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1.
Chem Biol Interact ; 315: 108908, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31778666

RESUMO

Alzheimer's disease (AD), the most common form of dementia, is a neurodegenerative disease characterized by neuronal atrophy in various brain regions. The expression of miR-107 is down-regulated in AD patients and target genes of miR-107 have been shown to directly involved in AD. In this study, we aimed to investigate the potential neuroprotective effects of miR-107. We first assessed brain activity in health controls and patients with AD. Then we examined miR-107 expression in SH-SY5Y and PC12 cells treated with 6-hydroxydopamine (6-OHDA), and investigated its function in cytotoxicity induced by 6-OHDA. We predicted a potential miR-107 target and assessed its role in miR-107 mediated effects and explored the intracellular signaling pathways downstream of miR-107. Finally, we assessed the function of miR-107 in the mouse model insulted by 6-OHDA. We found that 6-OHDA suppressed miR-107 expression and miR-107 played neuroprotective effects against 6-OHDA mediated cytotoxicity. We showed that miR-107 targeted programmed cell death 10 (PDCD10). MiR-107 suppressed PDCD10 expression and exogenous expression of PDCD10 inhibited miR-107 mediated neuroprotection. Additionally, we found that Notch signal pathway was downstream of miR-107/PDCD10. Finally, we found that 6-OHDA treatment suppressed miR-107 in mice and restoration of miR-107 alleviated motor disorder in the mouse model. Our study shows that miR-107 plays important neuroprotective roles against neurotoxicity both in vitro and in vivo by inhibiting PDCD10. Our findings confirm that miR-107 may be involved in AD pathogenesis and may be a therapeutic target for the treatment of AD-related impairments.


Assuntos
Encéfalo/metabolismo , MicroRNAs/metabolismo , Neurônios/metabolismo , Síndromes Neurotóxicas/metabolismo , Oxidopamina/farmacologia , Doença de Alzheimer/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Encéfalo/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Camundongos , Neurônios/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Células PC12 , Ratos , Transdução de Sinais/efeitos dos fármacos
2.
J Surg Res ; 246: 6-18, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31541709

RESUMO

BACKGROUND: Remote ischemic postconditioning (RIPost) has been shown to reduce the ischemia-reperfusion injury of the heart and brain. However, the protection mechanisms have not yet been fully elucidated. We have observed that RIPost could alleviate the brain injury after cardiac arrest (CA). The aim of this study was to explore whether α7 nicotinic acetylcholine receptor (α7nAChR) mediates the neuroprotection of RIPost in a rat model of asphyxial CA. MATERIALS AND METHODS: Asphyxial CA model was induced by occlusion of the tracheal tube for 8 min and resuscitated later. RIPost produced by three cycles of 15-min occlusion and 15-min release of the right hind limb by a tourniquet was performed respectively at the moment and the third hour after restoration of spontaneous circulation. The α7nAChR agonist PHA-543613 and the antagonist methyllycaconitine (MLA) were used to investigate the role of α7nAChR in mediating neuroprotective effects. RESULTS: Results showed that α7nAChR was decreased in hippocampus and cortex after resuscitation, whereas RIPost could attenuate the reduction. The use of PHA-543613 provided neuroprotective effects against cerebral injury after CA. Furthermore, RIPost decreased the levels of neuron-specific enolase, inflammatory mediators, the number of apoptotic cells, and phosphorylation of nuclear factor-κB while increased the phosphorylation of signal transducer and activator of transcription-3. However, the above effects of RIPost were attenuated by α7nAChR antagonist methyllycaconitine. CONCLUSIONS: Neuroprotection of RIPost was related with the activation of α7nAChR, which could suppress nuclear factor-κB and activate signal transducer and activator of transcription-3 in a rat asphyxial CA model.


Assuntos
Parada Cardíaca/terapia , Hipóxia Encefálica/terapia , Pós-Condicionamento Isquêmico , Neuroproteção/fisiologia , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Aconitina/análogos & derivados , Aconitina/farmacologia , Animais , Asfixia/complicações , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Modelos Animais de Doenças , Parada Cardíaca/etiologia , Hipocampo/irrigação sanguínea , Hipocampo/patologia , Humanos , Hipóxia Encefálica/etiologia , Hipóxia Encefálica/patologia , Masculino , NF-kappa B/metabolismo , Neuroproteção/efeitos dos fármacos , Quinuclidinas/farmacologia , Ratos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Resultado do Tratamento , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidores
3.
Life Sci ; 238: 116956, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31622607

