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1.
J Neuroinflammation ; 16(1): 214, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31722723

RESUMO

BACKGROUND: Neonatal hypoxic-ischemic brain damage (HIBD), a leading cause of neonatal mortality, has intractable sequela such as epilepsy that seriously affected the life quality of HIBD survivors. We have previously shown that ion channel dysfunction in the central nervous system played an important role in the process of HIBD-induced epilepsy. Therefore, we continued to validate the underlying mechanisms of TRPV1 as a potential target for epilepsy. METHODS: Neonatal hypoxic ischemia and oxygen-glucose deprivation (OGD) were used to simulate HIBD in vivo and in vitro. Primarily cultured astrocytes were used to assess the expression of TRPV1, glial fibrillary acidic protein (GFAP), cytoskeletal rearrangement, and inflammatory cytokines by using Western blot, q-PCR, and immunofluorescence. Furthermore, brain electrical activity in freely moving mice was recorded by electroencephalography (EEG). TRPV1 current and neuronal excitability were detected by whole-cell patch clamp. RESULTS: Astrocytic TRPV1 translocated to the membrane after OGD. Mechanistically, astrocytic TRPV1 activation increased the inflow of Ca2+, which promoted G-actin polymerized to F-actin, thus promoted astrocyte migration after OGD. Moreover, astrocytic TRPV1 deficiency decreased the production and release of pro-inflammatory cytokines (TNF, IL-6, IL-1ß, and iNOS) after OGD. It could also dramatically attenuate neuronal excitability after OGD and brain electrical activity in HIBD mice. Behavioral testing for seizures after HIBD revealed that TRPV1 knockout mice demonstrated prolonged onset latency, shortened duration, and decreased seizure severity when compared with wild-type mice. CONCLUSIONS: Collectively, TRPV1 promoted astrocyte migration thus helped the infiltration of pro-inflammatory cytokines (TNF, IL-1ß, IL-6, and iNOS) from astrocytes into the vicinity of neurons to promote epilepsy. Our study provides a strong rationale for astrocytic TRPV1 to be a therapeutic target for anti-epileptogenesis after HIBD.

2.
J Neuroinflammation ; 16(1): 114, 2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31142341

RESUMO

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) is a serious birth complication with high incidence in both advanced and developing countries. Children surviving from HIE often have severe long-term sequela including cerebral palsy, epilepsy, and cognitive disabilities. The severity of HIE in infants is tightly associated with increased IL-1ß expression and astrocyte activation which was regulated by transient receptor potential vanilloid 1 (TRPV1), a non-selective cation channel in the TRP family. METHODS: Neonatal hypoxic ischemia (HI) and oxygen-glucose deprivation (OGD) were used to simulate HIE in vivo and in vitro. Primarily cultured astrocytes were used for investigating the expression of glial fibrillary acidic protein (GFAP), IL-1ß, Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), and activation of the nucleotide-binding, oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome by using Western blot, q-PCR, and immunofluorescence. Brain atrophy, infarct size, and neurobehavioral disorders were evaluated by Nissl staining, 2,3,5-triphenyltetrazolium chloride monohydrate (TTC) staining and neurobehavioral tests (geotaxis reflex, cliff aversion reaction, and grip test) individually. RESULTS: Astrocytes were overactivated after neonatal HI and OGD challenge. The number of activated astrocytes, the expression level of IL-1ß, brain atrophy, and shrinking infarct size were all downregulated in TRPV1 KO mice. TRPV1 deficiency in astrocytes attenuated the expression of GFAP and IL-1ß by reducing phosphorylation of JAK2 and STAT3. Meanwhile, IL-1ß release was significantly reduced in TRPV1 deficiency astrocytes by inhibiting activation of NLRP3 inflammasome. Additionally, neonatal HI-induced neurobehavioral disorders were significantly improved in the TRPV1 KO mice. CONCLUSIONS: TRPV1 promotes activation of astrocytes and release of astrocyte-derived IL-1ß mainly via JAK2-STAT3 signaling and activation of the NLRP3 inflammasome. Our findings provide mechanistic insights into TRPV1-mediated brain damage and neurobehavioral disorders caused by neonatal HI and potentially identify astrocytic TRPV1 as a novel therapeutic target for treating HIE in the subacute stages (24 h).


