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1.
Khirurgiia (Mosk) ; (8): 69-74, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32869618

RESUMO

OBJECTIVE: To substantiate the advisability of using cytoflavin to correct postoperative cognitive dysfunction (POCD) in patients undergoing video laparoscopic cholecystectomy (VLCE) under conditions of inhalation anesthesia with sevoflurane. MATERIAL AND METHODS: The data of two representative groups of patients (n=60) who underwent video-laparoscopic cholecystectomy under the conditions of inhalation anesthesia with sevoflurane were analyzed. At the stages of the perioperative period, in order to monitor the state of higher mental functions, neuropsychological testing was performed: anxiety and depression scales (HADS), the Montreal scale of cognitive dysfunction (MoCA), and frontal dysfunction batteries (FAB). Patients of the first group (n=19) were not corrected for POKD. For the correction of cognitive impairment, patients of the second group (n=41) were treated with Cytoflavin according to the 20 ml regimen per 250 ml of 0.9% sodium chloride solution intravenously once before the operation, then within 4 days of the postoperative period. RESULTS: Neuropsychological testing in group I patients revealed the development of moderate POCD. The inclusion of Cytoflavin in the treatment regimen in the II group of patients contributed to an improvement in the state of HMF, accompanied by a decrease in the level of anxiety and depression. CONCLUSION: The inclusion of Cytoflavin in treatment regimens helps prevent the development of POKD and is accompanied by an improvement in the state of higher mental functions, which is manifested by a decrease in the level of anxiety and depression, favorably affecting the emotional background of patients.


Assuntos
Anestésicos Inalatórios/efeitos adversos , Colecistectomia Laparoscópica , Transtornos Cognitivos/terapia , Mononucleotídeo de Flavina/administração & dosagem , Inosina Difosfato/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Niacinamida/administração & dosagem , Sevoflurano/efeitos adversos , Succinatos/administração & dosagem , Anestesia por Inalação/efeitos adversos , Anestesia por Inalação/métodos , Colecistectomia Laparoscópica/efeitos adversos , Colecistectomia Laparoscópica/métodos , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/etiologia , Combinação de Medicamentos , Humanos , Cirurgia Vídeoassistida
2.
Yakugaku Zasshi ; 140(8): 1007-1012, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32741858

RESUMO

We previously showed that increased permeability of the blood-brain barrier (BBB) after ischemic stroke enables extravasation of nano-sized liposomes and accumulation in the ischemic region, and that delivery of neuroprotective agents using liposomal drug delivery systems (DDS) is applicable for treating cerebral ischemia/reperfusion (I/R) injury. However, entry of liposomes into the brain parenchyma was limited in the early stages after I/R possibly due to microvascular dysfunction induced by pathological progression. As such, new approaches to overcome the BBB are needed. Leukocytes can pass through inflamed BBB in I/R region due to membrane proteins displayed on their surface. We thus hypothesized that incorporation of leukocyte membrane proteins onto liposomal membranes would impart leukocyte-mimicking functions to liposomes and that leukocyte-mimetic liposomes (LM-Lipo) may pass through inflamed endothelial cells and BBB, similar to leukocytes. LM-Lipo prepared using intermembrane protein transfer from human leukemia cells showed significantly increased association to inflamed human umbilical vein endothelial cells relative to plain liposomes. Moreover, LM-Lipo passed through inflamed endothelial cell layer by regulating intercellular junctions. These results suggest that imparting leukocyte-like properties to liposomes via intermembrane protein transfer would be an effective strategy to overcome inflamed endothelial barriers. In this review, we describe our findings on ischemic stroke treatment using liposomal DDS and the potential of LM-Lipo to overcome inflamed endothelial barriers.


Assuntos
Barreira Hematoencefálica/metabolismo , Sistemas de Liberação de Medicamentos , Desenvolvimento de Medicamentos , Leucócitos , Lipossomos/metabolismo , Proteínas de Membrana/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo , Humanos , Permeabilidade , Transporte Proteico , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo
3.
Medicine (Baltimore) ; 99(23): e20380, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32501982

RESUMO

BACKGROUND: This study aims to assess the efficacy of neuroprotection (NP) for the management of patients with primary open-angle glaucoma (POAG). METHODS: A comprehensive search will be carried out from the beginning to the February 29, 2020 in the electronic databases: Scopus, Web of Science, PUBMED, EMBASE, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, WANGFANG, and China National Knowledge Infrastructure. There are no limitations related to the language and publication date. Two researchers will independently undertake study selection from searched literatures, extract data from included trials, and appraise study quality using Cochrane risk of bias tool. Any disagreements will be solved by a third researcher through consultation. RevMan 5.3 software will be employed for statistical analysis. RESULTS: This study will provide a high-quality synthesis of randomized controlled trials of NP for the management of patients with POAG. CONCLUSIONS: The results of this study will help to create proposals for the treatment of POAG using NP. SYSTEMATIC REVIEW REGISTRATION: INPLASY202040107.