RESUMO

AIMS: The aim of our study was to study the pathological mechanisms induced by the rheumatoid arthritis (RA) on the Enteric Nervous System (ENS). MAIN METHODS: We evaluated the effect of the chronic arthritis and its treatment with 50 mg/kg quercetin alone (AQ) and combined with 17.5 mg/kg ibuprofen (AIQ) for 60 days on neurons, glial cells and intestinal wall. Other groups were used: control (C), arthritic (A) and arthritic treated with 17.5 mg/kg ibuprofen (AI). After 60 days, the jejunum was removed and processed for immunohistochemical techniques. Immunostainings were performed for HuC/D and S100 (myenteric and submucosal plexuses), and GFAP (only myenteric plexus), while immunolabeling for CD45 and CD20 lymphocytes was performed using cryosections. Western blot was performed for GDNF, S100 and GFAP. KEY FINDINGS: A group yielded a remarkable density decrease of the neurons and glial cells with morphometric changes in the myenteric and submucosal plexuses, reduction of the GDNF expression and GFAP-related parameters (GFAP expression, occupancy area and GFAP-expressing glial cells) and intestinal inflammation and atrophy of the mucosa and intestinal wall. AQ group substantially reversed most of these effects, except for intestinal atrophy of the jejunum. The AI and AIQ groups displayed lower beneficial results than AQ for parameters related to the neurons and glial cells, although AIQ did not prevent the inflammation of the mucosa. SIGNIFICANCE: The severe chronic rheumatoid arthritis induced severe effects on ENS and mucosa, and quercetin treatment continues to be an important antioxidant supplement preventing the progression of the RA severity.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Experimental/complicações , Artrite Reumatoide/complicações , Inflamação/tratamento farmacológico , Jejuno/efeitos dos fármacos , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Quercetina/farmacologia , Animais , Antioxidantes/farmacologia , Artrite Experimental/induzido quimicamente , Sistema Nervoso Entérico/efeitos dos fármacos , Sistema Nervoso Entérico/patologia , Inflamação/etiologia , Inflamação/patologia , Jejuno/imunologia , Jejuno/patologia , Masculino , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/patologia , Neuroproteção/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
4.
Endocr Regul ; 53(1): 14-25, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31517620

RESUMO

OBJECTIVE: Diabetes induces sensory symptoms of neuropathy as positive (hyperalgesia), negative (hypoalgesia), or both. METHODS: In the present study, fifty male Wistar rats were allocated to five groups: control, control+nitrate, diabetes, diabetes+insulin, and diabetes+nitrate. Thirty days after diabetes confirmation, insulin (2-4 U/day) was injected subcutaneously in diabetes+insulin group and nitrate (100 mg/l) was added into drinking water of the control+nitrate and diabetes+nitrate groups for a period of 2 months. In order to assess the mechanical and thermal algesia, tail immersion, hot plate, and von Frey tests were performed. The serum insulin levels were determined with insulin ELISA Kit. Serum level of NOx was determined by the Griess method. RESULTS: Both thermal and mechanical nociceptive thresholds showed a significant decrease (p<0.05) which was followed by a significant increase (p<0.01) in the thermal nociceptive threshold in the diabetes group. Chronic nitrate or insulin treatment led to a significant decrease (p<0.01) in blood glucose levels, as well as a significant (p<0.05) increase in the body weight and serum NOx. Moreover, nitrate treatment significantly increased serum insulin levels (p<0.001) compared to the other groups. CONCLUSION: Chronic nitrate treatment modified the thermal and mechanical sensitivities in diabetic animals.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Nitratos/farmacologia , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Neuropatias Diabéticas/patologia , Avaliação Pré-Clínica de Medicamentos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Hiperalgesia/patologia , Masculino , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Nitratos/uso terapêutico , Nociceptividade/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Wistar , Estreptozocina
5.
ACS Appl Mater Interfaces ; 11(40): 36307-36315, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31513373

RESUMO

Molecular mobility in neuronal plasma membranes is a crucial factor in brain function. Microscopic viscosity is an important parameter that determines molecular mobility. This study presents the first direct measurement of the microviscosity of plasma membranes of live neurons. Microviscosity maps were obtained using fluorescence lifetime imaging of environment-sensing dyes termed "molecular rotors". Neurons were investigated both in the basal state and following common neurodegenerative stimuli, excitotoxicity, or oxidative stress. Both types of neurotoxic challenges induced microviscosity decrease in cultured neurons, and oxidant-induced membrane fluidification was counteracted by the wide-spectrum neuroprotectant, the H3 peptide. These results provide new insights into molecular mobility in neuronal membranes, paramount for basic brain function, and suggest that preservation of membrane stability may be an important aspect of neuroprotection in brain insults and neurodegenerative disorders.


Assuntos
Membrana Celular/fisiologia , Corantes Fluorescentes/metabolismo , Neurônios/citologia , Neuroproteção , Estresse Oxidativo , Animais , Compostos de Boro/química , Membrana Celular/efeitos dos fármacos , Corantes Fluorescentes/química , Células HeLa , Humanos , Peróxido de Hidrogênio/toxicidade , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fenômenos Ópticos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Viscosidade
6.
Int J Mol Sci ; 20(18)2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31540405

