto-Oncogene Proteins c-ret/metabolism , Structure-Activity Relationship
3.
Immunol Res ; 60(1): 112-26, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24895100

ABSTRACT

Psoriasis is a common chronic T-cell-mediated autoimmune skin disease, and traditional immunotherapies for psoriasis have focused on the direct inhibition of T cells, which often causes toxicity and lacks long-term effectiveness. Safe and effective therapeutic strategies are strongly needed for psoriasis. In this study, we show for the first time a significant accumulation of FLT3(+) CD11c(+) dendritic cells (DCs) in human psoriatic lesions and in the skin of experimental preclinical K14-VEGF transgenic homozygous mice, our animal model, although not an exact match for human psoriasis, displays many characteristics of inflammatory skin inflammation. SKLB4771, a potent and selective FLT3 inhibitor that we designed and synthesised, was used to treat cutaneous inflammation and psoriasis-like symptoms of disease in mice and almost completely cured the psoriasis-like disease without obvious toxicity. Mechanistic studies indicated that SKLB4771 treatment significantly decreased the number and activation of pDCs and mDCs in vitro and in vivo, and subsequent T-cell cascade reactions mediated by Th1/Th17 pathways. These findings show that targeted inhibition of FLT3, and hence direct interference with DCs, may be a novel therapeutic approach for the treatment of psoriasis.


Subject(s)
CD11c Antigen/immunology , Dendritic Cells/immunology , Psoriasis/immunology , fms-Like Tyrosine Kinase 3/immunology , Animals , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Dermatitis/immunology , Disease Models, Animal , Humans , Keratin-14/genetics , Mice, Inbred BALB C , Mice, Transgenic , Phenylurea Compounds/pharmacology , Phenylurea Compounds/therapeutic use , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Psoriasis/drug therapy , Thiadiazoles/pharmacology , Thiadiazoles/therapeutic use , Vascular Endothelial Growth Factor A/genetics , fms-Like Tyrosine Kinase 3/antagonists & inhibitors
4.
Mol Med Rep ; 8(2): 434-8, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23732650

ABSTRACT

Psoriasis is a common chronic inflammatory skin disease and its underlying pathogenesis is still not fully understood. Therapeutic interventions are currently limited and restricted to the treatment of symptoms rather than targeting the mechanisms underlying the disease. Vascular remodeling is a hallmark of psoriasis; however, anti-vascular strategies to treat psoriasis have received little attention to date, particularly systemic treatment with a small molecule compound. The aim of this study was to investigate the anti-inflammatory effect of a newly identified vascular endothelial growth factor (VEGF) receptor 2 inhibitor, SKLB1002, and its possible mechanism of action in a transgenic mouse model of psoriasis. Fifteen 8-12-week­old K14-VEGF transgenic mice received consecutive intraperitoneal (i.p.) injections of SKLB1002, vehicle or saline for 4 weeks. After 4 weeks of treatment, the disease symptoms were assessed and histological analyses were performed on ear sections by hematoxylin and eosin (HE) and immunohistochemistry staining. Systemic treatment with SKLB1002 reduced symptoms of ear inflammation in K14/VEGF transgenic mice, the pathological score was significantly decreased, and acanthosis, focal parakeratosis, hyperkeratosis and hemangiectasis were improved. Furthermore, systemic treatment with SKLB1002 significantly reduced vascular abnormalities, permeability and T-cell infiltration. These results demonstrated that targeted inhibition of VEGFR2 by a small molecule inhibitor is an effective method, which may be a new therapeutic option for psoriasis therapy.


Subject(s)
Psoriasis/metabolism , Quinazolines/pharmacology , Thiadiazoles/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Animals , Capillary Permeability/drug effects , Disease Models, Animal , Inflammation/drug therapy , Inflammation/genetics , Inflammation/pathology , Mice , Mice, Transgenic , Neovascularization, Pathologic/drug therapy , Psoriasis/drug therapy , Psoriasis/genetics , Quinazolines/administration & dosage , Skin/drug effects , Skin/metabolism , Skin/pathology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Thiadiazoles/administration & dosage , Vascular Endothelial Growth Factor Receptor-2/genetics , Vascular Endothelial Growth Factor Receptor-2/metabolism
5.
Oncol Rep ; 29(4): 1510-6, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23404510

