RESUMO
In this study, we explored the role and mechanism of repulsive guidance molecule B (RGMb, also known as Dragon) in the protective effects of curcumin against renal fibrosis and verified Dragon's effect on renal tubular epithelial cell apoptosis and cell programmability. Unilateral ureteral obstruction (UUO) was surgically induced in rats to establish a model of renal interstitial fibrosis (RIF). The rats were then treated with curcumin. Curcumin prominently decreased the serum creatinine (SCr) and blood urea nitrogen (BUN) levels, and also improved the tubular injury in the UUO-induced rats. Curcumin significantly downregulated the TGF-ß1, P-Smad2/3, cleaved caspase-3, cleaved caspase-8 and Dragon levels. Dragon knockdown also markedly reduced the TGF-ß1, P-Smad2/3, Smad2/3, cleaved caspase-3, cleaved caspase-8, fibronectin, collagen I, collagen IV, vimentin, and α-SMA expression levels. Conversely, Dragon overexpression caused higher expression levels of these proteins, and curcumin reversed this effect. Furthermore, Dragon knockdown increased the E-cadherin levels, whereas Dragon overexpression decreased these levels. Overexpressing Dragon significantly decreased the cell viability, and curcumin reversed this effect. In conclusion, curcumin acted on Dragon and attenuated RIF in UUO rat models. Curcumin downregulated the TGF-ß1/Smad signaling pathway and inhibited Dragon and fibrogenic molecules in both rats and HK-2 cells.
Assuntos
Curcumina/farmacologia , Fibrose/tratamento farmacológico , Proteínas Ligadas por GPI/biossíntese , Rim/efeitos dos fármacos , Proteínas do Tecido Nervoso/biossíntese , Receptores de Superfície Celular/biossíntese , Obstrução Ureteral/tratamento farmacológico , Animais , Nitrogênio da Ureia Sanguínea , Caspase 3/metabolismo , Creatinina/metabolismo , Fibrose/metabolismo , Fibrose/patologia , Proteínas Ligadas por GPI/efeitos dos fármacos , Humanos , Rim/metabolismo , Rim/patologia , Masculino , Proteínas do Tecido Nervoso/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Superfície Celular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Obstrução Ureteral/metabolismoRESUMO
Deregulation of synaptic function and neurotransmission has been linked with the development of major depression disorder (MDD). Tianeptine (Tian) has been used as antidepressant with anxiolytic properties and recently as a nootropic to improve cognitive performance, but its mechanism of action is unknown. We conducted a proteomic study on the hippocampal synaptosomal fractions of adult male Wistar rats exposed to chronic social isolation (CSIS, 6 weeks), an animal model of depression and after chronic Tian treatment in controls (nootropic effect) and CSIS-exposed rats (lasting 3 weeks of 6-week CSIS) (therapeutic effect). Increased expression of Syn1 and Camk2-related neurotransmission, vesicle transport and energy processes in Tian-treated controls were found. CSIS led to upregulation of proteins associated with actin cytoskeleton, signaling transduction and glucose metabolism. In CSIS rats, Tian up-regulated proteins involved in mitochondrial energy production, mitochondrial transport and dynamics, antioxidative defense and glutamate clearance, while attenuating the CSIS-increased glycolytic pathway and cytoskeleton organization proteins expression and decreased the expression of proteins involved in V-ATPase and vesicle endocytosis. Our overall findings revealed that synaptic vesicle dynamics, specifically exocytosis, and mitochondria-related energy processes might be key biological pathways modulated by the effective nootropic and antidepressant treatment with Tian and be a potential target for therapeutic efficacy of the stress-related mood disorders.
Assuntos
Antidepressivos/farmacologia , Transtorno Depressivo/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Nootrópicos/farmacologia , Proteoma/efeitos dos fármacos , Isolamento Social , Vesículas Sinápticas/efeitos dos fármacos , Tiazepinas/farmacologia , Animais , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Antidepressivos/uso terapêutico , Transtorno Depressivo/fisiopatologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/ultraestrutura , Masculino , Mitocôndrias/fisiologia , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Nootrópicos/uso terapêutico , Mapeamento de Interação de Proteínas , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Tiazepinas/uso terapêuticoRESUMO
Inflammation, demyelination, glial activation, and oxidative damage are the most pathological hallmarks of multiple sclerosis (MS). Piperine, a main bioactive alkaloid of black pepper, possesses antioxidant, anti-inflammatory, and neuroprotective properties whose therapeutic potential has been less studied in the experimental autoimmune encephalomyelitis (EAE) models. In this study, the efficiency of piperine on progression of EAE model and myelin repair mechanisms was investigated. EAE was induced in female Lewis rats and piperine and its vehicle were daily administrated intraperitoneally from day 8 to 29 post immunization. We found that piperine alleviated neurological deficits and EAE disease progression. Luxol fast blue and H&E staining and immunostaining of lumbar spinal cord cross sections confirmed that piperine significantly reduced the extent of demyelination, inflammation, immune cell infiltration, microglia, and astrocyte activation. Gene expression analysis in lumbar spinal cord showed that piperine treatment decreased the level of pro-inflammatory cytokines (TNF-α, IL-1ß) and iNOS and enhanced IL-10, Nrf2, HO-1, and MBP expressions. Piperine supplementation also enhanced the total antioxidant capacity (FRAP) and reduced the level of oxidative stress marker (MDA) in the CNS of EAE rats. Finally, we found that piperine has anti-apoptotic and neuroprotective effect in EAE through reducing caspase-3 (apoptosis marker) and enhancing BDNF and NeuN expressing cells. This study strongly indicates that piperine has a beneficial effect on the EAE progression and could be considered as a potential therapeutic target for MS treatment. Upcoming clinical trials will provide a deeper understanding of piperine's role for the treatment of the MS.