RESUMO

Compelling evidence from preclinical and clinical studies has shown that mild hypothermia is neuroprotective against ischemic stroke. We investigated the neuroprotective effect of post-risperidone (RIS) treatment against transient ischemic injury and its mechanisms in the gerbil brain. Transient ischemia (TI) was induced in the telencephalon by bilateral common carotid artery occlusion (BCCAO) for 5 min under normothermic condition (37 ± 0.2 °C). Treatment of RIS induced hypothermia until 12 h after TI in the TI-induced animals under uncontrolled body temperature (UBT) compared to that under controlled body temperature (CBT) (about 37 °C). Neuroprotective effect was statistically significant when we used 5 and 10 mg/kg doses (p < 0.05, respectively). In the RIS-treated TI group, many CA1 pyramidal neurons of the hippocampus survived under UBT compared to those under CBT. In this group under UBT, post-treatment with RIS to TI-induced animals markedly attenuated the activation of glial cells, an increase of oxidative stress markers [dihydroethidium, 8-hydroxy-2' -deoxyguanosine (8-OHdG), and 4-Hydroxynonenal (4-HNE)], and a decrease of superoxide dismutase 2 (SOD2) in their CA1 pyramidal neurons. Furthermore, RIS-induced hypothermia was significantly interrupted by NBOH-2C-CN hydrochloride (a selective 5-HT2A receptor agonist), but not bromocriptine mesylate (a D2 receptor agonist). Our findings indicate that RIS-induced hypothermia can effectively protect neuronal cell death from TI injury through attenuation of glial activation and maintenance of antioxidants, showing that 5-HT2A receptor is involved in RIS-induced hypothermia. Therefore, RIS could be introduced to reduce body temperature rapidly and might be applied to patients for hypothermic therapy following ischemic stroke.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Risperidona/uso terapêutico , Animais , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Gerbillinae , Hipocampo/metabolismo , Hipocampo/patologia , Hipotermia/induzido quimicamente , Hipotermia Induzida/métodos , Masculino , Estresse Oxidativo/efeitos dos fármacos
7.
Br J Anaesth ; 123(5): 601-609, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31470983

RESUMO

BACKGROUND: Noble gases may provide novel treatments for neurological injuries such as ischaemic and traumatic brain injury. Few studies have evaluated the complete series of noble gases under identical conditions in the same model. METHODS: We used an in vitro model of hypoxia-ischaemia to evaluate the neuroprotective properties of the series of noble gases, helium, neon, argon, krypton, and xenon. Organotypic hippocampal brain slices from mice were subjected to oxygen-glucose deprivation, and injury was quantified using propidium iodide fluorescence. RESULTS: Both xenon and argon were equally effective neuroprotectants, with 0.5 atm of xenon or argon reducing injury by 96% (P<0.0001), whereas helium, neon, and krypton were devoid of any protective effect. Neuroprotection by xenon, but not argon, was reversed by elevated glycine. CONCLUSIONS: Xenon and argon are equally effective as neuroprotectants against hypoxia-ischaemia in vitro, with both gases preventing injury development. Although xenon's neuroprotective effect may be mediated by inhibition of the N-methyl-d-aspartate receptor at the glycine site, argon acts via a different mechanism. These findings may have important implications for their clinical use as neuroprotectants.


Assuntos
Argônio/farmacologia , Hipocampo/efeitos dos fármacos , Hipóxia-Isquemia Encefálica/prevenção & controle , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Xenônio/farmacologia , Animais , Modelos Animais de Doenças , Feminino , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos
8.
Mol Med Rep ; 20(4): 3942-3950, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31485662

RESUMO

Intracarotid cold saline infusion (ICSI) brings about neuroprotective effects in ischemic stroke. However, the involvement of serum and glucocorticoid­regulated kinase 1 (SGK1) in the underlying mechanism of ICSI is not fully understood; therefore, we used the rat middle cerebral artery occlusion (MCAO) model to investigate the neuroprotective effects of ICSI on ischemic stroke in rats, as well as the involvement of SGK1 in these effects. ICSI decreased infarct size and brain swelling, as determined by 2,3,5­triphenyltetrazolium chloride staining and the dry­wet weight method, respectively. The results of terminal deoxynucleotidyl transferase mediated nick end labeling (TUNEL) and Nissl staining showed that ICSI also suppressed apoptosis and increased the relative integral optical density (IOD) values of Nissl bodies in the rat MCAO model. Regarding the mechanism, the results of immunohistochemistry and western blotting revealed that ICSI upregulated SGK1 expression and downregulated beclin­1 and LC­3 expression in the rat MCAO model. In addition, SGK1 knockdown increased ICSI­mediated infarct size and brain swelling, promoted apoptosis, and reduced the IOD values of Nissl bodies in the rat MCAO model. In addition, we found that SGK1 knockdown upregulated beclin­1 and LC­3 expression mediated by ICSI. Overall, ICSI had a neuroprotective effect on ischemic stroke after reperfusion by upregulating SGK1 and inhibiting autophagy.