Assuntos
Glaucoma de Ângulo Aberto/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Pressão Sanguínea , Humanos , Pressão Intraocular , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fluxo Sanguíneo Regional , Projetos de Pesquisa , Índice de Gravidade de Doença , Acuidade Visual
4.
Int J Nanomedicine ; 15: 3251-3266, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32440122

RESUMO

Background: Peripheral neuropathy is a common and painful side effect that occurs in patients with cancer induced by Oxaliplatin (OXL). The neurotoxicity correlates with the damage of dorsal root ganglion (DRG) neurons and Schwann cells (SCs). Hydroxysafflor yellow A (HSYA), icariin, epimedin B and 3, 4-dihydroxybenzoic acid (DA) are the main neuroprotective ingredients identified in Wen-Luo-Tong (WLT), a traditional Chinese medicinal topical compound. The purpose of this study was to prepare and evaluate the efficacy of an ethosomes gel formulation loaded with a combination of HSYA, icariin, epimedin B and DA. However, the low LogP value, poor solubility and macromolecule are several challenges for topical delivery of these drugs. Methods: Ethosomes were prepared by the single-step injection technique. Particle size, entrapment efficiency and in vitro drug deposition studies were determined to select the optimum ethosomes. The optimized ethosomes were further incorporated into carbopol to obtain a gel. The rheological properties, morphology, in vitro drug release, in vitro gel application and skin distribution of the ethosomes gels were studied. A rat model of oxaliplatin-induced neuropathy was established to assess the therapeutic efficacy of the ethosomes gel. Results: Seventy percent (v/v) ethanol, cinnamaldehyde and Phospholipon 90G were employed to develop ethosomes a carrier system. This system had a high entrapment efficiency, carried large amounts of HSYA, epimedin B, DA and icarrin, and penetrated deep into the epidermis and dermis. The optimized ethosomes had the maximum deposition of icariin, HSYA, epimedin B and relative higher amount of DA in epidermis (2.00±0.13 µg/cm2, 5.72±0.75 µg/cm2, 1.97±0.27 µg/cm2 and 9.25±1.21 µg/cm2, respectively). 0.5% carbopol 980 was selected to develop the ethosomes gel with desirable viscoelasticity and spreadability, which was suitable for topical application. The mechanical allodynia and hyperalgesia induced by OXL in rats were significantly reduced after the new ethosomes gel was applied to rats compared to model group. Conclusion: Based on our findings, the ethosomes gel delivery system provided a new formulation for the topical delivery of HSYA, icariin, epimedin B and DA to counteract OXL-induced peripheral neuropathy.


Assuntos
Géis/química , Fármacos Neuroprotetores/uso terapêutico , Oxaliplatina/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Acroleína/análogos & derivados , Acroleína/química , Administração Tópica , Animais , Comportamento Animal , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Gânglios Espinais/citologia , Lipossomos , Masculino , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Oxaliplatina/administração & dosagem , Tamanho da Partícula , Ratos Wistar , Reologia , Pele/metabolismo , Absorção Cutânea/efeitos dos fármacos
5.
Medicine (Baltimore) ; 99(20): e20151, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32443330

RESUMO

BACKGROUND: This study will specifically investigate the effect of butylphthalide on hemodynamics in patients with watershed stroke (WS). METHODS: We will search the following databases from their inceptions to the March 1, 2020: Cochrane Library, MEDLINE, EMBASE, PsycINFO, Web of Science, Cumulative Index to Nursing and Allied Health Literature, and China National Knowledge Infrastructure. All relevant randomized controlled trials on exploring the effect of butylphthalide on hemodynamics in patients with WS will be considered for inclusion. No language limitation will be imposed to this study. All study quality will be checked using Cochrane risk of bias tool. RevMan 5.3 software will be utilized for data analysis. RESULTS: This study will summarize the latest evidence to investigate the effect of butylphthalide on hemodynamics in patients with WS. CONCLUSION: Findings from this study will provide theoretical basis of butylphthalide on hemodynamics in patients with WS for clinician and future research. DISSEMINATION AND ETHICS: This study is carried out based on the published data, thus, no ethical approval is required. We will submit this study to a peer-reviewed journal for publication. SYSTEMATIC REVIEW REGISTRATION: INPLASY 202030006.