Assuntos
Alcaloides/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Benzodioxóis/uso terapêutico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Piperidinas/uso terapêutico , Alcamidas Poli-Insaturadas/uso terapêutico , Alcaloides/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Astrócitos/metabolismo , Benzodioxóis/farmacologia , Caspase 3/biossíntese , Caspase 3/genética , Citocinas/biossíntese , Citocinas/genética , Progressão da Doença , Avaliação Pré-Clínica de Medicamentos , Encefalomielite Autoimune Experimental/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Microglia/metabolismo , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Distribuição Aleatória , Ratos , Ratos Endogâmicos LewRESUMO
Manual acupuncture (MA) can be used to manage high blood pressure; however, the underlying molecular mechanism remains unknown. To explore the mechanism of acupuncture in the treatment of hypertension, Wistar Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) were subjected to either MA stimulation or the corresponding sham procedure as a negative control (Sham-MA) for 1 week. PET-CT scans, transcriptomics and molecular biology were used to evaluate the effect of MA. The results show that MA can regulate blood pressure in SHRs, change the glucose metabolism of the paraventricular hypothalamus (PVH), and affect the mRNA and protein expression levels of differentially expressed genes in the PVH. These genes may lower blood pressure by regulating angiotensin, endothelial function and inflammation. These findings reveal that MA regulates multiple biological processes and genes/proteins of the PVH, and provide a solid theoretical basis for exploring the mechanisms by which MA regulates hypertension.
Assuntos
Terapia por Acupuntura , Hipertensão Essencial/terapia , Regulação da Expressão Gênica , Terapia de Alvo Molecular , Núcleo Hipotalâmico Paraventricular/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Análise de Sequência de RNA , Animais , Pressão Sanguínea/fisiologia , Western Blotting , Hipertensão Essencial/diagnóstico por imagem , Hipertensão Essencial/genética , Ontologia Genética , Redes Reguladoras de Genes , Glucose/metabolismo , Masculino , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Núcleo Hipotalâmico Paraventricular/diagnóstico por imagem , RNA Mensageiro/análise , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Reação em Cadeia da Polimerase em Tempo Real , TranscriptomaRESUMO
Hypoxic-ischemic encephalopathy (HIE) is still a major cause of neonatal death and disability as therapeutic hypothermia (TH) alone cannot afford sufficient neuroprotection. The present study investigated whether ventilation with molecular hydrogen (2.1% H2) or graded restoration of normocapnia with CO2 for 4 h after asphyxia would augment the neuroprotective effect of TH in a subacute (48 h) HIE piglet model. Piglets were randomized to untreated naïve, control-normothermia, asphyxia-normothermia (20-min 4%O2-20%CO2 ventilation; Tcore = 38.5 °C), asphyxia-hypothermia (A-HT, Tcore = 33.5 °C, 2-36 h post-asphyxia), A-HT + H2, or A-HT + CO2 treatment groups. Asphyxia elicited severe hypoxia (pO2 = 19 ± 5 mmHg) and mixed acidosis (pH = 6.79 ± 0.10). HIE development was confirmed by altered cerebral electrical activity and neuropathology. TH was significantly neuroprotective in the caudate nucleus but demonstrated virtually no such effect in the hippocampus. The mRNA levels of apoptosis-inducing factor and caspase-3 showed a ~10-fold increase in the A-HT group compared to naïve animals in the hippocampus but not in the caudate nucleus coinciding with the region-specific neuroprotective effect of TH. H2 or CO2 did not augment TH-induced neuroprotection in any brain areas; rather, CO2 even abolished the neuroprotective effect of TH in the caudate nucleus. In conclusion, the present findings do not support the use of these medical gases to supplement TH in HIE management.
Assuntos
Asfixia Neonatal/terapia , Dano Encefálico Crônico/prevenção & controle , Dióxido de Carbono/uso terapêutico , Hidrogênio/uso terapêutico , Hipotermia Induzida , Hipóxia-Isquemia Encefálica/terapia , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Acidose/sangue , Acidose/etiologia , Acidose/prevenção & controle , Administração por Inalação , Animais , Animais Recém-Nascidos , Fator de Indução de Apoptose/biossíntese , Fator de Indução de Apoptose/genética , Asfixia Neonatal/complicações , Asfixia Neonatal/tratamento farmacológico , Dano Encefálico Crônico/etiologia , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Fator Neurotrófico Derivado do Encéfalo/genética , Dióxido de Carbono/administração & dosagem , Dióxido de Carbono/toxicidade , Caspase 3/biossíntese , Caspase 3/genética , Núcleo Caudado/patologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Eletroencefalografia , Potenciais Evocados Visuais/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/patologia , Hidrogênio/administração & dosagem , Hidrogênio/análise , Hipóxia-Isquemia Encefálica/complicações , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Hipóxia-Isquemia Encefálica/patologia , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Fármacos Neuroprotetores/administração & dosagem , Especificidade de Órgãos , Distribuição Aleatória , SuínosRESUMO
