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1.
Life Sci ; 252: 117654, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32277979

RESUMO

BACKGROUND: Septic encephalopathy, the most frequent complication of sepsis, is orchestrated by a complex interplay of signals that leads to high mortality rates among intensive care unit patients. However, the role of the vascular endothelial growth factor receptor-2 (VEGFR2) in endoplasmic reticulum stress response (ERSR), during septic encephalopathy, is still elusive. AIM: This study was aimed to examine the effect of an in-house designed/synthesized VEGFR2 antagonist, named WAG4S, on septic encephalopathy using cecal ligation and perforation (CLP). MAIN METHODS: Rats were intraperitoneally injected with WAG-4S (1 mg/kg/d) for 7 days post-CLP. KEY FINDINGS: In septic animals, VEGFR2 antagonism declined the expression of cortical p-VEGFR2 and p-mammalian target of rapamycin complex-1 (p-mTORC1). It also worsened the behavioral and histopathological alterations beyond CLP. However, and contrary to CLP, WAG-4S decreased the p-protein kinase R-like ER kinase (p-PERK) and eukaryotic initiation factor-2α (p-eIF2α) expression. Moreover, VEGFR2 blockade upregulated the mRNA expression of activating transcription factor-4 (ATF4), binding immunoglobulin protein/glucose-regulated protein-78 (Bip/GRP78), growth arrest and DNA damage-34 (GADD34) and spliced X-box binding protein-1 (XBP1s) above CLP. Similarly, it boosted inositol requiring enzyme-1α (IRE1α) activation and redox imbalance. In the same context, WAG-4S augmented the protein levels of CLP-induced ERSR apoptotic markers, namely C/EBP homologous protein (CHOP/GADD153), c-jun N-terminal kinase (JNK) and caspase-3. SIGNIFICANCE: In conclusion, the PERK/eIF2α axis inhibition, during septic encephalopathy, is VEGFR2-independent, whereas the activated IRE1α/XBP1s/CHOP/JNK/caspase-3 cue promotes the ERSR execution module through VEGFR2 inhibition. This has turned VEGFR2 into a potential therapeutic target for ameliorating such an ailment.


Assuntos
Encefalopatias/fisiopatologia , Estresse do Retículo Endoplasmático/fisiologia , Sepse/complicações , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator 4 Ativador da Transcrição/genética , Animais , Encefalopatias/etiologia , Encefalopatias/prevenção & controle , Modelos Animais de Doenças , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Sepse/tratamento farmacológico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , eIF-2 Quinase/metabolismo
2.
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
3.
Ann Neurol ; 87(3): 339-346, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31943325

RESUMO

OBJECTIVE: SCN8A encephalopathy is a developmental and epileptic encephalopathy (DEE) caused by de novo gain-of-function mutations of sodium channel Nav 1.6 that result in neuronal hyperactivity. Affected individuals exhibit early onset drug-resistant seizures, developmental delay, and cognitive impairment. This study was carried out to determine whether reducing the abundance of the Scn8a transcript with an antisense oligonucleotide (ASO) would delay seizure onset and prolong survival in a mouse model of SCN8A encephalopathy. METHODS: ASO treatment was tested in a conditional mouse model with Cre-dependent expression of the pathogenic patient SCN8A mutation p.Arg1872Trp (R1872W). This model exhibits early onset of seizures, rapid progression, and 100% penetrance. An Scn1a +/- haploinsufficient mouse model of Dravet syndrome was also treated. ASO was administered by intracerebroventricular injection at postnatal day 2, followed in some cases by stereotactic injection at postnatal day 30. RESULTS: We observed a dose-dependent increase in length of survival from 15 to 65 days in the Scn8a-R1872W/+ mice treated with ASO. Electroencephalographic recordings were normal prior to seizure onset. Weight gain and activity in an open field were unaffected, but treated mice were less active in a wheel running assay. A single treatment with Scn8a ASO extended survival of Dravet syndrome mice from 3 weeks to >5 months. INTERPRETATION: Reduction of Scn8a transcript by 25 to 50% delayed seizure onset and lethality in mouse models of SCN8A encephalopathy and Dravet syndrome. Reduction of SCN8A transcript is a promising approach to treatment of intractable childhood epilepsies. Ann Neurol 2020;87:339-346.