Assuntos
Astrócitos/metabolismo , Encéfalo/metabolismo , Hipóxia-Isquemia Encefálica/metabolismo , Interleucina-1beta/metabolismo , Canais de Cátion TRPV/deficiência , Animais , Astrócitos/patologia , Encéfalo/patologia , Células Cultivadas , Feminino , Hipóxia-Isquemia Encefálica/genética , Hipóxia-Isquemia Encefálica/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Canais de Cátion TRPV/genética
3.
J Neuroinflammation ; 15(1): 186, 2018 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-29925377

RESUMO

BACKGROUND: Neonatal hypoxic-ischemic brain damage, characterized by tissue loss and neurologic dysfunction, is a leading cause of mortality and a devastating disease of the central nervous system. We have previously shown that vitexin has been attributed various medicinal properties and has been demonstrated to have neuroprotective roles in neonatal brain injury models. In the present study, we continued to reinforce and validate the basic understanding of vitexin (45 mg/kg) as a potential treatment for epilepsy and explored its possible underlying mechanisms. METHODS: P7 Sprague-Dawley (SD) rats that underwent right common carotid artery ligation and rat brain microvascular endothelial cells (RBMECs) were used for the assessment of Na+-K+-Cl- co-transporter1 (NKCC1) expression, BBB permeability, cytokine expression, and neutrophil infiltration by western blot, q-PCR, flow cytometry (FCM), and immunofluorescence respectively. Furthermore, brain electrical activity in freely moving rats was recorded by electroencephalography (EEG). RESULTS: Our data showed that NKCC1 expression was attenuated in vitexin-treated rats compared to the expression in the HI group in vivo. Oxygen glucose deprivation/reoxygenation (OGD) was performed on RBMECs to explore the role of NKCC1 and F-actin in cytoskeleton formation with confocal microscopy, N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide, and FCM. Concomitantly, treatment with vitexin effectively alleviated OGD-induced NKCC1 expression, which downregulated F-actin expression in RBMECs. In addition, vitexin significantly ameliorated BBB leakage and rescued the expression of tight junction-related protein ZO-1. Furthermore, inflammatory cytokine and neutrophil infiltration were concurrently and progressively downregulated with decreasing BBB permeability in rats. Vitexin also significantly suppressed brain electrical activity in neonatal rats. CONCLUSIONS: Taken together, these results confirmed that vitexin effectively alleviates epilepsy susceptibility through inhibition of inflammation along with improved BBB integrity. Our study provides a strong rationale for the further development of vitexin as a promising therapeutic candidate treatment for epilepsy in the immature brain.


Assuntos
Anticonvulsivantes/uso terapêutico , Apigenina/uso terapêutico , Epilepsia/tratamento farmacológico , Epilepsia/etiologia , Hipóxia-Isquemia Encefálica/complicações , Membro 2 da Família 12 de Carreador de Soluto/metabolismo , Animais , Animais Recém-Nascidos , Hipóxia Celular/efeitos dos fármacos , Células Cultivadas , Cloretos/metabolismo , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/deficiência , Fator Estimulador de Colônias de Granulócitos/genética , Fator Estimulador de Colônias de Granulócitos/metabolismo , Interleucina-3/genética , Interleucina-3/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Membro 2 da Família 12 de Carreador de Soluto/genética , Proteína da Zônula de Oclusão-1/metabolismo
4.
CNS Neurosci Ther ; 24(10): 967-977, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29577640

RESUMO

AIM: Multiple sclerosis (MS) is a neurological autoimmune disorder characterized by mistaken attacks of inflammatory cells against the central nervous system (CNS), resulting in demyelination and axonal damage. Kv1.3 channel blockers can inhibit T-cell activation and have been designed for MS therapy. However, little is known about the effects of Kv1.3 blockers on protecting myelin sheaths/axons in MS. This study aimed at investigating the neuroprotection efficacy of a selective Kv1.3 channel blocker ImKTx88 (ImK) in MS animal model. METHODS: Experimental autoimmune encephalomyelitis (EAE) rat model was established. The neuroprotective effect of ImK was assessed by immunohistochemistry and transmission electron microscopy (TEM). In addition, the antiinflammatory effect of ImK by suppressing T-cell activation was assessed by flow cytometry and ELISA in vitro. RESULTS: Our results demonstrated that ImK administration ameliorated EAE clinical severity. Moreover, ImK increased oligodendrocytes survival, preserved axons, and myelin integrity and reduced the infiltration of activated T cells into the CNS. This protective effect of the peptide may be related to its suppression of autoantigen-specific T-cell activation via calcium influx inhibition. CONCLUSION: ImK prevents neurological damage by suppressing T-cell activation, suggesting the applicability of this peptide in MS therapy.