ABSTRACT

As tumor-associated antigens are not well characterized for the majority of human tumors, polyvalent vaccines prepared with whole-tumor antigens are an attractive approach for tumor vaccination. Vascular endothelial growth factor receptor-2 (VEGFR2), as a model antigen with which to explore the feasibility of immunotherapy, has shown great promise as a tumor vaccine. However, the efficacy of immunotherapy is often not ideal when used alone. In this study, we explored the therapeutic efficacy of an irradiated AdVEGFR2-infected cell vaccine-based immunotherapy in the weakly immunogenic and highly metastatic 4T1 murine mammary cancer model. An adenovirus encoding the VEGFR2 gene (AdVEGFR2) was constructed. Lethally irradiated, virus-infected 4T1 cells were used as vaccines. Vaccination with lethally irradiated AdVEGFR2-infected 4T1 cells inhibited subsequent tumor growth and pulmonary metastasis compared with challenge inoculations. Angiogenesis was inhibited, and the number of CD8+ T lymphocytes was increased within the tumors. Antitumor activity was also caused by the adoptive transfer of isolated spleen lymphocytes. In vitro, the expression of HMGB1 and HSP70 in the AdVEGFR2­infected 4T1 cells was increased, and was involved in the activation of tumor antigen-specific T-cell immunity. Our results indicate that the immunotherapy based on irradiated AdVEGFR2-infected whole-cancer cell vaccines may be a potentially effective strategy for 4T1 cancer treatment.


Subject(s)
Breast Neoplasms/therapy , Cancer Vaccines/administration & dosage , Fibroadenoma/therapy , Immunotherapy, Active , Vascular Endothelial Growth Factor Receptor-2/genetics , Adenoviridae/genetics , Adenoviridae/radiation effects , Animals , Antigens, Neoplasm/genetics , Antigens, Neoplasm/therapeutic use , Breast Neoplasms/immunology , Breast Neoplasms/pathology , CD8-Positive T-Lymphocytes/immunology , Female , Fibroadenoma/immunology , Fibroadenoma/pathology , Genetic Vectors , Humans , Mice , Mice, Inbred BALB C , Neoplasm Metastasis , Neovascularization, Pathologic/immunology , Vascular Endothelial Growth Factor Receptor-2/administration & dosage
6.
Eur J Med Chem ; 56: 30-8, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22944772

ABSTRACT

Aberrant activation of casein kinase 1 (CK1) has been demonstrated to be implicated in the pathogenesis of cancer and various central nervous system disorders. Discovery of CK1 inhibitors has thus attracted much attention in recent years. In this account, we describe the discovery of N6-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine derivatives as novel CK1 inhibitors. An optimal common-feature pharmacophore hypothesis, termed Hypo2, was firstly generated, followed by virtual screening using Hypo2 against several chemical databases. One of the best hit compounds, N6-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine, was chosen for the subsequent hit-to-lead optimization under the guide of Hypo2, which led to the discovery of a new lead compound (1-(3-(3-amino-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)phenyl)-3-(3-chloro-4-fluorophenyl)urea) that potently inhibits CK1 with an IC(50) value of 78 nM.


Subject(s)
Casein Kinase I/antagonists & inhibitors , Diamines/pharmacology , Drug Discovery , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Casein Kinase I/metabolism , Diamines/chemical synthesis , Diamines/chemistry , Dose-Response Relationship, Drug , High-Throughput Screening Assays , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity Relationship
7.
BMC Cancer ; 12: 129, 2012 Mar 30.
Article in English | MEDLINE | ID: mdl-22462776

ABSTRACT

BACKGROUND: Angiogenesis plays an important role in tumor growth and metastasis, therefore antiangiogenic therapy was widely investigated as a promising approach for cancer therapy. Recently, pigment epithelium-derived factor (PEDF) has been shown to be the most potent inhibitor of angiogenesis. Adeno-associated virus (AAV) vectors have been intensively studied due to their wide tropisms, nonpathogenicity, and long-term transgene expression in vivo. The objective of this work was to evaluate the ability of AAV-mediated human PEDF (hPEDF) as a potent tumor suppressor and a potential candidate for cancer gene therapy. METHODS: Recombinant AAV2 encoding hPEDF (rAAV2-hPEDF) was constructed and produced, and then was assigned for in vitro and in vivo experiments. Conditioned medium from cells infected with rAAV2-hPEDF was used for cell proliferation and tube formation tests of human umbilical vein endothelial cells (HUVECs). Subsequently, colorectal peritoneal carcinomatosis (CRPC) mouse model was established and treated with rAAV2-hPEDF. Therapeutic efficacy of rAAV2-hPEDF were investigated, including tumor growth and metastasis, survival time, microvessel density (MVD) and apoptosis index of tumor tissues, and hPEDF levels in serum and ascites. RESULTS: rAAV2-hPEDF was successfully constructed, and transmission electron microscope (TEM) showed that rAAV2-hPEDF particles were non-enveloped icosahedral shape with a diameter of approximately 20 nm. rAAV2-hPEDF-infected cells expressed hPEDF protein, and the conditioned medium from infected cells inhibited proliferation and tube-formation of HUVECs in vitro. Furthermore, in CRPC mouse model, rAAV2-hPEDF significantly suppressed tumor growth and metastasis, and prolonged survival time of treated mice. Immunofluorescence studies indicated that rAAV2-hPEDF could inhibit angiogenesis and induce apoptosis in tumor tissues. Besides, hPEDF levels in serum and ascites of rAAV2-hPEDF-treated mice were significant higher than those in rAAV2-null or normal saline (NS) groups. CONCLUSIONS: Thus, our results suggest that rAAV2-hPEDF may be a potential candidate as an antiangiogenic therapy agent.