Assuntos
Encefalopatias/prevenção & controle , Epilepsias Mioclônicas/prevenção & controle , Canal de Sódio Disparado por Voltagem NAV1.6/efeitos dos fármacos , Animais , Encefalopatias/complicações , Encefalopatias/mortalidade , Relação Dose-Resposta a Droga , Epilepsias Mioclônicas/complicações , Epilepsias Mioclônicas/mortalidade , Feminino , Infusões Intraventriculares , Masculino , Camundongos , Camundongos Transgênicos , Mutação , Canal de Sódio Disparado por Voltagem NAV1.6/administração & dosagem , Oligonucleotídeos Antissenso/farmacologia , Convulsões/complicações , Convulsões/prevenção & controle
4.
Toxicol Lett ; 319: 66-73, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31726083

RESUMO

Thallium ion (Tl+) and its neurotoxic products are widely known to cause severe neurological complications. However, the exact mechanism of action remains unknown, with limited therapeutic options available. This study aims to examine the toxic effects of Thallium (I) Nitrate (TlNO3) on primary hippocampal neurons of E17-E18 Wistar rat embryos, and the potential neuroprotective role of Nrf2- Keap1 signaling pathway against thallium-induced oxidative stress and mitochondrial dysfunction. TlNO3 induces a significant increase in reactive oxygen species levels and mitochondrial dysfunction in primary hippocampal neurons. Furthermore, the Nrf2-Keap1 signaling pathway played a protective role against TlNO3-induced hippocampal neuronal cytotoxicity. Moreover, mitochondrial fusion protein Mitofusin 2 (Mfn2) levels significantly decreased in hippocampal neurons when exposed to TlNO3, indicating that Mfn2 protein levels are linked to TlNO3-induced neurotoxicity. t-BHQ, a Nrf2 and phase II detoxification enzyme inducer, counteracted the oxidative damage in hippocampal neurons by activating the Nrf2-Keap1 signaling pathway after TlNO3 exposure; the activated Nrf2-Keap1 pathway could then maintain Mfn2 function by regulating Mfn2 protein expression. Thus, Nrf2-Keap1 pathway activation plays a protective role in Tl+-induced brain damage, and specific agonists have been identified to have great potential for treating thallium poisoning.


Assuntos
Hipocampo/efeitos dos fármacos , Proteína 1 Associada a ECH Semelhante a Kelch/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Tálio/toxicidade , Animais , Encefalopatias/induzido quimicamente , Encefalopatias/patologia , Encefalopatias/prevenção & controle , Feminino , Hipocampo/citologia , Proteínas de Membrana/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Proteínas Mitocondriais/efeitos dos fármacos , Proteínas Mitocondriais/metabolismo , Cultura Primária de Células , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
5.
Zool Res ; 41(1): 3-19, 2020 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-31840949

RESUMO

Hypobaric hypoxia (HH) exposure can cause serious brain injury as well as life-threatening cerebral edema in severe cases. Previous studies on the mechanisms of HH-induced brain injury have been conducted primarily using non-primate animal models that are genetically distant to humans, thus hindering the development of disease treatment. Here, we report that cynomolgus monkeys ( Macaca fascicularis) exposed to acute HH developed human-like HH syndrome involving severe brain injury and abnormal behavior. Transcriptome profiling of white blood cells and brain tissue from monkeys exposed to increasing altitude revealed the central role of the HIF-1 and other novel signaling pathways, such as the vitamin D receptor (VDR) signaling pathway, in co-regulating HH-induced inflammation processes. We also observed profound transcriptomic alterations in brains after exposure to acute HH, including the activation of angiogenesis and impairment of aerobic respiration and protein folding processes, which likely underlie the pathological effects of HH-induced brain injury. Administration of progesterone (PROG) and steroid neuroprotectant 5α-androst-3ß,5,6ß-triol (TRIOL) significantly attenuated brain injuries and rescued the transcriptomic changes induced by acute HH. Functional investigation of the affected genes suggested that these two neuroprotectants protect the brain by targeting different pathways, with PROG enhancing erythropoiesis and TRIOL suppressing glutamate-induced excitotoxicity. Thus, this study advances our understanding of the pathology induced by acute HH and provides potential compounds for the development of neuroprotectant drugs for therapeutic treatment.