Assuntos
Benzofuranos/farmacologia , Hemodinâmica/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , Benzofuranos/administração & dosagem , Benzofuranos/efeitos adversos , China/epidemiologia , Humanos , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/efeitos adversos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia , Resultado do Tratamento
7.
Life Sci ; 252: 117665, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32305521

RESUMO

AIMS: Thrombin formation is increased in patients with acute cerebral ischemic stroke, and augments coagulation and inflammation in the brain. Administration of antithrombin (AT) was previously reported to be protective against renal and myocardial ischemic injury. Thus, we hypothesized that treatment with AT would be neuroprotective against cerebral ischemic injury. This study evaluated the effects of AT treatment on ischemic inflammation and brain damage in mice subjected to middle cerebral artery occlusion (MCAO). MAIN METHODS: A mouse model of 4-hour MCAO was used to induce ischemic brain injury. Recombinant AT gamma was administered intravenously immediately after reperfusion at 4 h after MCAO. Infarct volume, neurological deficit, and regional cerebral blood flow (rCBF) were measured at 24 h after MCAO. To evaluate the effect of AT gamma on ischemic inflammation, we measured the number of Iba1-positive cells (marker of macrophage/microglial activation) and levels of proinflammatory cytokines. Further, we investigated the direct anti-inflammatory effects of rAT in the J774.1 cell line. KEY FINDINGS: Treatment with AT gamma (480 U/kg) reduced infarct volume and neurological deficit, and improved rCBF, in MCAO mice. Moreover, AT gamma treatment decreased the number of Iba1-positive cells and levels of proinflammatory cytokines. In vitro, treatment with thrombin significantly increased proinflammatory cytokine levels, which was significantly reduced by pretreatment with AT gamma. SIGNIFICANCE: Treatment with AT showed neuroprotective effects via anticoagulation actions, as well as direct anti-inflammatory effects on macrophage/microglial activation. These data suggest that AT may be a useful new therapeutic option for cerebral ischemia.


Assuntos
Antitrombinas/farmacologia , Isquemia Encefálica/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Antitrombinas/administração & dosagem , Isquemia Encefálica/patologia , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média , Inflamação/tratamento farmacológico , Inflamação/patologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microglia/efeitos dos fármacos , Microglia/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Proteínas Recombinantes , Acidente Vascular Cerebral/patologia
8.
Life Sci ; 252: 117679, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32325134

RESUMO

AIM: The neuronal damage and accompanied functional deficits induced by cerebral ischemia are among the most common causes of disabilities in adults. Activation of subtypes of peroxisome proliferator-activated receptors (PPARs); PPAR-α and PPAR-γ have shown neuroprotective effects in different neurodegenerative diseases including stroke. Thus, this study aimed to compare the effects of two different agonists: PPAR-α (fenofibrate) and PPAR-γ (pioglitazone) as well as the effect of their combination in ameliorating post-ischemia behavioral deficits. METHODS: Male Wistar rats were either pretreated with vehicle, fenofibrate (100 mg/kg/day p.o), pioglitazone (10 mg/kg/day p.o) or their combination for 14 days prior to bilateral common carotid artery occlusion followed by reperfusion for 24 hoursh. The sensory motor functions of rats were assessed, then rats were sacrificed to determine infarct volume and histopathological changes as well as oxidative stress, inflammatory and apoptotic markers in the brain tissue. KEY FINDINGS: Pre-treatment with fenofibrate and pioglitazone in addition to their combination improved neurobehavioral dysfunction, reduced cerebral infarct volume, attenuated inflammatory and apoptotic markers and ameliorated histopathological changes in I/R injured rats. The effect of pioglitazone in cerebral cortex was higher than its corresponding effect in fenofibrate while the combined administration of both drugs had additive neuroprotective effect and normalized inflammatory and apoptotic mediators in ischemic rats. SIGNIFICANCE: The study compared the neuroprotective effects of PPAR-α and PPAR-γ agonists, and tested the impact of their combination. We concluded that no additional benefits on the functional outcomes might be gained upon their combination.


Assuntos
Isquemia Encefálica/prevenção & controle , Fenofibrato/farmacologia , PPAR alfa/agonistas , PPAR gama/agonistas , Pioglitazona/farmacologia , Animais , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Infarto Cerebral/prevenção & controle , Modelos Animais de Doenças , Quimioterapia Combinada , Fenofibrato/administração & dosagem , Masculino , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Pioglitazona/administração & dosagem , Ratos , Ratos Wistar , Traumatismo por Reperfusão/tratamento farmacológico
9.
BJOG ; 127(10): 1217-1225, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32237024