Subject(s)
Antineoplastic Agents/administration & dosage , Carcinoma/therapy , Eye Proteins/administration & dosage , Genetic Therapy/methods , Nerve Growth Factors/administration & dosage , Peritoneal Neoplasms/therapy , Serpins/administration & dosage , Adenoviridae/genetics , Animals , Blotting, Western , Carcinoma/pathology , Carcinoma/secondary , Cell Line, Tumor , Cell Proliferation/drug effects , Disease Models, Animal , Genetic Vectors , Mice , Mice, Inbred BALB C , Microvessels/pathology , Neoplasm Metastasis , Neovascularization, Pathologic/drug therapy , Peritoneal Neoplasms/pathology
8.
J Med Chem ; 55(8): 3852-66, 2012 Apr 26.
Article in English | MEDLINE | ID: mdl-22452518

ABSTRACT

Structure-activity relationship (SAR) studies of 2-(quinazolin-4-ylthio)thiazole derivatives, which are for optimizing the in vitro and in vivo antiacute myeloid leukemia (AML) activity of a previously identified FLT3 inhibitor 2-(6,7-dimethoxyquinazolin-4-ylthio)thiazole (1), are described. SAR studies centering around the head (thiazole) and tails (6- and 7-positions) of the quinazoline moiety of 1 led to the discovery of a series of compounds that exhibited significantly increased potency against FLT3-driven AML MV4-11 cells. Preliminary in vivo assays were carried out on three highly active compounds, whose results showed that 1-{5-[7-(3-morpholinopropoxy)quinazolin-4-ylthio]-[1,3,4]thiadiazol-2-yl}-3-p-tolylurea (20c) had the highest in vivo activity. Further in vitro and in vivo anti-AML studies were then performed on 20c; in an MV4-11 xenograft mouse model, a once-daily dose of 20c at 100 mg/kg for 18 days led to complete tumor regression without obvious toxicity. Western blot and immunohistochemical analysis were carried out to illustrate the mechanism of action of 20c.


Subject(s)
Antineoplastic Agents/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Phenylurea Compounds/therapeutic use , Quinazolines/therapeutic use , Thiadiazoles/therapeutic use , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Animals , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Drug Design , Humans , Mice , Phenylurea Compounds/chemical synthesis , Quinazolines/chemical synthesis , Structure-Activity Relationship , Thiadiazoles/chemical synthesis , Xenograft Model Antitumor Assays
9.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 36(4): 533-6, 2005 Jul.
Article in Chinese | MEDLINE | ID: mdl-16078581

ABSTRACT

OBJECTIVE: To study the protective effect of tetramethylpyrazine (TMP) on the respiratory inhibition induced by hypoxia. METHODS: Forty-four SD rats were used. The hypoxic rat model was established. The effects of TMP on the responses of respiratory activity and life time to hypoxia were observed. The Nissl's staining and immunohistochemical technique were used to investigate the effect of hypoxia on the Nissl's bodies and FOS expression in the brainstem and the antagonistic action of TMP. RESULTS: In contrast to the group of hypoxia, the occurrence of respiratory inhibition was delayed and the life time was prolonged obviously in the rats of hypoxia plus TMP (P<0.01). Compared with the air contronl group, the intensity of the Nissl's staining of the brainstem neurons became weaker in the group of hypoxia, but in the group of hypoxia plus TMP, the Nissl's staining was stronger and the gray degree decreased obviously, compared with the group of hypoxia (P<0.05). FOS positive neurons were induced by hypoxia and mainly existed in the nucleus of solitary tract, area postrema, hypoglossal nucleus, lateral reticular nucleus, inferior olivary nucleus, nucleus raphe pallidus, facial nucleus, trapezoid nucleus, but in the group of hypoxia plus TMP, the level of FOS immunoreactivity decreased remarkably, compared with the group of hypoxia (P<0.05). CONCLUSION: TMP has protective effect on the respiratory inhibition induced by hypoxia and FOS may be involved in the protection.