Assuntos
Androstanóis/farmacologia , Hipóxia/veterinária , Macaca fascicularis , Doenças dos Macacos/prevenção & controle , Progesterona/farmacologia , Transcriptoma , Androstanóis/administração & dosagem , Animais , Encefalopatias/prevenção & controle , Encefalopatias/veterinária , Cálcio/metabolismo , Regulação da Expressão Gênica , Hipóxia/patologia , Leucócitos/metabolismo , Masculino , Fármacos Neuroprotetores/farmacologia , Pressão , Progesterona/administração & dosagem
7.
Nutrients ; 11(10)2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31591353

RESUMO

Iron deficiency anemia (IDA) is one of the most prevalent nutritional deficiencies worldwide. Iron plays critical roles in nervous system development and cognition. Despite the known detrimental consequences of IDA on cognition, available studies do not provide molecular mechanisms elucidating the role of iron in brain functions during iron deficiency and recovery with dairy components. In this study, 100 male Wistar rats were placed on a pre-experimental period of 40 days and randomly divided in two groups: a control group receiving a normal-Fe diet, (45 mg/kg), and an Fe-deficient group receiving a low-Fe diet (5 mg/kg). At day 40, 10 rats per group were sacrificed to anemia control, and 80 rats were divided into eight experimental groups fed with fermented goat or cow milk-based diets, with normal Fe content or Fe overload (450 mg/kg) for 30 days. IDA decreased most of the parameters related to brain molecular functions, namely dopamine, irisin, MAO-A, oxytocin, ß-endorphin, and α-MSH, while it increased synaptophysin. These alterations result in an impairment of brain molecular functions. In general, during anemia recovery, fermented goat milk diet consumption increased dopamine, oxytocin, serotonin, synaptophysin, and α-MSH, and decreased MAO-A and MAO-B, suggesting a potential neuroprotective effect in brain functions, which could enhance brain molecular functions.


Assuntos
Anemia Ferropriva/dietoterapia , Encefalopatias/prevenção & controle , Encéfalo/metabolismo , Produtos Fermentados do Leite , Leite , Anemia Ferropriva/sangue , Anemia Ferropriva/fisiopatologia , Ração Animal , Animais , Biomarcadores/sangue , Encéfalo/fisiopatologia , Encefalopatias/metabolismo , Encefalopatias/fisiopatologia , Modelos Animais de Doenças , Cabras , Masculino , Ratos Wistar
8.
Nitric Oxide ; 93: 71-77, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31526855

RESUMO

INTRODUCTION: Besides therapeutic hypothermia or targeted temperature management no novel therapies have been developed to improve outcomes of patients after cardiac arrest (CA). Recent studies suggest that nitrite reduces neurological damage after asphyxial CA. Nitrite is also implicated as a new mediator of remote post conditioning produced by tourniquet inflation-deflation, which is under active investigation in CA. However, little is known about brain penetration or pharmacokinetics (PK). Therefore, to define the optimal use of this agent, studies on the PK of nitrite in experimental ventricular fibrillation (VF) are needed. We tested the hypothesis that nitrite administered after resuscitation from VF is detectable in cerebrospinal fluid (CSF), brain and other organ tissues, produces no adverse hemodynamic effects, and improves neurologic outcome in rats. METHODS: After return of spontaneous circulation (ROSC) of 5 min untreated VF, adult male Sprague-Dawley rats were given intravenous nitrite (8 µM, 0.13 mg/kg) or placebo as a 5 min infusion beginning at 5 min after CA. Additionally, sham groups with and without nitrite treatment were also studied. Whole blood nitrite levels were serially measured. After 15 min, CSF, brain, heart and liver tissue were collected. In a second series, using a randomized and blinded treatment protocol, rats were treated with nitrite or placebo after arrest. Neurological deficit scoring (NDS) was performed daily and eight days after resuscitation, fear conditioning testing (FCT) and brain histology were assessed. RESULTS: In an initial series of experiments, rats (n = 21) were randomized to 4 groups: VF-CPR and nitrite therapy (n = 6), VF-CPR and placebo therapy (n = 5), sham (n = 5), or sham plus nitrite therapy (n = 5). Whole blood nitrite levels increased during drug infusion to 57.14 ±â€¯10.82 µM at 11 min post-resuscitation time (1 min after dose completion) in the VF nitrite group vs. 0.94 ±â€¯0.58 µM in the VF placebo group (p < 0.001). There was a significant difference between the treatment and placebo groups in nitrite levels in blood between 7.5 and 15 min after CPR start and between groups with respect to nitrite levels in CSF, brain, heart and liver. In a second series (n = 25 including 5 shams), 19 out of 20 animals survived until day 8. However, NDS, FCT and brain histology did not show any statistically significant difference between groups. CONCLUSIONS: Nitrite, administered early after ROSC from VF, was shown to cross the blood brain barrier after a 5 min VF cardiac arrest. We characterized the PK of intravenous nitrite administration after VF and were able to demonstrate nitrite safety in this feasibility study.