Alzheimer's disease (AD) is a common neurodegenerative disease that is always accompanied by synaptic loss in the brain. Safflower yellow (SY) is the extract of safflower, a traditional Chinese medicine, which has shown neuroprotective effects in recent studies. However, the mechanism of SY in protecting synapses remains unclear. In this study, we are going to study the mechanism of how SY treats AD in terms of synaptic plasticity. We found, via behavioral experiments, that SY treatment could improve the abilities of learning and memory in APP/PS1 mice. In addition, using Golgi staining and HE staining, we found that SY treatment could reduce the loss of dendritic spines in the pathological condition and could maintain the normal physiological state of the cells in cortex and in hippocampus. In addition, the results of immunofluorescence staining and western blotting showed that SY treatment could significantly increase the expression of synapse-related proteins. Moreover, after being treated with SY, the expression of iNOS (marker of M1 microglia) declined remarkably, and the level of Arginase-1 (marker of M2 microglia) increased significantly. Finally, we found BDNF/TrkB/ERK signaling cascade was activated. These results indicate that SY enhances synaptic plasticity in APP/PS1 mice by regulating microglia activation phenotypes and BDNF/TrkB/ERK signaling pathway.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Chalcona/análogos & derivados , Medicamentos de Ervas Chinesas/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Glicoproteínas de Membrana/fisiologia , Microglia/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Fitoterapia , Proteínas Tirosina Quinases/fisiologia , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Arginase/biossíntese , Arginase/genética , Córtex Cerebral/química , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Chalcona/uso terapêutico , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/ultraestrutura , Modelos Animais de Doenças , Donepezila/farmacologia , Donepezila/uso terapêutico , Indução Enzimática/efeitos dos fármacos , Reação de Fuga/efeitos dos fármacos , Feminino , Hipocampo/química , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Masculino , Memória de Longo Prazo/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/fisiologia , Teste do Labirinto Aquático de Morris/efeitos dos fármacos , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Plasticidade Neuronal/fisiologia , Óxido Nítrico Sintase Tipo II/biossíntese , Óxido Nítrico Sintase Tipo II/genética , Presenilina-1/genética , Distribuição AleatóriaRESUMO
Neurodegenerative diseases, including Alzheimer's and Parkinson's disease, are characterized by increased protein aggregation in the brain, progressive neuronal loss, increased inflammation, and neurogenesis impairment. We analyzed the effects of a new purine derivative drug, PDD005, in attenuating mechanisms involved in the pathogenesis of neurodegenerative diseases, using both in vivo and in vitro models. We show that PDD005 is distributed to the brain and can rescue cognitive deficits associated with aging in mice. Treatment with PDD005 prevents impairment of neurogenesis by increasing sex-determining region Y-box 2, nestin, and also enhances synaptic function through upregulation of synaptophysin and postsynaptic density protein 95. PDD005 treatment also reduced neuro-inflammation by decreasing interleukin-1ß expression, activation of astrocytes, and microglia. We identified prohibitin as a potential target in mediating the therapeutic effects of PDD005 for the treatment of cognitive deficit in aging mice. Additionally, in the current study, glycogen synthase kinase appears to attenuate tau pathology.
Assuntos
Transtornos Cognitivos/prevenção & controle , Hipocampo/efeitos dos fármacos , Terapia de Alvo Molecular , Proteínas do Tecido Nervoso/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Proteínas Repressoras/antagonistas & inibidores , Tauopatias/prevenção & controle , Envelhecimento/psicologia , Animais , Barreira Hematoencefálica , Encéfalo/metabolismo , Células Cultivadas , Transtornos Cognitivos/tratamento farmacológico , Donepezila/farmacologia , Avaliação Pré-Clínica de Medicamentos , Células Endoteliais/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/biossíntese , Glicogênio Sintase Quinase 3 beta/genética , Interleucina-1beta/biossíntese , Interleucina-1beta/genética , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias/efeitos dos fármacos , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Neurogênese/efeitos dos fármacos , Neuroglia/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Fármacos Neuroprotetores/farmacocinética , Fosforilação/efeitos dos fármacos , Proibitinas , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteínas Repressoras/biossíntese , Proteínas Repressoras/genética , Tauopatias/tratamento farmacológico , Proteínas tau/metabolismoRESUMO
In diabetic nephropathy (DN), intercellular communication is disrupted. Connexins (Cx) have a crucial role in that process. Dietary ratios and supplementation with polyunsaturated fatty acids (PUFAs) can alleviate diabetic complications and cause alterations in Cx levels. Although pannexins (Panx) share similarities with members of the Cx family, their function in diabetic nephropathy has still not been fully determined. We studied the influence of PUFA supplementation on the immunoexpression of Px1 and Cx family members in diabetic kidneys of rats. Four groups of rats in experimental DM1 model were supplemented with different dietary n-6/n-3 ratios; ≈7 in control (C) and diabetic groups (STZ), ≈ 60 in the STZ + N6 group and ≈ 1 (containing 16% EPA and 19% DHA) in the STZ + N3 group. Immunoexpression of Cx40, Cx43, Cx45 and Panx1 was evaluated in the renal tissue of diabetic rats using immunohistochemistry. Diabetes significantly decreased the protein expression of Cx40 and Cx43 and increased Panx1 protein expression in the renal cortex (p < 0.05-p < 0.01). There was a significant impact of diet on Cx and Panx1 immunoexpression. Dietary supplementation with a high n-6/n-3 ratio downregulated the protein expression of Cx45 and Panx1 in diabetic rats (p < 0.05-p < 0.01), while Cx43 immunoexpression was increased in diabetic rats fed with high and low n-6/n-3 ratios (p < 0.01-p < 0.001). Hyperglycaemic conditions in DN interfere with cell-to-cell communication and disturb the connection between cells and their immediate environment due to variations in connexin and pannexin immunoexpression. These variations can be regulated by PUFA dietary intake, suggesting their beneficial effect and possible therapeutic option.