RESUMO

OBJECTIVE: To study the effect of antenatal magnesium sulphate (MgSO4 ) on cerebral palsy (CP) in a manner that also provides adequate power for a linked trial sequential analysis. DESIGN: Double-blind, randomised, placebo-controlled, multi-centre trial. SETTING: Fourteen Danish obstetric departments. POPULATION: In total, 560 pregnant women at risk for preterm delivery before 32 weeks of gestation were randomised from December 2011 to January 2018. Those women gave birth to 680 children. METHODS: Women were randomised to receive either a loading dose of 5 g MgSO4 followed by 1 g/hour or a placebo in identical volumes. The children were followed up at a corrected age of 18 months or older with a review of their medical charts and with the Ages and Stages Questionnaire. MAIN OUTCOME MEASURE: The primary outcome measure was moderate to severe CP. Secondary outcomes included mortality, neonatal morbidity, blindness and mild CP. RESULTS: The crude rates of moderate to severe CP in the MgSO4 group and the placebo group were 2.0% and 3.3%, respectively. The adjusted odds of moderate to severe CP were lower in the MgSO4 group than in the placebo group (odds ratio 0.61; 95% CI 0.23-1.65). CONCLUSIONS: Antenatal MgSO4 before 32 weeks of gestation decreases the likelihood of moderate to severe CP; these results are entirely consistent with other randomised evidence summarised in the linked trial sequential analysis. TWEETABLE ABSTRACT: Antenatal magnesium sulphate may decrease the risk of moderate to severe cerebral palsy in children born before 32 weeks of gestation.


Assuntos
Paralisia Cerebral/prevenção & controle , Sulfato de Magnésio/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Nascimento Prematuro/tratamento farmacológico , Adulto , Dinamarca , Método Duplo-Cego , Feminino , Humanos , Lactente , Recém-Nascido , Gravidez , Nascimento Prematuro/etiologia , Cuidado Pré-Natal/métodos , Índice de Gravidade de Doença
10.
Life Sci ; 253: 117684, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32315728

RESUMO

Brain oxidative stress and neuroinflammation have been implicated in various psychiatric disorders. The current study investigated the effect and mechanism of 25-Methoxyhispidol A (25-MHA) against CCl4-induced anxiety and depression. Mice were challenged with CCl4 (1 ml/kg; i.p.) after 30 min of 25-MHA (1, 5 and 10 mg/kg; i.p.) administration. Pretreatment with 25-MHA (10 mg/kg) significantly attenuated the anxiety and depression-like behavior in testing models. The oxidative stress induced by CCl4 was significantly attenuated by pretreatment with 25-MHA. The immunohistochemical (IHC) analysis showed a reduction in kelch-like ECH-associated protein 1 (Keap1) and improvement in expression of nuclear factor erythroid-2-related factor (Nrf-2) and heme oxygenase (HO)-1. In addition, 25-MHA significantly attenuated the CCl4-mediated depletion of antioxidant enzymes in hippocampus (HC) and prefrontal cortex (PFC) region and reduced the expression of toll-like receptor (TLR)-4 and nuclear factor kappa B (NF-κB), along with a decreased production of pro-inflammatory cytokines in HC and PFC region. Pretreatment with 25-MHA also showed an improved expression of neurotrophic factors i.e., brain derived growth factor (BDNF) and vascular endothelial growth factor (VEGF). Furthermore, 25-MHA inhibited malondialdehyde (MDA) and ammonia level in plasma, liver, HC and PFC regions of mice brain. 25-MHA also exhibited anti-apoptotic effect evident from the reduced expression of caspase-3 and decreased hippocampal DNA damage in comet assay. Furthermore, decreased serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and corticosterone level, along with prevention of CCl4-induced alterations in thickness of dentate gyrus and intact hepatic cells morphology, represented by hippocampal and liver histopathology, indicated the neuroprotective effect of 25-MHA.


Assuntos
Comportamento Animal/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Tetracloreto de Carbono/toxicidade , Caspase 3/metabolismo , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fármacos Neuroprotetores/administração & dosagem , Triterpenos/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/metabolismo
11.
PLoS One ; 15(3): e0229156, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32160210

RESUMO

Dantrolene has been demonstrated to be neuroprotective for multiple neurodegenerative diseases. However, dantrolene's limited penetration into the CNS hampers its effectiveness as a neuroprotective agent. Here, we studied whether the intranasal administration of dantrolene provided better penetration into the brain than the commonly used oral approach. C57BL/6 mice, aged 2-4 months, received a single dose of either intranasal or oral dantrolene (5mg/kg). Inhibition of dantrolene clearance from the brain was examined by co-administration with P-gp/BCRP inhibitors, nimodipine or elacridar. The concentration of dantrolene in the brain and plasma was measured at 10, 20, 30, 50, 70, 120, 150 and 180 minutes after administration. Separate cohorts of mice were given intranasal dantrolene (5mg/kg) or vehicle, 3 times/ week, for either 3 weeks or 4 months, to examine potential adverse side effects on olfaction and motor coordination, respectively. We found that Dantrolene concentrations were sustained in the brain after intranasal administration for 180 min, while concentrations fell to zero at 120 min for oral administration. Chronic use of intranasal dantrolene did not impair olfaction or motor function in these mice. Blood brain barrier pump inhibitors did not further increase dantrolene peak concentrations in the brain. Our results suggested that Intranasal administration of dantrolene is an effective route to increase its concentration and duration in the brain compared to the oral approach, without any obvious side effects on olfaction or motor function.