Assuntos
Parada Cardíaca/tratamento farmacológico , Nitritos/farmacocinética , Nitritos/uso terapêutico , Fibrilação Ventricular/tratamento farmacológico , Administração Intravenosa , Animais , Barreira Hematoencefálica/metabolismo , Encefalopatias/etiologia , Encefalopatias/prevenção & controle , Parada Cardíaca/complicações , Humanos , Masculino , Nitritos/administração & dosagem , Ratos Sprague-Dawley , Distribuição Tecidual , Fibrilação Ventricular/complicações
10.
PLoS One ; 14(8): e0220404, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31369614

RESUMO

BACKGROUND: Patients experiencing cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) often die or suffer from severe neurological impairment. Post resuscitation syndrome is characterized by a systemic inflammatory response. Toll-like receptor 4 (TLR4) is a major mediator of inflammation and TLR4 has been implicated in the pathogenesis of post-resuscitation encephalopathy. The aim of this study was to evaluate whether TLR4 deficiency or inhibition can modulate survival and neurofunctional outcome after CA/CPR. METHODS: Following intubation and central venous cannulation, CA was induced in wild type (C57Bl/6J, n = 38), TLR4 deficient (TLR4-/-, n = 37) and TLR4 antibody treated mice (5mg/kg MTS510, n = 15) by high potassium. After 10min, CPR was performed using a modified sewing machine until return of spontaneous circulation (ROSC). Cytokines and cerebral TNFalpha levels were measured 8h after CA/CPR. Survival, early neurological recovery, locomotion, spatial learning and memory were assessed over a period of 28 days. RESULTS: Following CA/CPR, all mice exhibited ROSC and 31.5% of wild type mice survived until day 28. Compared to wild type mice, neither TLR4-/- nor MTS510 treated wild type mice had statistically significant altered survival following CA/CPR (51.3 and 26.7%, P = 0.104 and P = 0.423 vs. WT, respectively). Antibody-treated but not TLR4-/- mice had higher IL-1ß and IL-6 levels and TLR4-/- mice had higher IL-10 and cerebral TNFalpha levels. No differences existed between mice of all groups in early neurological recovery, locomotion, spatial learning ability or remembrance. CONCLUSION: Therapeutic strategies targeting TLR4 may not be suitable for the reduction of mortality or neurofunctional impairment after CA/CPR.


Assuntos
Encefalopatias/etiologia , Reanimação Cardiopulmonar , Parada Cardíaca/complicações , Receptor 4 Toll-Like/deficiência , Animais , Encefalopatias/prevenção & controle , Reanimação Cardiopulmonar/efeitos adversos , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Parada Cardíaca/mortalidade , Hemodinâmica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Síndrome de Resposta Inflamatória Sistêmica/complicações , Síndrome de Resposta Inflamatória Sistêmica/etiologia , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/fisiologia , Fator de Necrose Tumoral alfa/metabolismo
11.
Neurochem Int ; 129: 104501, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31299417

RESUMO

Brain is a site of diabetic end-organ damage. Diabetes-associated cognitive dysfunction, referred as "diabetic encephalopathy" (DE) has been coined for the patients with type 2 diabetes mellitus showing decline in their cognitive function, especially weak episodic memory, cognitive inflexibility and poor psychomotor performance leading towards Alzheimer's disease. Current evidence supported that aberrant synapses, energy metabolism imbalance, advanced glycation end products (AGEs) accumulation and Tau hyperphosphorylation are associated with cognition deficits induced by diabetes. Oleoylethanolamide (OEA), an endogenous peroxisome proliferator-activated receptor alpha (PPARα) agonist, has anti-hyperlipidemia, anti-inflammatory and neuroprotective activities. However, the effect of OEA on DE is unknown. Therefore, we tested its influence against cognitive dysfunction in high fat diet and streptozotocin (HFD + STZ)-induced diabetic C57BL/6J and PPARα--/- mice using Morris water maze (MWM) test. Neuron staining, dementia markers and neuroplasticity in the hippocampus were assessed to evaluate the neuropathological changes. The results showed that chronic OEA treatment significantly lowered hyperglycemia, recovered cognitive performance, reduced dementia markers, and inhibited hippocampal neuron loss and neuroplasticity impairments in diabetic mice. In contrast, the changes in MWM performance and neuron loss were not observed in PPARα knockout mice via OEA administration. These results indicated that OEA may provide a potential alternative therapeutic for DE by activating PPARα signaling.