Assuntos
Conexinas/antagonistas & inibidores , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Ácidos Graxos Insaturados/farmacologia , Rim/efeitos dos fármacos , Proteínas do Tecido Nervoso/antagonistas & inibidores , Animais , Conexinas/análise , Conexinas/biossíntese , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/induzido quimicamente , Nefropatias Diabéticas/metabolismo , Suplementos Nutricionais , Ácidos Graxos Insaturados/administração & dosagem , Rim/metabolismo , Rim/patologia , Masculino , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/biossíntese , Ratos , Ratos Wistar , EstreptozocinaRESUMO
Sonic hedgehog (SHH) signaling plays a pivotal role in 2 different phases during brain development. Early SHH signaling derived from the prechordal plate (PrCP) triggers secondary Shh induction in the forebrain, which overlies the PrCP, and the induced SHH signaling, in turn, directs late neuronal differentiation of the forebrain. Consequently, Shh regulation in the PrCP is crucial for initiation of forebrain development. However, no enhancer that regulates prechordal Shh expression has yet been found. Here, we identified a prechordal enhancer, named SBE7, in the vicinity of a cluster of known forebrain enhancers for Shh This enhancer also directs Shh expression in the ventral midline of the forebrain, which receives the prechordal SHH signal. Thus, the identified enhancer acts not only for the initiation of Shh regulation in the PrCP but also for subsequent Shh induction in the forebrain. Indeed, removal of the enhancer from the mouse genome markedly down-regulated the expression of Shh in the rostral domains of the axial mesoderm and in the ventral midline of the forebrain and hypothalamus in the mouse embryo, and caused a craniofacial abnormality similar to human holoprosencephaly (HPE). These findings demonstrate that SHH signaling mediated by the newly identified enhancer is essential for development and growth of the ventral midline of the forebrain and hypothalamus. Understanding of the Shh regulation governed by this prechordal and brain enhancer provides an insight into the mechanism underlying craniofacial morphogenesis and the etiology of HPE.
Assuntos
Elementos Facilitadores Genéticos , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Prosencéfalo/embriologia , Animais , Sistemas CRISPR-Cas , Proteínas do Olho/fisiologia , Técnicas de Inativação de Genes , Genes Reporter , Proteínas Hedgehog/biossíntese , Proteínas Hedgehog/genética , Holoprosencefalia/genética , Proteínas de Homeodomínio/fisiologia , Hipotálamo/anormalidades , Hipotálamo/embriologia , Hipotálamo/metabolismo , Óperon Lac , Mesencéfalo/embriologia , Mesencéfalo/metabolismo , Mesoderma/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Prosencéfalo/anormalidades , Prosencéfalo/metabolismo , Transdução de Sinais , Transgenes , Proteína Homeobox SIX3RESUMO
As a central feature of neuroinflammation, microglial dysfunction has been increasingly considered a causative factor of neurodegeneration implicating an intertwined pathology with amyloidogenic proteins. Herein, we report the smallest synthetic molecule (N,N'-diacetyl-p-phenylenediamine [DAPPD]), simply composed of a benzene ring with 2 acetamide groups at the para position, known to date as a chemical reagent that is able to promote the phagocytic aptitude of microglia and subsequently ameliorate cognitive defects. Based on our mechanistic investigations in vitro and in vivo, 1) the capability of DAPPD to restore microglial phagocytosis is responsible for diminishing the accumulation of amyloid-ß (Aß) species and significantly improving cognitive function in the brains of 2 types of Alzheimer's disease (AD) transgenic mice, and 2) the rectification of microglial function by DAPPD is a result of its ability to suppress the expression of NLRP3 inflammasome-associated proteins through its impact on the NF-κB pathway. Overall, our in vitro and in vivo investigations on efficacies and molecular-level mechanisms demonstrate the ability of DAPPD to regulate microglial function, suppress neuroinflammation, foster cerebral Aß clearance, and attenuate cognitive deficits in AD transgenic mouse models. Discovery of such antineuroinflammatory compounds signifies the potential in discovering effective therapeutic molecules against AD-associated neurodegeneration.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Cognição/efeitos dos fármacos , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fagocitose/efeitos dos fármacos , Fenilenodiaminas/farmacologia , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Anti-Inflamatórios/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/genética , Aprendizagem em Labirinto , Camundongos , Camundongos Transgênicos , Microglia/fisiologia , Estrutura Molecular , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Fármacos Neuroprotetores/uso terapêutico , Fragmentos de Peptídeos/genética , Fenilenodiaminas/química , Fenilenodiaminas/uso terapêutico , Presenilina-1/genética , Memória Espacial/efeitos dos fármacosRESUMO
Obviously, opiates (e.g., morphine) are associated with the suppression and dysfunction of reproductive axis. It has been reported that substance P (SP) and RF-amid-related peptide-3 (RFRP-3) can exhibit anti-opioid effects in some regions of the nervous system. Moreover, SP and RFRP-3 are deemed as neuropeptides which exert modulatory and regulatory impacts on the function of the reproductive axis. The precise interactions of morphine with SP or RFRP-3 on the parameters of the reproductive activity, however, are not fully known. The present study was aimed to determine the impacts of the interaction of morphine either with SP or RFRP-3 on the hormonal and behavioral parameters of reproductive activity in male rats. In addition, it was aimed at determining whether the effects of these interactions rely on kisspeptin/G protein coupled receptor 54 (GPR54) pathway as the main upstream pulse generator and the mediator of the function of many inputs of gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) system or not. Altogether, the resulted data from the sexual behavior tests, radioimmunoassay of LH/testosterone, and real-time quantitative PCR for the assessment of the expression of hypothalamic Kiss1, Gpr54, and Gnrh1 genes following concomitant administration of morphine with SP or RFRP-3 revealed that the suppressing effects of morphine on the parameters of reproductive axis activity can be affected by the administration of either RFRP-3 or SP. It is advocated that SP and RFRP-3, by the modulation of the expression of hypothalamic Kiss1, can possibly antagonize the effects of morphine on GnRH/LH system and sexual behavior.