Assuntos
Proteínas Imediatamente Precoces/genética , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Proteínas Serina-Treonina Quinases/genética , Solução Salina/uso terapêutico , Regulação para Cima/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Edema Encefálico/tratamento farmacológico , Edema Encefálico/genética , Edema Encefálico/patologia , Temperatura Baixa , Proteínas Imediatamente Precoces/análise , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/patologia , Infusões Intra-Arteriais , Masculino , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Proteínas Serina-Treonina Quinases/análise , Interferência de RNA , Ratos , Ratos Sprague-Dawley , Solução Salina/administração & dosagem
9.
Food Chem Toxicol ; 133: 110755, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31408720

RESUMO

This study aimed to investigate the effects of Coriandrum sativum aqueous extract (CSAE) on the rat progeny of mothers exposed to methylmercury (MeHg). The presence of bioactive compounds and CSAE's antioxidant capacity been evaluated, and the offspring were assessed for their total mercury levels, motor behavioral parameters and oxidative stress in the cerebellum. The analysis of the bioactive compounds revealed significant amounts of polyphenols, flavonoids, and anthocyanins, as well as a variety of minerals. A DPPH test showed the CSAE had important antioxidant activity. The MeHg + CSAE group performed significantly better spontaneous locomotor activity, palmar grip strength, balance, and motor coordination in behavioral tests compared the MeHg group, as well as in the parameters of oxidative stress, with similar results to those of the control group. The MeHg + CSAE group also had significantly reduced mercury levels in comparison to the MeHg group. Based on the behavioral tests, which detected large locomotor, balance, and coordination improvements, as well as a reduction in oxidative stress, we conclude that CSAE had positive functional results in the offspring of rats exposed to MeHg.


Assuntos
Coriandrum/química , Intoxicação do Sistema Nervoso por Mercúrio/prevenção & controle , Compostos de Metilmercúrio/toxicidade , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Extratos Vegetais/uso terapêutico , Animais , Cerebelo/efeitos dos fármacos , Feminino , Peroxidação de Lipídeos/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Exposição Materna , Atividade Motora/efeitos dos fármacos , Transtornos dos Movimentos/prevenção & controle , Fármacos Neuroprotetores/isolamento & purificação , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Caules de Planta/química , Gravidez , Ratos , Espécies Reativas de Oxigênio/metabolismo
10.
AAPS PharmSciTech ; 20(7): 283, 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31407115

RESUMO

A redispersible spray-dried formulation containing curcumin-loaded, lipid-core nanocapsules (LNC-C) was developed for oral administration. The neuroprotective activity of curcumin after the spray-drying process was evaluated in vitro. The spray-dried powder (SD-LNC-C) was produced using a drying adjuvant composed of a blend of maltodextrin and L-leucine (90:10 w/w). Acceptable process yield (~ 70%) and drug content (6.5 ± 0.2 mg g-1) were obtained. SD-LNC-C was formed by smooth, spherical-shaped particles, and confocal Raman analysis indicated the distribution of the LNC-C on the surface of the leucine/maltodextrin agglomerates. The surface of the agglomerates was formed by a combination of LNC-C and adjuvants, and laser diffraction showed that SD-LNC-C had adequate aqueous redispersion, with no loss of controlled drug release behaviour of LNC-C. The in vitro curcumin activity against the lipopolysaccharide (LPS)-induced proinflammatory response in organotypic hippocampal slice cultures was evaluated. Both formulations (LNC-C and SD-LNC-C) reduced TNF-α to similar levels. Therefore, neuroprotection of curcumin in vitro may be improved by nanoencapsulation followed by spray-drying, with no loss of this superior performance. Hence, the redispersible spray-dried powder proposed here represents a suitable approach for the development of innovative nanomedicines containing curcumin for the prevention/treatment of neurodegenerative diseases.


Assuntos
Curcumina/farmacologia , Dessecação/métodos , Neuroproteção/efeitos dos fármacos , Administração Oral , Animais , Curcumina/administração & dosagem , Curcumina/química , Hipocampo/efeitos dos fármacos , Técnicas In Vitro , Masculino , Nanocápsulas , Tamanho da Partícula , Polissacarídeos/química , Pós , Ratos Wistar
11.
Acta Histochem ; 121(6): 732-741, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31270014

RESUMO

The aim of this study was to investigate neuroprotective effect of bradykinin postconditioning on the rabbit spinal cord after 20 min of ischemia and 3 days of reperfusion. Bradykinin was administered by single i.p. application at 1, 6, 12 or 24 h after ischemia. Assessment of neurological function of hind limbs (Tarlov score) was estimated. Quantitative analysis was evaluated by Fluoro Jade B method, NeuN and ubiquitin immunohistochemistry in anterior horn neurons of the spinal cord. Histomorphologically distribution of ubiquitin and endogenous antioxidant enzymes (SOD1, SOD2, catalase) immunoreaction was described. Bradykinin postconditioning showed decreased number of degenerated neurons, increased number of surviving neurons and increase in number of ubiquitin positive neurons in all bradykinin postconditioned groups versus ischemia/reperfusion group. According to our results bradykinin postconditioning applied 24 h after ischemia significantly decreased (p < 0.001) number of degenerated neurons versus ischemia/reperfusion group. The least effective time window for bradykinin postconditioning was at 12 h after ischemia. Tarlov score was significantly improved (p < 0.05) in groups with bradykinin postconditioning applied 1, 6 or 24 h after ischemia versus ischemia/reperfusion group. Tarlov score in group with bradykinin application 12 h after ischemia was significantly decreased (p < 0.05) versus sham control group. Neuronal immunoreaction of ubiquitin, SOD1, SOD2 and catalase influenced by bradykinin postconditioning was dependent on neuronal survival or degeneration. In conclusion, bradykinin postconditioning showed protective effect on neurons in anterior horns of the rabbit spinal cord and improved motor function of hind limbs.