Assuntos
Encefalomielite Autoimune Experimental/complicações , Canal de Potássio Kv1.3/metabolismo , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/etiologia , Bloqueadores dos Canais de Potássio/uso terapêutico , Linfócitos T/fisiologia , Animais , Animais Recém-Nascidos , Células Cultivadas , Modelos Animais de Doenças , Feminino , Canal de Potássio Kv1.3/antagonistas & inibidores , Microscopia Eletrônica de Transmissão , Mycobacterium tuberculosis/patogenicidade , Proteína Básica da Mielina/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Linfócitos T/efeitos dos fármacos , Linfócitos T/ultraestrutura
5.
Oncotarget ; 8(15): 25513-25524, 2017 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-28424420

RESUMO

Neonatal hypoxic-ischemic is a major cause of death and disability in neonates. In this study, we suggest for the first time that pretreatment with vitexin may suppress a pro-apoptotic signaling pathway in hypoxic-ischemic neuronal injury in neonates by inhibition of the phosphorylation of Ca2+/Calmodulin-dependent protein kinase II. Here we found that vitexin pretreatment reduced brain infarct volume in a dose-dependent manner. In addition, vitexin decreased the number of TUNEL-positive cells and brain atrophy. Furthermore, vitexin improved neurobehavioral outcomes. Vitexin also reduced oxygen glucose deprivation-induced neuronal injury and calcium entry. Vitexin pretreatment increased the Bcl-2/Bax protein ratio and decreased phosphorylation of Ca2+/Calmodulin-dependent protein kinase II and NF-κB, cleaved caspase-3 protein expression 24 hours after injury. Our data indicate that pretreatment with vitexin protects against neonatal hypoxic-ischemic brain injury and thus has potential as a treatment for hypoxic-ischemic brain injury.


Assuntos
Apigenina/farmacologia , Apoptose/efeitos dos fármacos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Hipóxia-Isquemia Encefálica/metabolismo , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Atrofia , Infarto Encefálico/etiologia , Infarto Encefálico/metabolismo , Infarto Encefálico/patologia , Cálcio/metabolismo , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Glucose/metabolismo , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Hipóxia-Isquemia Encefálica/patologia , Camundongos , NF-kappa B/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oxigênio/metabolismo
6.
Brain Res Bull ; 130: 188-199, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28161194

RESUMO

Hypoxia-ischemia brain damage (HIBD) is one of prevalent causes of neonatal mortality and morbidity. Our data demonstrated that hypoxia-ischemia (HI) induced Na+-K+-Cl--co-transporter 1 (NKCC1) increasing in hippocampus. Previous studies demonstrated that NKCC1 regulates various stages of neurogenesis. In this study, we studied the role of increased NKCC1 in regulating of HI-induced neurogenesis. HIBD model was established in 7days old Sprague-Dawley rat pup, and the expression of NKCC1 was detected by western blot and qPCR. Brain electrical activity in freely rats was monitored by electroencephalography (EEG) recordings. HI-induced neurogenesis was detected by immunofluorescence staining. Neurobehavioral test was to investigate the neuro-protective role of bumetanide, an inhibitor of NKCC1, on neonatal rats after HI. The results showed that bumetanide treatment significantly reduced brain electrical activity and the seizure stage of epilepsy induced by pentylenetetrazol (PTZ) in vivo after HI. In addition, bumetanide restored aberrant hippocampal neurogenesis and associated cognitive function. Our data demonstrated that bumetanide reduces the susceptibility of epilepsy induced by PTZ in rats suffering from HI injury during neonatal period via restoring the ectopic newborn neurons in dentate gyrus (DG) and cognitive function.


Assuntos
Anticonvulsivantes/administração & dosagem , Bumetanida/administração & dosagem , Hipocampo/fisiopatologia , Hipóxia-Isquemia Encefálica/complicações , Neurogênese/efeitos dos fármacos , Convulsões/fisiopatologia , Animais , Animais Recém-Nascidos , Movimento Celular/efeitos dos fármacos , Proliferação de Células , Eletroencefalografia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Memória/efeitos dos fármacos , Pentilenotetrazol/administração & dosagem , Ratos Sprague-Dawley , Convulsões/induzido quimicamente , Convulsões/complicações , Convulsões/metabolismo , Membro 2 da Família 12 de Carreador de Soluto/metabolismo
7.
Fitoterapia ; 115: 74-85, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27693342

RESUMO

Vitexin and isovitexin are active components of many traditional Chinese medicines, and were found in various medicinal plants. Vitexin (apigenin-8-C-glucoside) has recently received increased attention due to its wide range of pharmacological effects, including but not limited to anti-oxidant, anti-cancer, anti-inflammatory, anti-hyperalgesic, and neuroprotective effects. Isovitexin (apigenin-6-C-glucoside), an isomer of vitexin, generally purified together with vitexin, also exhibits diverse biological activities. Latest research has suggested that vitexin and isovitexin could be potential substitute medicines for diversity diseases, and may be adjuvants for stubborn diseases or health products. This review summarized recent findings on various pharmacological activities and associative signalling pathways of vitexin and isovitexin to provide a reference for future research and clinical applications.