Subject(s)
Hypoxia/complications , Pyrazines/pharmacology , Respiration/drug effects , Respiratory Insufficiency/prevention & control , Animals , Brain Stem/metabolism , Brain Stem/physiopathology , Female , Male , Protective Agents/pharmacology , Protective Agents/therapeutic use , Proto-Oncogene Proteins c-fos/biosynthesis , Pyrazines/therapeutic use , Rats , Rats, Sprague-Dawley , Respiratory Insufficiency/etiology
10.
Sheng Li Xue Bao ; 57(2): 147-53, 2005 Apr 25.
Article in Chinese | MEDLINE | ID: mdl-15830098

ABSTRACT

The aim of the present study was to investigate the effect of tetramethylpyrazine (TMP) on the changes of respiration and expression of neuronal nitric oxide synthase (nNOS) in brainstem induced by hypoxia in the rats. Hypoxia was induced by inhalation of 8% O2-balanced N2.The electromyogram (EMG) of diaphragm was monitored to evaluate the respiratory response of the rats to hypoxia. The immunohistochemical staining technique was used to study the change of the expression of nNOS in the brainstem during hypoxia. In the rats of hypoxia group, a successive process of response, excitatory followed by inhibitory, was produced. Twenty min after hypoxia, a significant inhibition of respiration occurred, which was characterized with a marked decrease in the inspiratory duration, the respiratory frequency, and the amplitude of inspiration and a prolongation of expiratory duration (P<0.05). In the rats of pretreated with TMP, the respiratory activity was not obviously depressed (P>0.05). In the rats of hypoxia group, the level of nNOS immunoreactivity was enhanced remarkably in the lateral reticular nucleus, nucleus of trapezoid, hypoglossal nucleus and the facial nucleus compared with the control group (P<0.05). In the rats of pretreated with TMP, the nNOS level increased further in the nuclei mentioned above (P<0.05). The results obtained indicate that TMP can reverse the inhibitory effect of hypoxia on respiration in the rats and that nNOS may be involved in the respiratory protective action of TMP.


Subject(s)
Brain Stem/enzymology , Hypoxia/physiopathology , Nitric Oxide Synthase Type I/metabolism , Pyrazines/pharmacology , Respiration/drug effects , Animals , Brain Stem/physiopathology , Female , Male , Nitric Oxide Synthase Type I/genetics , Random Allocation , Rats , Rats, Sprague-Dawley , Respiratory Insufficiency/prevention & control
11.
Sheng Li Xue Bao ; 56(6): 665-70, 2004 Dec 25.
Article in Chinese | MEDLINE | ID: mdl-15614412

ABSTRACT

The experiments were carried out on adult Sprague-Dawley rats. We investigated the discharge response of respiratory neurons (RNs) in the pre-Bözinger complex (PBC) to electrical stimulation of the facial nucleus in which the motor neurons were retrogradely degenerated and the antagonistic effects of microiontophoresis of CNQX, bicuculline (BIC), strychnine (Stry) and atropine on the discharge responses of the neurons. In 12 rats with retrograde degeneration of the facial motor neurons, 116 RNs in the PBC ipsilateral to the facial nerve sectioned were extracellularly recorded. The response of pre-inspiratory (Pre-I) (24 / 26) and inspiratory (I) (30 / 35) neurons to the electrical stimulation of the facial nucleus was mainly excitatory, and the response of expiratory (E) (20 / 22) and inspiratory-expiratory phase-spanning (I-E) (28 / 33) neurons was mainly inhibitory. CNQX partially or completely block the excitatory effect of the stimulation on Pre-I (18 / 24) and I (23 / 27) neurons. Stry could partially or completely block the immediate transient inhibition on Pre-I (12 / 18) and I (14 / 23) neurons and the inhibitory effect on I-E (20 / 28) and E (9 / 16) neurons induced by the stimulation. BIC partially or completely blocked the inhibitory effect on I-E (22 / 25) and E (9 / 9) neurons induced by the stimulation. Atropine did not have obvious influence on the response of RNs to the stimulation. These results suggest that non-motoneurons in the facial nucleus may participate in the modulation of respiration by affecting the activities of RNs in the PBC and that Glu, GABA and Gly serve as neurotransmitters or modulators to regulate the activities of the RNs in the PBC and hence the rhythmic respiratory movement.


Subject(s)
Facial Nerve/physiology , Medulla Oblongata/physiology , Neurotransmitter Agents/metabolism , Respiration , Respiratory Center/physiology , Animals , Electric Stimulation , Female , Glutamic Acid/metabolism , Glycine/metabolism , Male , Motor Neurons/physiology , Neurons/physiology , Rats , Rats, Sprague-Dawley , gamma-Aminobutyric Acid/metabolism
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