Assuntos
Antioxidantes/metabolismo , Bradicinina/farmacologia , Catalase/metabolismo , Precondicionamento Isquêmico , Neuroproteção/efeitos dos fármacos , Medula Espinal/enzimologia , Superóxido Dismutase-1/metabolismo , Superóxido Dismutase/metabolismo , Ubiquitina/metabolismo , Animais , Masculino , Neurônios/enzimologia , Neurônios/patologia , Coelhos , Medula Espinal/patologia
12.
Biomed Res Int ; 2019: 6847685, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31360720

RESUMO

Xiaoxuming decoction (XXMD), a classic traditional Chinese medicine (TCM) prescription, has been used as a therapeutic in the treatment of stroke in clinical practice for over 1200 years. However, the pharmacological mechanisms of XXMD have not yet been elucidated. The purpose of this study was to develop neuroprotective models for identifying neuroprotective compounds in XXMD against hypoxia-induced and H2O2-induced brain cell damage. In this study, a phenotype-based classification method was designed by machine learning to identify neuroprotective compounds and to clarify the compatibility of XXMD components. Four different single classifiers (AB, kNN, CT, and RF) and molecular fingerprint descriptors were used to construct stacked naïve Bayesian models. Among them, the RF algorithm had a better performance with an average MCC value of 0.725±0.014 and 0.774±0.042 from 5-fold cross-validation and test set, respectively. The probability values calculated by four models were then integrated into a stacked Bayesian model. In total, two optimal models, s-NB-1-LPFP6 and s-NB-2-LPFP6, were obtained. The two validated optimal models revealed Matthews correlation coefficients (MCC) of 0.968 and 0.993 for 5-fold cross-validation and of 0.874 and 0.959 for the test set, respectively. Furthermore, the two models were used for virtual screening experiments to identify neuroprotective compounds in XXMD. Ten representative compounds with potential therapeutic effects against the two phenotypes were selected for further cell-based assays. Among the selected compounds, two compounds significantly inhibited H2O2-induced and Na2S2O4-induced neurotoxicity simultaneously. Together, our findings suggested that machine learning algorithms such as combination Bayesian models were feasible to predict neuroprotective compounds and to preliminarily demonstrate the pharmacological mechanisms of TCM.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Aprendizado de Máquina , Medicina Tradicional Chinesa/estatística & dados numéricos , Algoritmos , Teorema de Bayes , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Humanos , Peróxido de Hidrogênio/química , Neuroproteção/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/epidemiologia
13.
Mol Cell Biochem ; 461(1-2): 81-89, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31342299

RESUMO

In pathogenesis of Parkinson's disease (PD), mitochondrial dysfunction causes substantial reactive oxygen species (ROS) production and oxidative stress, leading to dopaminergic (DA) neuronal cell death. Mitochondrial toxins, including MPP+ (1-methyl-4-phenylpyridinium ion) and rotenone, induce oxidative injury in cultured DA neuronal cells. The current study tested the potential effect of SC79, a first-in-class small-molecule Akt activator, against the process. In SH-SY5Y cells and primary murine DA neurons, SC79 significantly attenuated MPP+- and rotenone-induced viability reduction, cell death, and apoptosis. SC79 activated Akt signaling in DA neuronal cells. Akt inhibition (by LY294002 and MK-2206) or CRISPR-Cas9-mediated Akt1 knockout completely abolished SC79-induced DA neuroprotection against MPP+. Further studies demonstrated that SC79 attenuated MPP+- and rotenone-induced ROS production, mitochondrial depolarization, and lipid peroxidation in SH-SY5Y cells and primary DA neurons. Moreover, upregulation of Nrf2-dependent genes (HO1 and NQO1) and Nrf2 protein stabilization were detected in SC79-treated SH-SY5Y cells and primary DA neurons. Together we show that SC79 protects DA neuronal cells from mitochondrial toxins possibly via activation of Akt-Nrf2 signaling.