Assuntos
Apigenina/farmacologia , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Apigenina/farmacocinética , Medicamentos de Ervas Chinesas/química , Humanos , Estrutura Molecular , Fármacos Neuroprotetores/farmacologia , Plantas Medicinais/química
8.
Neuropharmacology ; 99: 38-50, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26187393

RESUMO

Previous studies have demonstrated that the early suppression of HIF-1α after hypoxia-ischemia (HI) injury provides neuroprotection. Vitexin (5, 7, 4-trihydroxyflavone-8-glucoside), an HIF-1α inhibitor, is a c-glycosylated flavone that has been identified in medicinal plants. Therefore, we hypothesized that treatment with vitexin would protect against HI brain injury. Newborn rat pups were subjected to unilateral carotid artery ligation followed by 2.5 h of hypoxia (8% O2 at 37 °C). Vitexin (30, 45 or 60 mg/kg) was administered intraperitoneally at 5 min or 3 h after HI. Vitexin, administered 5 min after HI, was neuroprotective as seen by decreased infarct volume evaluated at 48 h post-HI. This neuroprotection was removed when vitexin was administered 3 h after HI. Neuronal cell death, blood-brain barrier (BBB) integrity, brain edema, HIF-1α and VEGF protein levels were evaluated using a combination of Nissl staining, IgG staining, brain water content, immunohistochemistry and Western blot at 24 and 48 h after HI. The long-term effects of vitexin were evaluated by brain atrophy measurement, Nissl staining and neurobehavioral tests. Vitexin (45 mg/kg) ameliorated brain edema, BBB disruption and neuronal cell death; Upregulation of HIF-1α by dimethyloxalylglycine (DMOG) increased the BBB permeability and brain edema compared to HI alone. Vitexin attenuated the increase in HIF-1α and VEGF. Vitexin also had long-term effects of protecting against the loss of ipsilateral brain and improveing neurobehavioral outcomes. In conclusion, our data indicate early HIF-1α inhibition with vitexin provides both acute and long-term neuroprotection in the developing brain after neonatal HI injury.


Assuntos
Apigenina/farmacologia , Encéfalo/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Animais , Animais Recém-Nascidos , Apigenina/química , Atrofia/tratamento farmacológico , Atrofia/fisiopatologia , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/fisiopatologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Edema Encefálico/tratamento farmacológico , Edema Encefálico/patologia , Edema Encefálico/fisiopatologia , Permeabilidade Capilar/efeitos dos fármacos , Permeabilidade Capilar/fisiologia , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia-Isquemia Encefálica/patologia , Hipóxia-Isquemia Encefálica/fisiopatologia , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/fisiologia , Fármacos Neuroprotetores/química , Distribuição Aleatória , Ratos Sprague-Dawley , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/metabolismo
9.
Brain Behav Immun ; 48: 68-77, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25801060

RESUMO

Febrile seizure (FS) is the most common seizure disorder in children, and children with FS are regarded as a high risk for the eventual development of epilepsy. Brain inflammation may be implicated in the mechanism of FS. Transient receptor potential vanilloid 1 (TRPV1) is believed to act as a monitor and regulator of body temperature. The role of inflammation in synaptic plasticity mediation indicates that TRPV1 is relevant to several nervous system diseases, such as epilepsy. Here, we report a critical role for TRPV1 in a febrile seizure mouse model and reveal increased levels of pro-inflammatory factors in the immature brain. Animals were subjected to hyperthermia for 30 min, which generates seizures lasting approximately 20 min, and then were used for experiments. To invoke frequently repetitive febrile seizures, mice are exposed to hyperthermia for three times daily at an interval of 4h between every time induced seizure, and a total of 4 days to induce. Behavioral testing for febrile seizures revealed that a TRPV1 knock-out mouse model demonstrated a prolonged onset latency and a shortened duration and seizure grade of febrile seizure when compared with wild type (WT) mice. The expression levels of both TRPV1 mRNA and protein increased after a hyperthermia-induced febrile seizure in WT mice. Notably, TRPV1 activation resulted in a significant elevation in the expression of pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α and HMGB1) in the hippocampus and cortex. These data indicate that the reduction of TRPV1 expression parallels a decreased susceptibility to febrile seizures. Thus, preventative strategies might be developed for use during febrile seizures.