Assuntos
Hipotálamo/efeitos dos fármacos , Kisspeptinas/fisiologia , Morfina/farmacologia , Proteínas do Tecido Nervoso/fisiologia , Neuropeptídeos/farmacologia , Receptores de Kisspeptina-1/fisiologia , Comportamento Sexual Animal/efeitos dos fármacos , Substância P/farmacologia , Animais , Interações Medicamentosas , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/biossíntese , Hormônio Liberador de Gonadotropina/genética , Hormônio Liberador de Gonadotropina/fisiologia , Hipotálamo/metabolismo , Kisspeptinas/biossíntese , Kisspeptinas/genética , Hormônio Luteinizante/fisiologia , Masculino , Naloxona/farmacologia , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Precursores de Proteínas/biossíntese , Precursores de Proteínas/genética , RNA Mensageiro/biossíntese , Ratos , Ratos Wistar , Receptores de Kisspeptina-1/biossíntese , Receptores de Kisspeptina-1/genética , Transdução de Sinais/fisiologiaRESUMO
Glutamatergic excitotoxicity is crucial in the pathogenesis of epileptic seizures. Dexmedetomidine, a potent and highly selective α2 adrenoceptor agonist, inhibits glutamate release from nerve terminals in rat cerebrocortical nerve terminals. However, the ability of dexmedetomidine to affect glutamate-induced brain injury is still unknown. Therefore, the present study evaluated the protective effect of dexmedetomidine against brain damage by using a kainic acid (KA) rat model, a frequently used model for temporal lobe epilepsy. Rats were treated with dexmedetomidine (1 or 5 µg/kg, intraperitoneally) 30â¯min before the KA (15â¯mg/kg) intraperitoneal injection. KA-induced seizure score and elevations of glutamate release in rat hippocampi were inhibited by pretreatment with dexmedetomidine. Histopathological and TUNEL staining analyzes showed that dexmedetomidine attenuated KA-induced neuronal death in the hippocampus. Dexmedetomidine ameliorated KA-induced apoptosis, and this neuroprotective effect was accompanied by inhibited the KA-induced caspase-3 expression as well as MAPKs phosphorylation, and reversed Bcl-2 down-expression, coupled with increased Nrf2, BDNF and TrkB expression in KA-treated rats. The results suggest that dexmedetomidine protected rat brains from KA-induced excitotoxic damage by reducing glutamate levels, suppressing caspase-3 activation and MAPKs phosphorylation, and enhancing Bcl-2, Nrf2, BDNF and TrkB expression in the hippocampus. Therefore, dexmedetomidine may be beneficial for preventing or treating brain disorders associated with excitotoxic neuronal damage. In conclusion, these data suggest that dexmedetomidine has the therapeutic potential for treating epilepsy.
Assuntos
Anticonvulsivantes/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/agonistas , Dexmedetomidina/uso terapêutico , Ácido Glutâmico/metabolismo , Hipocampo/efeitos dos fármacos , Ácido Caínico/antagonistas & inibidores , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Convulsões/prevenção & controle , Animais , Anticonvulsivantes/farmacologia , Apoptose/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Fator Neurotrófico Derivado do Encéfalo/genética , Dexmedetomidina/farmacologia , Avaliação Pré-Clínica de Medicamentos , Hipocampo/fisiopatologia , Ácido Caínico/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Fator 2 Relacionado a NF-E2/biossíntese , Fator 2 Relacionado a NF-E2/genética , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Neurônios/fisiologia , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor trkB/biossíntese , Receptor trkB/genética , Convulsões/induzido quimicamenteRESUMO
Depression is one of the most prevalent and crucial public health problem connected to significant mortality and co-morbidity. Recently, numerous studies suggested that dietary flavanones exhibit neuroprotective and antidepressant effects against various psycho-physiological conditions including depression. The present study is focused on the antidepressant and neuroprotective effects of naringenin (NAR) and the involvement of sonic hedgehog (Shh) signaling in the chronic unpredictable mild stress (CUMS)-induced depression. Twenty-four male Wistar rats were randomly assigned into four groups: CON group (saline s.c.), NAR group (NAR 50 mg/kg, p.o.), CUMS group (subjected to CUMS along with saline p.o.), and CUMS + NAR group (NAR 50 mg/kg p.o. along with CUMS) for 28 days including 1-week pre-treatment with NAR. The results showed that NAR was found to inhibit behavioral abnormalities including increased despair in force swim test, and reduced locomotor activity caused by CUMS in open field test. Moreover, Morris water maze revealed that NAR also mitigates CUMS-associated cognitive impairment. In addition to the antidepressant-like effect, NAR mitigates morphological anomalies in the hippocampal CA1 region and cortex. Furthermore, we observed brain-derived neurotrophic factor (BDNF), Shh, GLI1, NKX2.2, and PAX6 were downregulated in the hippocampus of CUMS-exposed rats, which can be upregulated by NAR pre-treatment. GLI1 is main downstream signaling component of Shh signaling cascade, which further regulates the expression of homeodomain transcription factors PAX6 and NKX2.2.
Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Flavanonas/uso terapêutico , Proteínas Hedgehog/fisiologia , Deficiências da Aprendizagem/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Proteína GLI1 em Dedos de Zinco/fisiologia , Animais , Antidepressivos/farmacologia , Doença Crônica , Depressão/etiologia , Depressão/metabolismo , Depressão/prevenção & controle , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Comportamento Exploratório/efeitos dos fármacos , Flavanonas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/química , Hipocampo/efeitos dos fármacos , Proteína Homeobox Nkx-2.2 , Deficiências da Aprendizagem/etiologia , Deficiências da Aprendizagem/metabolismo , Deficiências da Aprendizagem/prevenção & controle , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Transtornos da Memória/prevenção & controle , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Fármacos Neuroprotetores/farmacologia , Distribuição Aleatória , Ratos , Ratos Wistar , Estresse Psicológico/fisiopatologia , NataçãoRESUMO
Resveratrol (3,5,4'-trihydroxy-trans-stilbene) (RES) is a naturally-derived phytoestrogen found in the skins of red grapes and berries and has potential as a novel and effective therapeutic agent. In the current study, we investigated the role of microRNA (miRNA) in RES-mediated attenuation of experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis. Administration of RES effectively decreased disease severity, including inflammation and central nervous system immune cell infiltration. miRNA microarray analysis revealed an altered miRNA profile in encephalitogenic CD4+ T cells from EAE mice exposed to RES treatment. Additionally, bioinformatics and in silico pathway analysis suggested the involvement of RES-induced miRNA in pathways and processes that regulated cellular proliferation. Additional studies confirmed that RES affected cell cycle progression and apoptosis in activated T cells, specifically in the brain. RES treatment significantly upregulated miR-124 during EAE, while suppressing associated target gene, sphingosine kinase 1 (SK1), and this too was specific to mononuclear cells in the brains of treated mice, as peripheral immune cells remained unaltered upon RES treatment. Collectively, these studies demonstrate that RES treatment leads to amelioration of EAE development through mechanism(s) potentially involving suppression of neuroinflammation via alteration of the miR-124/SK1 axis, thereby halting cell-cycle progression and promoting apoptosis in activated encephalitogenic T cells. Graphical Abstract Resveratrol alters the miR-124/sphingosine kinase 1 (SK1) axis in encephalitogenic T cells, promotes cell-cycle arrest and apoptosis, and decreases neuroinflammation in experiemental autoimmune encephalomyelitis (EAE).
Assuntos
Encéfalo/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Encefalomielite Autoimune Experimental/tratamento farmacológico , MicroRNAs/biossíntese , Proteínas do Tecido Nervoso/biossíntese , Fosfotransferases (Aceptor do Grupo Álcool)/biossíntese , Resveratrol/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Subpopulações de Linfócitos T/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Encéfalo/imunologia , Linfócitos T CD4-Positivos/metabolismo , Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Encefalomielite Autoimune Experimental/metabolismo , Indução Enzimática/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/fisiologia , Microglia/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/fisiologia , Resveratrol/farmacologia , Subpopulações de Linfócitos T/metabolismoRESUMO
Histone acetylation is a key regulatory factor for gene expression in cells. Modulation of histone acetylation by targeting of histone acetyltransferases (HATs) effectively alters many gene expression profiles and synaptic plasticity in the brain. However, the role of HATs on L-DOPA-induced dyskinesia of Parkinson's disease (PD) has not been reported. Our aim was to determine whether HAT inhibitors such as anacardic acid, garcinol, and curcumin from natural plants reduce severity of L-DOPA-induced dyskinesia using a unilaterally 6-hydroxydopamine (6-OHDA)-lesioned PD mouse model. Anacardic acid 2 mg/kg, garcinol 5 mg/kg, or curcumin 100 mg/kg co-treatment with L-DOPA significantly reduced the axial, limb, and orofacial (ALO) score indicating less dyskinesia with administration of HAT inhibitors in 6-OHDA-lesioned mice. Additionally, L-DOPA's efficacy was not altered by the compounds in the early stage of treatment. The expression levels of c-Fos, Fra-2, and Arc were effectively decreased by administration of HAT inhibitors in the ipsilateral striatum. Our findings indicate that HAT inhibitor co-treatment with L-DOPA may have therapeutic potential for management of L-DOPA-induced dyskinesia in patients with PD.
Assuntos
Ácidos Anacárdicos/uso terapêutico , Antiparkinsonianos/toxicidade , Curcumina/uso terapêutico , Discinesia Induzida por Medicamentos/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Histona Acetiltransferases/antagonistas & inibidores , Levodopa/toxicidade , Transtornos Parkinsonianos/tratamento farmacológico , Terpenos/uso terapêutico , Ácidos Anacárdicos/farmacologia , Animais , Curcumina/farmacologia , Proteínas do Citoesqueleto/biossíntese , Proteínas do Citoesqueleto/genética , Avaliação Pré-Clínica de Medicamentos , Discinesia Induzida por Medicamentos/etiologia , Discinesia Induzida por Medicamentos/genética , Inibidores Enzimáticos/farmacologia , Antígeno 2 Relacionado a Fos/biossíntese , Antígeno 2 Relacionado a Fos/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Código das Histonas/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Oxidopamina/toxicidade , Proteínas Proto-Oncogênicas c-fos/biossíntese , Proteínas Proto-Oncogênicas c-fos/genética , Organismos Livres de Patógenos Específicos , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Terpenos/farmacologiaRESUMO
Our previous studies demonstrated that the multifunctional agent TBN, a derivative of tetramethylpyrazine armed with a nitrone moiety, displayed high therapeutic efficacy in experimental ischemic stroke models. However, its molecular mechanisms of action underlying the neuroprotective effect need further exploration. In the present study, we found that TBN had significant activities scavenging free radicals such as ·OH, O 2·- and ONOO-, inhibiting Ca2+ overload, maintaining mitochondrial function and preventing neuronal damage in primary cortical cultures. Further, TBN was effective in reducing brain infarction and ameliorating impairment of behavioral functions in the permanent middle cerebral artery occlusion (p-MCAo) rat model. TBN down-regulated the expression of pro-apoptotic factors Bax, while up-regulated the expression of anti-apoptotic factor Bcl-2 and increased the expression of pro-survival factors including p-Akt and p-GSK3ß in the peri-infarct cortex of p-MCAo rats. In addition, LY-294002 (a PI3K inhibitor) and MK2206 (an Akt inhibitor) significantly blocked the protective effect of TBN against OGD-induced death of cortical neurons. Taken together, the multifunctional mechanisms including scavenging free radicals, blocking calcium overload, maintaining mitochondrial function and activating the PI3K/Akt/p-GSK3ß cell survival pathway were possibly involved in the neuroprotective effects of TBN, making it a promising clinical candidate for the treatment of ischemic stroke.