Assuntos
Encefalopatias/prevenção & controle , Transtornos Cognitivos/prevenção & controle , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Endocanabinoides/uso terapêutico , Ácidos Oleicos/uso terapêutico , PPAR alfa/agonistas , Animais , Glicemia/análise , Encefalopatias/tratamento farmacológico , Encefalopatias/etiologia , Encefalopatias/patologia , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/patologia , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/psicologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/psicologia , Dieta Hiperlipídica/efeitos adversos , Produtos Finais de Glicação Avançada/sangue , Hipocampo/patologia , Resistência à Insulina , Lipídeos/sangue , Masculino , Aprendizagem em Labirinto , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Transtornos da Memória/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurogênese/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , PPAR alfa/deficiência , PPAR alfa/genética , PPAR alfa/fisiologia , Organismos Livres de Patógenos Específicos , Estreptozocina , Proteínas tau/metabolismo
12.
Handb Clin Neurol ; 162: 315-328, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31324318

RESUMO

Despite notable advances in the care and survival of preterm infants, a significant proportion of preterm neonates will have life-long cognitive, behavioral, and motor deficits, and robustly effective neuroprotective strategies are still missing. These therapies must target the pathophysiologic mechanisms observed in contemporaneous infants and rely on modern epidemiology, imaging, and experimental models and assessment techniques. Two drugs, magnesium sulfate and caffeine, are already in use in several units, and although their targets are apnea of prematurity and myometrial contractility (respectively), they do offer improved odds of positive outcomes. Nevertheless, these drugs have limited efficacy, and NICU-to-NICU administration varies greatly. As such, there is an obvious need for additional specific neurotherapeutic strategies to further enhance the outcome of this very fragile population of neonates. The chapter reviews these issues, highlights bottlenecks that need to be solved for meaningful progress in the field, and proposes future innovative avenues for intervention, including delayed interventions.


Assuntos
Encefalopatias/prevenção & controle , Doenças do Prematuro/prevenção & controle , Neuroproteção , Adulto , Encefalopatias/congênito , Encefalopatias/fisiopatologia , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Gravidez
14.
Neurotoxicology ; 74: 19-27, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31095963

RESUMO

A common consequence of exposure to organophosphate nerve agents is the centrally mediated seizure activity that appears even after conventional treatment with atropine and oximes. We have previously demonstrated a major inflammatory response with subsequent brain damage which was correlated with the duration of the sarin-induced seizures (Chapman et al., 2006). In the present work seizures were induced by the nerve agent sarin (1.2 LD50) insufficiently treated 1 min later by atropine and trimedoxime bromide (TA), with additional midazolam treatment either 5 or 30 min after continuous seizure activity. The efficacy of both steroidal and nonsteroidal anti-inflammatory drugs (NSAIDs), as well as other drugs that were reported as beneficial in neuroprotection, were evaluated for their contribution as adjunct treatment against sarin induced seizures and the ensuing inflammatory brain damage. Results show that both steroids and NSAIDs were harmful when administered during convulsions, and steroids were at best ineffective if administered at their termination. However, if administered at termination of convulsions, the NSAID ibuprofen, the selective COX 2 inhibitor nimesulide and the PLA2 inhibitor quinacrine were partially effective in reducing brain inflammatory markers. Administration of exogenous analogs of prostaglandins (PGE2) immediately following sarin-induced convulsions was found to have a beneficial effect in reducing brain inflammatory markers measured at 24 h and one week post sarin exposure. These findings support the hypothesis that elevated levels of PGE2 have a beneficial role immediately following sarin induced seizures, and that early inhibition of PGE2 production by both steroids and NSAID is contraindicative.