Assuntos
Encéfalo/metabolismo , Citocinas/metabolismo , Hipertermia Induzida , Convulsões Febris/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Encéfalo/imunologia , Linhagem Celular , Modelos Animais de Doenças , Hipocampo/imunologia , Hipocampo/metabolismo , Camundongos , Camundongos Knockout , Convulsões Febris/imunologia , Canais de Cátion TRPV/genética
10.
Int J Clin Exp Med ; 8(10): 17536-50, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26770345

RESUMO

BACKGROUND: Existing literature has shown that patients with coronary artery disease (CAD) can benefit greatly from the strength training; therefore, the strength training should play a more important role in cardiac rehabilitation. However, the medical community may still have conservation to apply the strength training owing to no comprehensive study so far to compare the effectiveness of the strength training to the other trainings, such as aerobic training. OBJECTIVE: To evaluate the effect of strength training on motor function in patients with CAD. METHODS: Published articles from the earliest date available to July 2015 were identified using electronic searches. Two reviewers selected independently relevant randomized controlled trials (RCTs) investigating exercise program with strength training versus control interventions (exercise without strength training, including aerobic training and no exercise group) for the treatment of CAD patients. We examined effects of exercise with strength training versus control interventions on peak oxygen uptake (VO2peak), duration of exercise test and muscle strength. Two reviewers extracted data independently. RESULTS: Twenty seven trials that represented 1151 participants passed the selection criteria and were evaluated for the effects of strength training in CAD patients. For improving VO2peak [SMD (95%CI) = 0.58 (0.11, 1.06)] and muscle strength [upper limb, SMD (95% CI) =0.44 (0.34, 0.55); lower limb, SMD (95% CI) =0.33 (0.16, 0.50)], exercise program with strength training were significantly more effective than one without it. But there is no significantly difference on duration of exercise test [SMD (95%CI) = 0.17 (-0.04, 0.39)] in strength training group than in control group. CONCLUSIONS: We conclude strength training is effective in improving muscle strength and VO2peak, in CAD patients, when compared to patients with control group. Furthermore, our evaluations suggest that strength training does not compromise clinical trial completion or safety.

11.
Zhen Ci Yan Jiu ; 40(6): 479-83, 488, 2015 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-26887211

RESUMO

OBJECTIVE: To observe the effect of acupuncture stimulation of acupoints of the Conception Vessel, Kidney Meridian, Spleen Meridian, and Bladder Meridian on menstrual cycles and duration, and serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estrogen 2 (E(2)) levels in patients with diminished ovarian reserve (DOR). METHODS: A total of 96 patients with DOR of both yin and yang deficiency were randomly divided into medication group and acupuncture group (n = 48 cases in each group). Patients of the medication group were treated by Estradiol Valerate tablets, 2 mg/d on the first 10 days, and Estradiol Cyproterone, 3 mg/d from day 11 to 21, followed by 5 -7 days' rest, and the next therapeutic course, continuously for 6 months. For patients of the acupuncture group, filiform acupuncture needles were separately inserted into every 5 points of the Conceptional Vessel, Kidney, Spleen and Bladder Meridians, manipulated with uniform reinforcing and reducing methods till Deqi, and retained for 40 min. The treatment was conducted once daily for consecutive 10 days in one menstrual cycle, beginning from the 10(th) day on after menstruation, which was repeated for 6 months. The integrative scores (normal = 0, mild=2, moderate=4 and severe=6 points) of menstrual cycle, menstrual duration, amount, color, quality [blood blot or ame- nia, symptoms of traditional Chinese medicine (TCM)] were assessed according to "Guiding Principles for Clinical Trials of New Drugs of Chinese Materia Medica". Serum FSH, LH and E(2) contents were detected by Roche's electrochemical luminescence method. RESULTS: After the treatment, of the two 48 cases in the medication and acupuncture groups, 12 (25.0%) and 20 (4.7) were cured, 11 (22.9 %) and 12 (25.0 %) experienced marked improvement in their symptoms, 20 (41.7%) and 10 (20.8%) were effective, and 5 (10.4%) and 6 (12.5%) failed, with the effective rate being 89.6% and 87.5%, respectively. The integral score of TOM symptoms, menstrual cycle, serum FSH, LH and E2 contents were considerably diminished in both groups after 6 months of treatment (P<0.05), and the TOM symptom score, menstrual cycle, and serum FSH, LH and E2 levels were significantly lower in the acupuncture group than in the medication group 6 months after cease of the treatment (P<0.05), while the menstrual duration in each cycle was notably longer in both groups after the treatment, and evidently longer in the acupuncture group than in the medication group 6 months after cease of the treatment (P<0.05). No significant differences were found between the two groups in the effective rate, score of TOM symptoms, menstrual cycle and duration, and serum FSH, LH and E(2) contents following the treatment (P>0.05). CONCLUSION: Acupuncture stimulation of acupoints of the Conception Vessel, Kidney, Spleen, and Bladder Meridians is effective in improving clinical symptoms of DOR patients with deficiency of both yin and yang, and has a longer effect, which may be closely associated with its functions in lowering serum FSH, LH and E(2) levels through regulating the hypothalamic-pituitary-ovarian axis.