Assuntos
Encéfalo/metabolismo , Dantroleno/administração & dosagem , Dantroleno/farmacocinética , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacocinética , Administração Intranasal , Administração Oral , Animais , Dantroleno/sangue , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/sangue , Distribuição Tecidual
12.
Psychopharmacology (Berl) ; 237(6): 1851-1860, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32221697

RESUMO

Alzheimer's disease (AD) is the most common neurodegenerative disease. However, effective drugs for this disease have not yet been developed. The analysis of big data indicated that childhood herpes virus infection may be associated with the incidence of AD, suggesting that anti-herpetic drugs, such as acyclovir, may have preventive and suppressive effects in AD therapy. Moreover, short-term use of dexamethasone (DXMT), a clinical used synthetic corticosteroid, could effectively inhibit AD-related neuroinflammation. In this study, we have found that the combination of acyclovir and DXMT, but not acyclovir or DXMT alone, could protect against AD causing ß-amyloid (Aß) oligomer-induced spatial cognitive impairments. Moreover, acyclovir and DXMT could prevent Aß oligomer-induced over-activation of microglia and astrocytes, and over-expression of pro-inflammatory cytokines, indicating that anti-AD effects of drug combination might be at least partially via neuroinflammation inhibition and immunomodulation. Furthermore, Aß oligomer-induced decrease of PSD-95 and increase of pTau expression was prevented by the combination of acyclovir and DXMT, suggesting the involvement of synaptic protective effects of the drug combination. Taken together, our studies indicated that the combination of acyclovir and DXMT might be an alternative therapy for the treatment of AD.


Assuntos
Aciclovir/administração & dosagem , Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/toxicidade , Disfunção Cognitiva/prevenção & controle , Dexametasona/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Fragmentos de Peptídeos/toxicidade , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Quimioterapia Combinada , Masculino , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo
13.
Pediatrics ; 145(4)2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32217739

RESUMO

BACKGROUND: Approximately 25% of children with concussion have persistent postconcussive symptoms (PPCS) with resultant significant impacts on quality of life. Melatonin has significant neuroprotective properties, and promising preclinical data suggest its potential to improve outcomes after traumatic brain injury. We hypothesized that treatment with melatonin would result in a greater decrease in PPCS symptoms when compared with a placebo. METHODS: We conducted a randomized, double-blind trial of 3 or 10 mg of melatonin compared with a placebo (NCT01874847). We included youth (ages 8-18 years) with PPCS at 4 to 6 weeks after mild traumatic brain injury. Those with significant medical or psychiatric histories or a previous concussion within the last 3 months were excluded. The primary outcome was change in the total youth self-reported Post-Concussion Symptom Inventory score measured after 28 days of treatment. Secondary outcomes included change in health-related quality of life, cognition, and sleep. RESULTS: Ninety-nine children (mean age: 13.8 years; SD = 2.6 years; 58% girls) were randomly assigned. Symptoms improved over time with a median Post-Concussion Symptom Inventory change score of -21 (95% confidence interval [CI]: -16 to -27). There was no significant effect of melatonin when compared with a placebo in the intention-to-treat analysis (3 mg melatonin, -2 [95% CI: -13 to 6]; 10 mg melatonin, 4 [95% CI: -7 to 14]). No significant group differences in secondary outcomes were observed. Side effects were mild and similar to the placebo. CONCLUSIONS: Children with PPCS had significant impairment in their quality of life. Seventy-eight percent demonstrated significant recovery between 1 and 3 months postinjury. This clinical trial does not support the use of melatonin for the treatment of pediatric PPCS.


Assuntos
Melatonina/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Síndrome Pós-Concussão/tratamento farmacológico , Adolescente , Concussão Encefálica/complicações , Criança , Cognição/efeitos dos fármacos , Intervalos de Confiança , Método Duplo-Cego , Feminino , Humanos , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Masculino , Melatonina/administração & dosagem , Melatonina/efeitos adversos , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/efeitos adversos , Síndrome Pós-Concussão/etiologia , Qualidade de Vida , Tamanho da Amostra , Sono/efeitos dos fármacos , Fatores de Tempo , Resultado do Tratamento
14.
Toxicol Appl Pharmacol ; 395: 114963, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32209366