Assuntos
1-Metil-4-fenilpiridínio/toxicidade , Acetatos/farmacologia , Benzopiranos/farmacologia , Neurônios Dopaminérgicos/patologia , Ativadores de Enzimas/farmacologia , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Rotenona/toxicidade , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Neurônios Dopaminérgicos/efeitos dos fármacos , Humanos , Camundongos Endogâmicos C57BL , Neuroproteção/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos
14.
Invest Ophthalmol Vis Sci ; 60(8): 3064-3073, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31348824

RESUMO

Purpose: Determine the toxicity, bioavailability in the retina, and neuroprotective effects of a hybrid antioxidant-nitric oxide donor compound SA-2 against oxidative stress-induced retinal ganglion cell (RGC) death in neurodegenerative animal models. Methods: Optic nerve crush (ONC) and ischemia reperfusion (I/R) injury models were used in 12-week-old C57BL/6J mice to mimic conditions of glaucomatous neurodegeneration. Mice were treated intravitreally with either vehicle or SA-2. Retinal thickness was measured by spectral-domain optical coherence tomography (SD-OCT). The electroretinogram and pattern ERG (PERG) were used to assess retinal function. RGC survival was determined by counting RBPMS-positive RGCs and immunohistochemical analysis of superoxide dismutase 1 (SOD1) levels was carried out in the retina sections. Concentrations of SA-2 in the retina and choroid were determined using HPLC and MS. In addition, the direct effect of SA-2 treatment on RGC survival was assessed in ex vivo rat retinal explants under hypoxic (0.5% O2) conditions. Results: Compound SA-2 did not induce any appreciable change in retinal thickness, or in a- or b-wave amplitude in naive animals. SA-2 was found to be bioavailable in both the retina and choroid after a single intravitreal injection (2% wt/vol). An increase in SOD1 levels in the retina of mice subjected to ONC and SA-2 treatment, suggests an enhancement in antioxidant activity. SA-2 provided significant (P < 0.05) RGC protection in all three of the tested RGC injury models in rodents. PERG amplitudes were significantly higher in both I/R and ONC mouse eyes following SA-2 treatment (P ≤ 0.001) in comparison with the vehicle and control groups. Conclusions: Compound SA-2 was effective in preventing RGC death and loss of function in three different rodent models of acute RGC injury: ONC, I/R, and hypoxia.


Assuntos
Neuroproteção/efeitos dos fármacos , Doadores de Óxido Nítrico/farmacocinética , Estresse Oxidativo , Degeneração Retiniana/tratamento farmacológico , Células Ganglionares da Retina/patologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Eletrorretinografia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley , Degeneração Retiniana/metabolismo , Degeneração Retiniana/patologia , Células Ganglionares da Retina/metabolismo , Tomografia de Coerência Óptica
15.
Int Rev Neurobiol ; 146: 83-102, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31349933

RESUMO

There is a growing trend of hypertension among military and civilian populations due to lifetime stressful situations. If hypertension is uncontrolled it leads to development of diabetes and serious neurological complications. Most of the World populations live in temperate zone across the World. Thus, a possibility exists that these hypertensive and diabetic people may have external heat as potential risk factors for brain damage. We have seen brain edema and brain damage following exposure to heat stress at 38°C for 4h. A possibility exists that heat exposure in diabetic-hypertensive (DBHY) cases exacerbates exacerbation of brain pathology and edema formation. This hypothesis is examined in a rat model. The role of nitric oxide (NO) in exacerbation of HS-induced brain pathology was also evaluated using nitric oxide synthase (NOS) immunoreactivity. Hypertensive rats (produced by two-kidney one clip (2K1C) method) were made diabetic with streptozotocine (50mg/kg, i.p./day for 3days) treatment. After 6weeks, DBHY rats show 20-30mM/L Blood Glucose and hypertension (180-200mmHg). Subjection of these rats to 4h HS resulted in six- to eightfold higher BBB breakdown, brain edema formation and brain pathology. At this time, neuronal or inducible NOS expression was four- to sixfold higher in DBHY rats compared to controls. Interestingly, iNOS expression was higher than nNOS in DBHY rats. Cerebrolysin in high doses (10-mL/kg, i.v. instead of 5-mL/kg) induced significant neuroprotection and downregulation of nNOS and iNOS in DBHY animals whereas normal animals need only 5-mL/kg doses for this purpose. Our observations demonstrate that co-morbidly factors exacerbate brain damage in HS through NOS expression and require double dose of cerebrolysin for neuroprotection as compared to normal rats, not reported earlier.


Assuntos
Aminoácidos/farmacologia , Barreira Hematoencefálica/metabolismo , Edema Encefálico/fisiopatologia , Encéfalo/patologia , Diabetes Mellitus Experimental/prevenção & controle , Golpe de Calor/patologia , Golpe de Calor/fisiopatologia , Hipertensão/prevenção & controle , Óxido Nítrico Sintase/biossíntese , Animais , Encéfalo/metabolismo , Diabetes Mellitus Experimental/complicações , Hipertensão/complicações , Masculino , Neuroproteção/efeitos dos fármacos , Ratos , Estreptozocina , Regulação para Cima
16.
Invest Ophthalmol Vis Sci ; 60(8): 3221-3235, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31335948