Assuntos
Terapia por Acupuntura , Meridianos , Reserva Ovariana , Deficiência da Energia Yang/terapia , Deficiência da Energia Yin/terapia , Pontos de Acupuntura , Adulto , Estrogênios/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Deficiência da Energia Yang/metabolismo , Deficiência da Energia Yang/fisiopatologia , Deficiência da Energia Yin/metabolismo , Deficiência da Energia Yin/fisiopatologia , Adulto Jovem
12.
Onco Targets Ther ; 7: 1901-9, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25364261

RESUMO

Gene therapy has promised to be a highly effective antitumor treatment by introducing a tumor suppressor gene or the abrogation of an oncogene. Among the potential therapeutic transgenes, the tumor suppressor gene p53 serves as an attractive target. Restoration of wild-type p53 function in tumors can be achieved by introduction of an intact complementary deoxyribonucleic acid copy of the p53 gene using a suitable viral vector, in most cases an adenoviral vector (Adp53). Preclinical in vitro and in vivo studies have shown that Adp53 triggers a dramatic tumor regression response in various cancers. These viruses are engineered to lack certain early proteins and are thus replication defective, including Gendicine, SCH-58500, and Advexin. Several types of tumor-specific p53-expressing conditionally replicating adenovirus vectors (known as replication-competent CRAdp53 vectors) have been developed, such as ONYX 015, AdDelta24-p53, SG600-p53, OBP-702, and H101. Various clinical trials have been conducted to investigate the safety and efficiency of these adenoviral vectors. In this review we will talk about the biological mechanisms, clinical utility, and therapeutic potentials of the replication-deficient Adp53-based and replication-competent CRAdp53-based gene therapy.

13.
Neurosci Bull ; 30(6): 985-998, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25370443

RESUMO

Gamma-amino-butyric acid (GABA)-containing interneurons are crucial to both development and function of the brain. Down-regulation of GABAergic inhibition may result in the generation of epileptiform activity. Loss, axonal sprouting, and dysfunction of interneurons are regarded as mechanisms involved in epileptogenesis. Recent evidence suggests that network connectivity and the properties of interneurons are responsible for excitatory-inhibitory neuronal circuits. The balance between excitation and inhibition in CA1 neuronal circuitry is considerably altered during epileptic changes. This review discusses interneuron diversity, the causes of interneuron dysfunction in epilepsy, and the possibility of using GABAergic neuronal progenitors for the treatment of epilepsy.


Assuntos
Epilepsia/fisiopatologia , Neurônios GABAérgicos/fisiologia , Hipocampo/fisiopatologia , Interneurônios/fisiologia , Animais , Humanos , Rede Nervosa/fisiologia , Inibição Neural/fisiologia
14.
Front Cell Neurosci ; 8: 329, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25352783

RESUMO

We previously observed that A-type potassium currents were decreased and membrane excitability increased in hippocampal dentate granule cells after neonatal global hypoxia associated with seizures. Here, we studied the effects of hypoxia on the function and expression of Kv4.2 and Kv4.3 α subunit channels, which encode rapidly inactivating A-type K currents, in transfected HEK-293 cells to determine if hypoxia alone could regulate IA in vitro. Global hypoxia in neonatal rat pups resulted in early decreased hippocampal expression of Kv4.2 mRNA and protein with 6 or 12 h post-hypoxia. Whole-cell voltage-clamp recordings revealed that similar times after hypoxia (1%) in vitro decreased peak currents mediated by recombinant Kv4.2 but not Kv4.3 channels. Hypoxia had no significant effect on the voltage-dependencies of activation and inactivation of Kv4.2 channels, but increased the time constant of activation. The same result was observed when Kv4.2 and Kv4.3 channels were co-expressed in a 1:1 ratio. These data suggested that hypoxia directly modulates A-type potassium channels of the subfamily typically expressed in principal hippocampal neurons, and does so in a manner to decrease function. Given the role of IA to slow action potential firing, these data are consistent with a direct effect of hypoxia to decrease IA as a mechanism of increased neuronal excitability and promotion of seizures.