RESUMO

BACKGROUND: Sarin is an irreversible organophosphate cholinesterase inhibitor. Following toxic signs, an extensive long-term brain damage is often reported. Thus, we evaluated the efficacy of a novel anticonvulsant drug retigabine, a modulator of neuronal voltage gated K+ channels, as a neuroprotective agent following sarin exposure. METHODS: Rats were exposed to 1 LD50 or 1.2 LD50 sarin and treated at onset of convulsions with retigabine (5 mg/kg, i.p.) alone or in combination with 5 mg/kg atropine and 7.5 mg/kg TMB-4 (TA) respectively. Brain biochemical and immunohistopathological analyses were processed 24 h and 1 week following 1 LD50 sarin exposure and at 4 weeks following exposure to 1.2 LD50 sarin. EEG activity in freely moving rats was also monitored by telemetry during the first week following exposure to 1.2 LD50 and behavior in the Open Field was evaluated 3 weeks post exposure. RESULTS: Treatment with retigabine following 1 LD50 sarin exposure or in combination with TA following 1.2 LD50 exposure significantly reduced mortality rate compared to the non-treated groups. In both experiments, the retigabine treatment significantly reduced gliosis, astrocytosis and brain damage as measured by translocator protein (TSPO). Following sarin exposure the combined treatment (retigabine+ TA) significantly minimized epileptiform seizure activity. Finally, in the Open Field behavioral test the non-treated sarin group showed an increased mobility which was reversed by the combined treatment. CONCLUSIONS: The M current modulator retigabine has been shown to be an effective adjunct therapy following OP induced convulsion, minimizing epileptiform seizure activity and attenuating the ensuing brain damage.


Assuntos
Anticonvulsivantes/administração & dosagem , Encefalopatias/induzido quimicamente , Encefalopatias/prevenção & controle , Carbamatos/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Fenilenodiaminas/administração & dosagem , Sarina/toxicidade , Animais , Atropina/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encefalopatias/patologia , Substâncias para a Guerra Química/toxicidade , Inibidores da Colinesterase/toxicidade , Masculino , Neuroglia/patologia , Neurônios/patologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/efeitos dos fármacos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/fisiologia , Ratos , Ratos Sprague-Dawley , Convulsões/induzido quimicamente , Convulsões/prevenção & controle , Trimedoxima/administração & dosagem
15.
PLoS One ; 15(3): e0229499, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32126102

RESUMO

Excitotoxicity mediated by the N-methyl-D-aspartate receptor (NMDAR) is believed to be a primary mechanism of neuronal injury following stroke. Thus, many drugs and therapeutic peptides were developed to inhibit either the NMDAR at the cell surface or its downstream intracellular death-signaling cascades. Nevertheless, the majority of focal ischemia studies concerning NMDAR antagonism were performed using the intraluminal suture-induced middle cerebral arterial occlusion (MCAO) model, which produces a large cortical and subcortical infarct leading to hypothalamic damage and fever in experimental animals. Here, we investigated whether NMDAR antagonism by drugs and therapeutic peptides was neuroprotective in a mouse model of distal MCAO (dMCAO), which produces a small cortical infarct sparing the hypothalamus and other subcortical structures. For establishment of this model, mice were subjected to dMCAO under normothermic conditions or body-temperature manipulations, and in the former case, their brains were collected at 3-72 h post-ischemia to follow the infarct development. These mice developed cortical infarction 6 h post-ischemia, which matured by 24-48 h post-ischemia. Consistent with the hypothesis that the delayed infarction in this model can be alleviated by neuroprotective interventions, hypothermia strongly protected the mouse brain against cerebral infarction in this model. To evaluate the therapeutic efficacy of NMDAR antagonism in this model, we treated the mice with MK801, Tat-NR2B9c, and L-JNKI-1 at doses that were neuroprotective in the MCAO model, and 30 min later, they were subjected to 120 min of dMCAO either in the awake state or under anesthesia with normothermic controls. Nevertheless, NMDAR antagonism, despite exerting pharmacological effects on mouse behavior, repeatedly failed to show neuroprotection against cerebral infarction in this model. The lack of efficacy of these treatments is reminiscent of the recurrent failure of NMDAR antagonism in clinical trials. While our data do not exclude the possibility that these treatments could be effective at a different dose or treatment regimen, they emphasize the need to test drug efficacy in different stroke models before optimal doses and treatment regimens can be selected for clinical trials.