Assuntos
Infarto da Artéria Cerebral Média/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Óxidos de Nitrogênio/uso terapêutico , Pirazinas/uso terapêutico , Animais , Proteínas Reguladoras de Apoptose/biossíntese , Proteínas Reguladoras de Apoptose/genética , Cálcio/metabolismo , Hipóxia Celular , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Sequestradores de Radicais Livres/farmacologia , Sequestradores de Radicais Livres/uso terapêutico , Glucose/farmacologia , Ácido Glutâmico/toxicidade , Infarto da Artéria Cerebral Média/prevenção & controle , Peroxidação de Lipídeos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Atividade Motora/efeitos dos fármacos , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Fármacos Neuroprotetores/farmacologia , Óxidos de Nitrogênio/farmacologia , Técnicas de Patch-Clamp , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacosRESUMO
Dietary administration of orotic acid (OA), an intermediate in the pyrimidine biosynthetic pathway, is considered to provide a wide range of beneficial effects, including cardioprotection and exercise adaptation. Its mechanisms of action, when applied extracellularly, however, are barely understood. In this study, we evaluated potential effects of OA on skeletal muscle using an in vitro contraction model of electrically pulse-stimulated (EPS) C2C12 myotubes. By analyzing a subset of genes representing inflammatory, metabolic, and structural adaptation pathways, we could show that OA supplementation diminishes the EPS-provoked expression of inflammatory transcripts (interleukin 6, Il6; chemokine (C-X-C Motif) ligand 5, Cxcl5), and attenuated transcript levels of nuclear receptor subfamily 4 group A member 3 (Nr4A3), early growth response 1 (Egr1), activating transcription factor 3 (Atf3), and fast-oxidative MyHC-IIA isoform (Myh2). By contrast, OA had no suppressive effect on the pathogen-provoked inflammatory gene response in skeletal muscle cells, as demonstrated by stimulation of C2C12 myotubes with bacterial LPS. In addition, we observed a suppressive effect of OA on EPS-induced phosphorylation of AMP-activated protein kinase (AMPK), whereas EPS-triggered phosphorylation/activation of the mammalian target of rapamycin (mTOR) was not affected. Finally, we demonstrate that OA positively influences glycogen levels in EP-stimulated myotubes. Taken together, our results suggest that in skeletal muscle cells, OA modulates both the inflammatory and the metabolic reaction provoked by acute contraction. These results might have important clinical implications, specifically in cardiovascular and exercise medicine.
Assuntos
Contração Muscular/efeitos dos fármacos , Mioblastos Esqueléticos/metabolismo , Ácido Orótico/farmacologia , Fator 3 Ativador da Transcrição/biossíntese , Animais , Quimiocina CXCL5/biossíntese , Proteínas de Ligação a DNA/biossíntese , Proteína 1 de Resposta de Crescimento Precoce/biossíntese , Estimulação Elétrica , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-6/biossíntese , Camundongos , Mioblastos Esqueléticos/citologia , Proteínas do Tecido Nervoso/biossíntese , Receptores de Esteroides/biossíntese , Receptores dos Hormônios Tireóideos/biossíntese , Serina-Treonina Quinases TOR/biossínteseRESUMO
Acute inflammation can exacerbate brain injury after ischemic stroke. Beyond its well-characterized role in calcium metabolism, it is becoming increasingly appreciated that the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25-VitD3), has potent immunomodulatory properties. Here, we aimed to determine whether 1,25-VitD3 supplementation could reduce subsequent brain injury and associated inflammation after ischemic stroke. Male C57Bl6 mice were randomly assigned to be administered either 1,25-VitD3 (100 ng/kg/day) or vehicle i.p. for 5 day prior to stroke. Stroke was induced via middle cerebral artery occlusion for 1 h followed by 23 h reperfusion. At 24 h post-stroke, we assessed infarct volume, functional deficit, expression of inflammatory mediators and numbers of infiltrating immune cells. Supplementation with 1,25-VitD3 reduced infarct volume by 50% compared to vehicle. Expression of pro-inflammatory mediators IL-6, IL-1ß, IL-23a, TGF-ß and NADPH oxidase-2 was reduced in brains of mice that received 1,25-VitD3 versus vehicle. Brain expression of the T regulatory cell marker, Foxp3, was higher in mice supplemented with 1,25-VitD3 versus vehicle, while expression of the transcription factor, ROR-γ, was decreased, suggestive of a reduced Th17/γδ T cell response. Immunohistochemistry indicated that similar numbers of neutrophils and T cells were present in the ischemic hemispheres of 1,25-VitD3- and vehicle-supplemented mice. At this early time point, there were also no differences in the impairment of motor function. These data indicate that prior administration of exogenous vitamin D, even to vitamin D-replete mice, can attenuate infarct development and exert acute anti-inflammatory actions in the ischemic and reperfused brain.