15.
Sci Rep ; 4: 6605, 2014 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-25308382

RESUMO

This study examined whether a novel imidazoline I2 receptor ligand CR4056 could serve as a discriminative stimulus and whether it shares similar discriminative stimulus effects with other reported I2 receptor ligands. Eight male Sprague-Dawley rats were trained to discriminate 10.0 mg/kg CR4056 (i.p.) from vehicle in a two-lever food-reinforced drug discrimination procedure. Once rats acquired the discrimination, substitution and combination studies were conducted to elucidate the underlying receptor mechanisms. All rats acquired CR4056 discrimination after an average of 26 training sessions. Several I2 receptor ligands (phenyzoline, tracizoline, RS45041, and idazoxan, 3.2-75 mg/kg, i.p.) all occasioned > 80% CR4056-associated lever responding. Other drugs that occasioned partial or no CR4056-associated lever responding included methamphetamine, ketamine, the endogenous imidazoline ligand agmatine, the monoamine oxidase (MAO) inhibitor harmane, the α2-adrenoceptor agonist clonidine, the µ-opioid receptor agonists morphine and methadone, and the selective I2 receptor ligands BU224 and 2-BFI. The α1 adrenoceptor antagonist WB4101, α2 adrenoceptor antagonist yohimbine and µ-opioid receptor antagonist naltrexone failed to alter the stimulus effects of CR4056. Together, these results show that CR4056 can serve as a discriminative stimulus in rats, which demonstrates high pharmacological specificity and appears to be mediated by imidazoline I2 receptors.


Assuntos
Imidazóis/administração & dosagem , Receptores de Imidazolinas/metabolismo , Quinazolinas/administração & dosagem , Animais , Benzofuranos/química , Imidazóis/química , Imidazóis/uso terapêutico , Imidazolinas/química , Masculino , Metadona/química , Metadona/uso terapêutico , Morfina/química , Morfina/uso terapêutico , Quinazolinas/química , Ratos
16.
Mol Cell Endocrinol ; 394(1-2): 59-69, 2014 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-24997359

RESUMO

Prenatal nicotine exposure causes adverse birth outcome. However, the corresponding metabonomic alterations and underlying mechanisms of nicotine-induced developmental toxicity remain unclear. The aims of this study were to characterize the metabolic alterations in biofluids in nicotine-induced intrauterine growth retardation (IUGR) rat model. In the present study, pregnant Wistar rats were intragastrically administered with different doses of nicotine (0.5, 1.0 and 2.0 mg/kg d) from gestational day (GD) 11-20. The metabolic profiles of the biofluids, including maternal plasma, fetal plasma and amniotic fluid, were analyzed using (1)H nuclear magnetic resonance (NMR)-based metabonomic techniques. Prenatal nicotine exposure caused noticeably lower body weights, higher IUGR rates of fetal rats, and elevated maternal and fetal corticosterone (CORT) levels compared to the controls. The correlation analysis among maternal, fetal serum CORT levels and fetal bodyweight suggested that the levels of maternal and fetal serum CORT presented a positive correlation (r=0.356, n=32, P<0.05), while there was a negative correlation between fetal (r=-0.639, n=32, P<0.01) and maternal (r=-0.530, n=32, P<0.01) serum CORT level and fetal bodyweight. The fetal metabonome alterations included the stimulation of lipogenesis and the decreased levels of glucose and amino acids. The maternal metabonome alterations involved the enhanced blood glucose levels, fatty acid oxygenolysis, proteolysis and amino acid accumulation. These results suggested that prenatal nicotine exposure is associated with an altered maternal and fetal metabonome, which may be related to maternal increased glucocorticoid level induced by nicotine.