RESUMO

Purpose: Retinitis pigmentosa (RP) refers to a group of inherited blinding retinal diseases, whereby the death of mutated rod photoreceptors is followed closely by the death of cone photoreceptors. Cone cell death can be hugely debilitating as color/daytime vision becomes impaired. Thus, treatments that are effective against cone cell death are urgently needed. Our research has been working toward development of a neuroprotective treatment for RP. We have previously demonstrated significant neuroprotective properties of norgestrel, a progesterone analogue, in the mouse retina. The current study further investigates the potential of norgestrel as a treatment for RP, with a focus on long-term preservation of cone photoreceptors. Methods: Using the well-established rd10 mouse model of RP, we administered a norgestrel-supplemented diet at postnatal day (P)30, following widespread loss of rod photoreceptors and at the outset of cone degeneration. We subsequently assessed cone cell morphology and retinal function at P50, P60, and P80, using immunohistochemistry, electroretinograph recordings, and optomotor testing. Results: While cone cell degeneration was widespread in the untreated rd10 retina, we observed profound preservation of cone photoreceptor morphology in the norgestrel-treated mice for at least 50 days, out to P80. This was demonstrated by up to 28-fold more cone arrestin-positive photoreceptors. This protection transpired to functional preservation at all ages. Conclusions: This work presents norgestrel as an incredibly promising long-term neuroprotective compound for the treatment of RP. Crucially, norgestrel could be used in the mid-late stages of the disease to protect remaining cone cells and help preserve color/daytime vision.


Assuntos
Neuroproteção/efeitos dos fármacos , Norgestrel/farmacologia , Progesterona/farmacologia , Células Fotorreceptoras Retinianas Cones/efeitos dos fármacos , Retinite Pigmentosa/tratamento farmacológico , Animais , Modelos Animais de Doenças , Eletrorretinografia , Feminino , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Progestinas/farmacologia , Células Fotorreceptoras Retinianas Cones/patologia , Retinite Pigmentosa/patologia , Retinite Pigmentosa/fisiopatologia , Transdução de Sinais
17.
J Steroid Biochem Mol Biol ; 193: 105421, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31265900

RESUMO

Increasing evidence has shown that one of the major neurosteroids, estradiol, has potent neuroprotective actions. We have reported that estradiol synthesis was enhanced when retinoic acid was added into rat hippocampal slice culture. In this study, we investigated the effects of a potent retinoid X receptor (RXR) agonist, bexarotene, on estrogen synthesis and neuroprotective action in hippocampal slices. Treatment with bexarotene increased estradiol levels as well as estrogen-synthesizing enzymes and CYP19 expression in hippocampal slice cultures. Bexarotene significantly suppressed neuronal cell death induced by oxygen-glucose deprivation (OGD)/reoxygenation. RXR agonists other than bexarotene, such as CD3254, also suppressed neuronal cell death accompanied by OGD/reoxygenation. The RXR antagonists HX531 and UVI3003 and the CYP19 inhibitor letrozole abolished the neuroprotection elicited by bexarotene, indicating that estradiol produced by RXR stimulation protects neurons from ischemic insult. The human brain-specific CYP19 promoter had 6 RXR half sites, and 2 of 6 half sites were responsible for CYP19 expression induced by bexarotene. Bexarotene increased the expression of catalase and glutathione peroxidase 1 and inhibited lipid peroxidation elicited by OGD/reoxygenation, suggesting that the antioxidative property of estrogen contributes to RXR-mediated neuroprotection. Bexarotene also suppressed neuronal injury induced by lipopolysaccharide in the hippocampal slices. Taken together, RXR stimulation can protect neurons via enhanced synthesis of estradiol with antioxidative mechanisms. The RXR-estrogen axis might be a novel mechanism-based strategy to prevent or ameliorate ischemic and/or inflammatory neuronal disorders.


Assuntos
Aromatase/genética , Bexaroteno/farmacologia , Estradiol/metabolismo , Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Receptores X Retinoide/agonistas , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Hipocampo/metabolismo , Humanos , Neurônios/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Gravidez , Ratos Wistar , Receptores X Retinoide/genética , Regulação para Cima
18.
Horm Behav ; 114: 104545, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31228421

RESUMO

The memory-enhancing effects of 17ß-estradiol (E2) depend upon rapid activation of several cell-signaling cascades within the dorsal hippocampus (DH). Among the many cell-signaling pathways that mediate memory processes, Wnt/ß-catenin signaling has emerged as a potential key player because of its importance to hippocampal development and synaptic plasticity. However, whether E2 interacts with Wnt/ß-catenin signaling to promote memory consolidation is unknown. Therefore, the present study examined whether Wnt/ß-catenin signaling within the DH is necessary for E2-induced memory consolidation in ovariectomized mice tested in the object recognition and object placement tasks. Ovariectomized C57BL/6 mice received immediate post-training infusions of E2 or vehicle into the dorsal third ventricle plus the endogenous Wnt/ß-catenin antagonist Dickkopf-1 (Dkk-1) or vehicle into the DH to assess whether the memory-enhancing effects of E2 depend on activation of Wnt/ß-catenin signaling. Our results suggest that Dkk-1 blocks E2-induced memory enhancement as hypothesized, but may do so by only moderately blunting Wnt/ß-catenin signaling while concurrently activating Wnt/JNK signaling. The current study provides novel insights into the mechanisms through which E2 enhances memory consolidation in the DH, as well as critical information about the mechanistic actions of Dkk-1.