Assuntos
Infarto Cerebral/prevenção & controle , Maleato de Dizocilpina/administração & dosagem , Hipotermia Induzida/métodos , Infarto da Artéria Cerebral Média/terapia , Animais , Infarto Cerebral/etiologia , Modelos Animais de Doenças , Maleato de Dizocilpina/farmacologia , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/etiologia , Masculino , Camundongos , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Peptídeos/administração & dosagem , Peptídeos/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Resultado do Tratamento
16.
Gene ; 742: 144601, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32198124

RESUMO

Morphine is a natural alkaloid which derived from the opium poppy Papaver somniferum. Many studies have reported the effect of morphine on learning, memory and gene expression. CART (cocaine-amphetamine regulated transcript)is an important neuropeptide which has a critical role in physiological processes including drug dependence and antioxidant activity. ΔfosB is a transcription factor which modulates synaptic plasticity and affects learning and memory. TFAM (the mitochondrial transcription factor A) and PGC-1α (Peroxisome proliferator-activated receptor γ coactivator-1α) are critically involved in mitochondrial biogenesis and antioxidant pathways. NeuroAid is a Chinese medicine that induces neuroprotective and anti-apoptotic effects. In this research, we aimed to investigate the effect of NeuroAid on morphine-induced amnesia with respect to the expression of TFAM, PGC-1α, ΔfosB and CART in the rat's hippocampus. In this study, Morphine sulfate (at increasing doses), Naloxone hydrochloride (2.5 mg/kg) and NeuroAid (2.5 mg/kg) were administered intraperitoneal and real-time PCR reactions were done to assess gene expression. The results showed, morphine impaired memory of step-through passive avoidance, while NeuroAid had no effect. NeuroAid attenuated (but not reversed) morphine-induced memory impairment in morphine-addicted rats. Morphine increased the expression of PGC-1α and decreased the expression of CART. However, NeuroAid increased the expression of TFAM, PGC-1α, ΔfosB and CART. NeuroAid restored the effect of morphine on the expression of CART and PGC-1α. In conclusion, morphine impaired memory of step-through passive avoidance and NeuroAid attenuated this effect. The effect of NeuroAid on morphine-induced memory impairment/gene expression may be related to its anti-apoptotic and neuroprotective effects.


Assuntos
Amnésia/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Hipocampo/patologia , Morfina/toxicidade , Fármacos Neuroprotetores/administração & dosagem , Amnésia/induzido quimicamente , Amnésia/diagnóstico , Amnésia/patologia , Animais , Apoptose/efeitos dos fármacos , Técnicas de Observação do Comportamento , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Humanos , Injeções Intraperitoneais , Masculino , Morfina/administração & dosagem , Proteínas do Tecido Nervoso/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar , Fatores de Transcrição/metabolismo
17.
World Neurosurg ; 138: e736-e742, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32200016

RESUMO

OBJECTIVE: Caffeic acid phenethyl ester (CAPE), a phenolic compound, besides being 1 of the biologically active components of propolis, is a compound with antioxidant, antiinflammatory, antiviral, reperfusion damage prevention, immune stimulant, and carcinostatic, anticancer properties. The aim of this study was to investigate the possible effects of CAPE on cerebral vasospasm and early brain injury, which were experimentally administered intraperitoneally in rats with subarachnoid hemorrhage. METHODS: Thirty-two Wistar Albino rats weighing 200 to 300 g were used in our study. The rats divided into 3 groups: the control group (n = 10), subarachnoid hemorrhage group (n = 11), and subarachnoid hemorrhage + CAPE group (n = 11). These groups were evaluated according to the Ischemia index in hippocampal CA3 regions and the morphometric analysis of basilar artery diameter after being sacrificed at the end of 72nd hour. RESULTS: A significant difference was found between group 1 and group 2 for the CA-3 region, it was concluded that early brain damage occurred after subarachnoid hemorrhage. When the neuronal damage in CA-3 region was evaluated between group 2 and group 3, a statistically significant difference was found between the groups. There was a statistically significant difference between group 1 and group 3 in terms of ischemia detection. CONCLUSIONS: It was shown that CAPE has a preventive effect on early brain injury after subarachnoid hemorrhage and has a positive effect on reducing cerebral vasospasm. Our study is the first study in the literature showing that CAPE inhibits ischemic brain injury following subarachnoid hemorrhage.


Assuntos
Região CA3 Hipocampal/efeitos dos fármacos , Ácidos Cafeicos/administração & dosagem , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Álcool Feniletílico/análogos & derivados , Hemorragia Subaracnóidea/patologia , Vasoespasmo Intracraniano/patologia , Animais , Região CA3 Hipocampal/patologia , Modelos Animais de Doenças , Neurônios/patologia , Álcool Feniletílico/administração & dosagem , Própole , Ratos Wistar
18.
J Agric Food Chem ; 68(10): 3099-3111, 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32067456

RESUMO

Sesamol, a lignan in sesame, possesses several bioactivities, such as antioxidation, anti-inflammation, and neuroprotective capability. In this study, the effects of sesamol on aging-caused cognitive defects are investigated. Twelve-month-old mice were treated with sesamol (0.1%, w/w) as dietary supplementation for 12 weeks. Behavioral tests revealed that sesamol improved aging-associated cognitive impairments. Sesamol decreased aging-induced oxidative stress via suppression of malondialdehyde production and increased antioxidant enzymes. Histological staining showed that sesamol treatment improved aging-induced neuronal damage and synaptic dysfunction in the hippocampus. Furthermore, sesamol significantly reduced aging-induced neuroinflammation by inhibiting the microglial overactivation and inflammatory cytokine expressions. Meanwhile, the accumulation of Aß1-42 was reduced by sesamol treatment. Moreover, sesamol protected the gut barrier integrity and reduced LPS release, which was highly associated with its beneficial effects on behavioral and inflammatory changes. In conclusion, our findings indicated that the use of sesamol is feasible in the treatment of aging-related diseases.