Assuntos
Encéfalo/efeitos dos fármacos , Colecalciferol/uso terapêutico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Animais , Encéfalo/patologia , Colecalciferol/farmacologia , Citocinas/biossíntese , Citocinas/genética , Fatores de Transcrição Forkhead/biossíntese , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Inflamação , Mediadores da Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Fármacos Neuroprotetores/farmacologia , Infiltração de Neutrófilos/efeitos dos fármacos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/biossíntese , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/metabolismoRESUMO
Autism is a neurodevelopmental disorder characterized by deficits in qualitative impairments in communication, repetitive and social interaction, restricted, and stereotyped patterns of behavior. Resveratrol has been extensively studied pharmacologically and biologically and has anti-inflammatory, antioxidant, and neuroprotective effects on neuronal damage in neurodegenerative disorders. The BTBR T+ Itpr3tf/J (BTBR) autistic mouse model has been explored for treatment of autism, which shows low reciprocal social interactions, impaired juvenile play, and decreased social approach. Here, we explored whether resveratrol treatment decreases neuroimmune dysregulation mediated through toll-like receptor (TLR4) and nuclear factor-κB (NF-κB) signaling pathway in BTBR mice. We investigated the effect of resveratrol treatment on TLR2, TLR3, TLR4, NF-κB, and inducible nitric oxide synthase (iNOS or NOS2) levels in CD4 spleen cells. We also assessed the effect of resveratrol treatment on TLR2, TLR3, TLR4, NF-κB, iNOS, and cyclooxygenase (COX-2) mRNA expression levels in the brain tissue. We further explored TLR2, TLR4, NF-κB, iNOS, and COX-2 protein expression levels in the brain tissue. Resveratrol treatment on BTBR mice significantly decreased CD4+TLR2+, CD4+TLR3+, CD4+TLR4+ CD4+NF-κB+, and CD4+iNOS+ levels in spleen cells. Resveratrol treatment on BTBR mice decreased TLR2, TLR3, TLR4, NF-κB, iNOS, and COX-2 mRNA expression levels in brain tissue. Moreover, resveratrol treatment resulted in decreased protein expression of TLR2, TLR3, TLR4, NF-κB, iNOS, and COX-2 in brain tissue. Taken together, these results indicate that resveratrol treatment improves neuroimmune dysregulation through the inhibition of proinflammatory mediators and TLRs/NF-κB transcription factor signaling, which might be help devise future therapies for neuroimmune disorders.
Assuntos
Transtorno Autístico/tratamento farmacológico , Ciclo-Oxigenase 2/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Óxido Nítrico Sintase Tipo II/fisiologia , Resveratrol/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Receptores Toll-Like/fisiologia , Animais , Transtorno Autístico/metabolismo , Química Encefálica/efeitos dos fármacos , Células Cultivadas , Ciclo-Oxigenase 2/biossíntese , Ciclo-Oxigenase 2/genética , Avaliação Pré-Clínica de Medicamentos , Receptores de Inositol 1,4,5-Trifosfato , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes Neurológicos , NF-kappa B/fisiologia , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico Sintase Tipo II/biossíntese , Óxido Nítrico Sintase Tipo II/genética , Especificidade de Órgãos , Resveratrol/farmacologia , Baço , Receptores Toll-Like/biossíntese , Receptores Toll-Like/genéticaRESUMO
BACKGROUND AND OBJECTIVE: Teucrium polium Lamiaceae. an antidiabetic traditional medicine was observed to stimulate insulin secretion and ß-cell mass restoration in pancreatic of diabetic rats. Bioactive compounds in T. polium such as terpenoids and flavonoids have a wide range of antioxidant properties. Given this background, our research was aimed at probing the effective molecular mechanism of T. polium which in turn protects the pancreatic ß-cells of diabetic rats through attenuation of streptozotocin-induced oxidative stress. MATERIALS AND METHODS: Induction of diabetes by streptozotocin (STZ) injection followed by treatment of the rats with T. polium extract (0.5g/kg) and glibenclamide as a standard drug (600µg/kg) for six consecutive weeks. Besides, biochemical indexes including sera glucose and lipids were investigated once every two weeks. Moreover, oxidative stress markers were also measured in the sixth week of treatment to assess the antioxidant capacity of T. polium. Prior to sacrifice of rats, the oral glucose tolerance test was carried out and thereafter western blot analysis was performed on pancreatic tissues to detect the expression of JNK, FoxO1 and Pdx1 proteins in the experimental groups. RESULTS: Oral administration of T. polium extract not only disclosed the significant anti-hyperglycemic potential of the plant, but also relieved dyslipidemia and oxidative stress related to diabetes. Furthermore, remarkable improvement of glucose tolerance was exhibited among the treated groups, confirming the presence of insulin in the blood. Subsequently, the effective molecular mechanism of T. polium was partially revealed by western blot analyses which detected considerable up-regulation of p-FoxO1 and Pdx1 proteins parallel to reduction of p-JNK expression among the treated diabetic rats. CONCLUSION: This study demonstrates that T. polium extract is able to restore the ß-cell mass and insulin secretion by regulation of pivotal transcription factor of the pancreatic ß-cells Pdx1 in JNK pathway.