Assuntos
Retardo do Crescimento Fetal/metabolismo , Feto/efeitos dos fármacos , Exposição Materna , Metabolômica , Nicotina/toxicidade , Aminoácidos/metabolismo , Líquido Amniótico/química , Animais , Glicemia/metabolismo , Corticosterona/sangue , Ácidos Graxos/metabolismo , Feminino , Retardo do Crescimento Fetal/induzido quimicamente , Retardo do Crescimento Fetal/patologia , Peso Fetal/efeitos dos fármacos , Feto/patologia , Idade Gestacional , Lipogênese , Masculino , Gravidez , Ratos , Ratos Wistar
17.
Neuroreport ; 25(6): 379-85, 2014 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-24488030

RESUMO

Transient receptor potential vanilloid 1 (TRPV1) channel has been found to be expressed in a variety of tissues over the last few years, including the central nervous system (CNS). However, the distribution of TRPV1 in the CNS remains a controversial question. Here, we reveal that the expression of TRPV1 can be detected in the C57BL/6 mouse hippocampus and cortex using real-time PCR and western blot. Beyond that, mRNA and protein expression levels of TRPV1 show dynamic changes during brain development. Compared with the earliest timepoint examined at 2 weeks, the expression levels of mRNA progressively increased at 4 and 8 weeks, peaking at the later timepoint, then declined at 16 weeks but remained elevated. However, compared with 2-week-old mice, the expression levels of the other three groups (4-, 8-, and 16-week-old mice) increased overall. These results indicate that TRPV1 channel expression is detectable in the CNS and it varies during postnatal development.


Assuntos
Córtex Cerebral/metabolismo , Hipocampo/metabolismo , RNA Mensageiro/biossíntese , Canais de Cátion TRPV/biossíntese , Fatores Etários , Animais , Camundongos , Camundongos Endogâmicos C57BL
18.
Epilepsy Behav ; 31: 276-80, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24269027

RESUMO

This study was designed to investigate the role of experimental febrile seizures in the induction of generalized clonic seizures and the involvement of heat-sensitive channel TRPV1. Pentylenetetrazol-induced clonic seizure was used as the seizure model, and Trpv1 gene knock-out and wild-type C57/BL6 mice were used as experimental subjects. Electroencephalograph and seizure behavior were recorded for the evaluation of the severity of seizures. Increased frequency of the experimental febrile seizures facilitated PTZ-induced generalized clonic seizures. Trpv1 gene deficiency decreased the properties of generalized clonic seizure. The intensity of experimental febrile seizures reduced the threshold to generalized clonic seizure, and Trpv1 gene deficiency decreased the susceptibility to PTZ-induced seizures following early-life hyperthermia challenges in mice.


Assuntos
Convulsivantes/toxicidade , Hipertermia Induzida , Pentilenotetrazol/toxicidade , Convulsões Febris/induzido quimicamente , Convulsões Febris/genética , Canais de Cátion TRPV/metabolismo , Análise de Variância , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Eletroencefalografia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Canais de Cátion TRPV/deficiência , Fatores de Tempo
20.
Epilepsia ; 54(7): 1223-31, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23815572

RESUMO

PURPOSE: Cerebral hypoxia is a major cause of neonatal seizures, and can lead to epilepsy. Pathologic anatomic and physiologic changes in the dentate gyrus have been associated with epileptogenesis in many experimental models, as this region is widely believed to gate the propagation of limbic seizures. However, the consequences of hypoxia-induced seizures for the immature dentate gyrus have not been extensively examined. METHODS: Seizures were induced by global hypoxia (5-7% O2 for 15 min) in rat pups on postnatal day 10. Whole-cell voltage-clamp recordings were used to examine A-type potassium currents (IA ) in dentate granule cells in hippocampal slices obtained 1-17 days after hypoxia treatment. KEY FINDINGS: Seizure-inducing hypoxia resulted in decreased maximum IA amplitude in dentate granule cells recorded within the first week but not at later times after hypoxia treatment. The decreased IA amplitude was not associated with changes in the voltage-dependence of activation or inactivation removal, or in sensitivity to inhibition by 4-aminopyridine (4-AP). However, consistent with the role of IA in shaping firing patterns, we observed in the hypoxia group a significantly decreased latency to first spike with depolarizing current injection from hyperpolarized potentials. These differences were not associated with changes in resting membrane potential or input resistance, and were eliminated by application of 10 m 4-AP. SIGNIFICANCE: Given the role of IA to slow action potential firing, decreased IA could contribute to long-term hippocampal pathology after neonatal seizure-inducing hypoxia by increasing dentate granule cell excitability during a critical window of activity-dependent hippocampal maturation.


Assuntos
Hipocampo/patologia , Hipóxia/complicações , Neurônios/fisiologia , Canais de Potássio/fisiologia , Convulsões/etiologia , Convulsões/patologia , 4-Aminopiridina/farmacologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Animais Recém-Nascidos , Biofísica , Modelos Animais de Doenças , Estimulação Elétrica/efeitos adversos , Técnicas In Vitro , Masculino , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio/efeitos dos fármacos , Ratos , Ratos Long-Evans
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