Assuntos
Estradiol/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Consolidação da Memória/efeitos dos fármacos , Animais , Feminino , Hipocampo/efeitos dos fármacos , Infusões Intraventriculares , Peptídeos e Proteínas de Sinalização Intercelular/administração & dosagem , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Ovariectomia , Transdução de Sinais/efeitos dos fármacos
19.
Chem Biol Interact ; 310: 108721, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31233715

RESUMO

OBJECTIVE: Increasing consumption of fructose is a major contributor to epidemic metabolic syndrome (MS), and the risk of renal disorders and/or injuries remains high among individuals with MS particularly during pregnancy. Glutamine (GLT) has been demonstrated to have a modulatory effect in MS and/or insulin resistance (IR). This study investigated the effect of GLT on renal lipid accumulation and glutathione depletion induced by high fructose-enriched drink (FED) in pregnant rats and also tested the hypothesis that the renoprotective role of GLT is by suppression of adenosine deaminase (ADA)/xanthine oxidase (XO)/uric acid (UA) pathway. METHODS: Pregnant Wistar rats weighing between 160 and 180 g were allotted into Control, GLT, FED and FED + GLT groups (6 rats/group). The groups received distilled water (vehicle, p. o.), 1 g/kg bw GLT (p.o.), 10% Fructose (w/v) and 10% Fructose (w/v) plus 1 g/kg bw GLT (p.o.) respectively, daily for 19 days. RESULTS: Data showed that FED caused IR, increased body weight gain, blood glucose, plasma insulin, creatinine, urea, lipid accumulation, lipid peroxidation, lactate production, aspartate transaminase and alanine aminotransferase, depressed Glucose-6-phosphate dehydrogenase, sodium-potassium-ATPase activities and glutathione. These alterations were accompanied by increased activity of ADA/XO/UA pathway. However, the FED-induced renal injury and its correlates were normalized by GLT supplementation. CONCLUSION: The present results demonstrate that renal lipid accumulation and glutathione depletion-driven renal injury in pregnant rats is accompanied by increased activity of ADA/XO/UA pathway. The findings also suggest that GLT would confer protection against renal injury by protecting against lipid accumulation and glutathionedepletion, at least in part, through suppression of ADA/XO/UA pathway.


Assuntos
Glutamina/farmacologia , Glutationa/análise , Resistência à Insulina , Lipídeos/análise , Neuroproteção/efeitos dos fármacos , Adenosina Desaminase/metabolismo , Animais , Feminino , Frutose/efeitos adversos , Glutationa/efeitos dos fármacos , Síndrome Metabólica , Gravidez , Ratos , Ratos Wistar , Ácido Úrico/metabolismo , Xantina Oxidase/metabolismo
20.
Inflammation ; 42(5): 1830-1842, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31230155

RESUMO

Salidroside, an active constituent of Rhodiola rosea, is neuroprotective after transient middle cerebral artery occlusion (tMCAO). However, its effects in other experimental stroke models are less understood. Here, we investigated the effect of daily intraperitoneal injections of salidroside in rats after permanent MCAO (pMCAO). Cerebral infarct volumes at 1 day after pMCAO were significantly reduced by treatment with 100 mg/kg/day salidroside, but not by 25 or 50 mg/kg/day, and this benefit of salidroside increased significantly over at least 7 days of treatment, when it was also accompanied by decreased neurological deficit scores. These observations led us to investigate the underlying mechanism of action of salidroside. 100 mg/kg salidroside for 1 day increased NeuN, Nrf2, and its downstream mediator HO-1, while it reduced nuclear NFκB p50, IL-6, and TNFα. Brusatol, a Nrf2 inhibitor, blocked the actions of salidroside on Nrf2, NFκB p50, IL-6, and TNFα. Salidroside also increased the ratio of p-PKB/PKB at 1 day after pMCAO even in the presence of brusatol. LY294002, a PI3K inhibitor, prevented all these effects of salidroside, including those on NeuN, p-PKB/PKB, Nrf2, HO-1, and pro-inflammatory mediators. In contrast, salidroside had no significant effect on the level of cerebral complement C3 after pMCAO, or on the activity of C3 as measured by the expression of cerebral Egr1. Our findings therefore suggest that salidroside reduces neuroinflammation and neural damage by regulating the PI3K/PKB/Nrf2/NFκB signaling pathway after pMCAO, and that this neuroprotective effect does not involve modulation of complement C3 activity.


Assuntos
Lesões Encefálicas/prevenção & controle , Complemento C3/metabolismo , Glucosídeos/farmacologia , Inflamação/prevenção & controle , Fenóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Isquemia Encefálica/prevenção & controle , Glucosídeos/uso terapêutico , Infarto da Artéria Cerebral Média/complicações , Fator 2 Relacionado a NF-E2/metabolismo , Neuroproteção/efeitos dos fármacos , Fenóis/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Ratos
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