Assuntos
Envelhecimento/efeitos dos fármacos , Benzodioxóis/administração & dosagem , Disfunção Cognitiva/tratamento farmacológico , Fármacos Neuroprotetores/administração & dosagem , Fenóis/administração & dosagem , Envelhecimento/imunologia , Envelhecimento/psicologia , Peptídeos beta-Amiloides/imunologia , Animais , Disfunção Cognitiva/imunologia , Disfunção Cognitiva/psicologia , Hipocampo/efeitos dos fármacos , Hipocampo/imunologia , Humanos , Masculino , Malondialdeído/imunologia , Camundongos , Microglia/efeitos dos fármacos , Microglia/imunologia , Estresse Oxidativo/efeitos dos fármacos
19.
Nat Commun ; 11(1): 941, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32071304

RESUMO

Oxidative stress is a major pathogenic mechanism in Parkinson's disease (PD). As an important cellular antioxidant, glutathione (GSH) balances the production and incorporation of free radicals to protect neurons from oxidative damage. GSH level is decreased in the brains of PD patients. Hence, clarifying the molecular mechanism of GSH deficiency may help deepen our knowledge of PD pathogenesis. Here we report that the astrocytic dopamine D2 receptor (DRD2) regulates GSH synthesis via PKM2-mediated Nrf2 transactivation. In addition we find that pyridoxine can dimerize PKM2 to promote GSH biosynthesis. Further experiments show that pyridoxine supplementation increases the resistance of nigral dopaminergic neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in wild-type mice as well as in astrocytic Drd2 conditional knockout mice. We conclude that dimerizing PKM2 may be a potential target for PD treatment.


Assuntos
Glutationa/biossíntese , Intoxicação por MPTP/patologia , Fator 2 Relacionado a NF-E2/genética , Fármacos Neuroprotetores/administração & dosagem , Piruvato Quinase/metabolismo , Receptores de Dopamina D2/metabolismo , Animais , Astrócitos , Técnicas de Observação do Comportamento , Comportamento Animal/efeitos dos fármacos , Células Cultivadas , Dopamina/metabolismo , Neurônios Dopaminérgicos , Intoxicação por MPTP/diagnóstico , Intoxicação por MPTP/tratamento farmacológico , Camundongos Knockout , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Cultura Primária de Células , Multimerização Proteica/efeitos dos fármacos , Piridoxina/administração & dosagem , Espécies Reativas de Oxigênio/metabolismo , Receptores de Dopamina D2/genética , Substância Negra/citologia , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Ativação Transcricional
20.
J Agric Food Chem ; 68(8): 2381-2392, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32037817

RESUMO

Increasing level of inflammation and oxidative stress could lead to memory impairment. The purpose of this study was to determine the neuroprotective effects of walnut peptides against memory deficits induced by lipopolysaccharide (LPS) in mice and further to explore the underlying anti-inflammatory mechanisms against LPS-elicited inflammation in BV-2 cells. Results showed that walnut protein hydrolysate (WPH) and its low-molecular-weight fraction (WPHL) could ameliorate the memory deficits induced by LPS via normalizing the inflammatory response and oxidative stress in brain, especially WPHL. Furthermore, 18 peptides with anti-inflammatory activities on LPS-activated BV-2 cells were identified from WPHL and it was found that Trp, Gly, and Leu residues in peptides might contribute to the anti-inflammation. Meanwhile, the strong anti-inflammatory effects of LPF, GVYY, and APTLW might be related to their hydrophobic and aromatic amino acid residues as well. LPF, GVYY, and APTLW could reduce the content of proinflammatory mediators and cytokines by downregulating related enzyme expressions and mRNA expressions. Additionally, ROS and mitochondria homeostasis might also contribute to their anti-inflammatory effects.


Assuntos
Anti-Inflamatórios/administração & dosagem , Disfunção Cognitiva/tratamento farmacológico , Juglans/química , Estresse Oxidativo/efeitos dos fármacos , Peptídeos/administração & dosagem , Animais , Anti-Inflamatórios/química , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/imunologia , Disfunção Cognitiva/psicologia , Humanos , Lipopolissacarídeos/efeitos adversos , Aprendizagem em Labirinto , Camundongos , Peso Molecular , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/química , Nozes/química , Peptídeos/química
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