Assuntos
Anti-Inflamatórios/uso terapêutico , Encefalopatias/induzido quimicamente , Encefalopatias/prevenção & controle , Substâncias para a Guerra Química , Inibidores da Colinesterase/toxicidade , Encefalite/induzido quimicamente , Encefalite/prevenção & controle , Prostaglandinas/metabolismo , Sarina/toxicidade , Animais , Anticonvulsivantes/uso terapêutico , Atropina/uso terapêutico , Reativadores da Colinesterase/uso terapêutico , Dinoprostona/metabolismo , Masculino , Midazolam/uso terapêutico , Agentes Neurotóxicos , Fármacos Neuroprotetores/uso terapêutico , Ratos , Ratos Sprague-Dawley , Convulsões/induzido quimicamente , Convulsões/prevenção & controle , Trimedoxima/uso terapêutico
15.
Brain Dev ; 41(7): 618-624, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30862409

RESUMO

BACKGROUND: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is the most prevalent encephalopathy in Japanese children. AESD is characterized by a prolonged febrile seizure on day 1 followed by secondary seizures and MRI abnormality on days 4-6, resulting in high incidence of neurological sequelae. We aimed to clarify whether early administration of vitamins (vitamin B1, vitamin B6, and l-carnitine) would improve the clinical course of AESD. METHODS: We retrospectively reviewed 34 patients with acute encephalopathy who were admitted to our hospital between January 2009 and August 2016. Of the retrospectively registered 34 patients, 22 (65%) since 2011 were treated with the drug cocktail (prescription group) within 24 h of onset, whereas 12 (35%) before 2011 were not (non-prescription group). We compared clinical course, laboratory data, and MRI findings historically in both groups. RESULTS: The two groups did not differ in terms of laboratory findings except for blood lactate values. There were no differences between the two groups regarding duration of ICU admission, intubation, or the duration of seizures. Among the prescription group, two patients developed AESD while 20 had mild encephalopathy (single phasic). In contrast, seven patients inthe non-prescription group developed AESD while five did not. The incidence of AESD was lower in the prescription group (P = 0.004). As for outcomes, the rate of developmental delay and epilepsy was significantly lower in the prescription group. CONCLUSIONS: Our data suggested that early administration of vitamins would improve the clinical course of acute encephalopathy. Mitochondrial rescue and neuroprotection are thought to be responsible for the favorable results.


Assuntos
Encefalopatias/tratamento farmacológico , Carnitina/uso terapêutico , Tiamina/uso terapêutico , Vitamina B 6/uso terapêutico , Encefalopatias/prevenção & controle , Estudos de Casos e Controles , Pré-Escolar , Diagnóstico Diferencial , Progressão da Doença , Epilepsia/complicações , Epilepsia/tratamento farmacológico , Feminino , Humanos , Lactente , Recém-Nascido , Imagem por Ressonância Magnética , Masculino , Estudos Retrospectivos , Convulsões/tratamento farmacológico , Convulsões Febris/diagnóstico
16.
Lipids Health Dis ; 18(1): 43, 2019 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-30736810

RESUMO

BACKGROUND: Diabetic encephalopathy is a chronic complications of diabetes mellitus that affects the central nervous system. We evaluated the effect of ω3 and ω6 polyunsaturated fatty acids (PUFAs) supplementation plus the antioxidant agent nordihydroguaiaretic acid (NDGA) on the etiopathology of diabetic encephalopathy in eSS rats, a spontaneous model of type 2 diabetes. METHODS: One hundred twenty spontaneous diabetic eSS male rats and 38 non-diabetic Wistar, used as healthy control, received monthly by intraperitoneal route, ω3 or ω6 PUFA (6.25 mg/kg) alone or plus NDGA (1.19 mg/kg) for 12 months. Diabetic rats had a worse performance in behavioural Hole-Board test. Histopathological analysis confirmed lesions in diabetic rats brain tissues. We also detected low expression of synaptophysin, a protein linked to release of neurotransmitters, by immunohistochemically techniques in eSS rats brain. Biochemical and histopathological studies of brain were performed at 12th month. Biochemical analysis showed altered parameters related to metabolism. High levels of markers of oxidative stress and inflammation were detected in plasma and brain tissues. Data were analysed by ANOVA test and paired t test was used by comparison of measurements of the same parameter at different times. RESULTS: The data obtained in this work showed that behavioural, biochemical and morphological alterations observed in eSS rats are compatible with previously reported indices in diabetic encephalopathy and are associated with increased glucolipotoxicity, chronic low-grade inflammation and oxidative stress burden. Experimental treatments assayed modulated the values of studied parameters. CONCLUSIONS: The treatments tested with ω3 or ω3 plus NDGA showed improvement in the values of the studied parameters in eSS diabetic rats. These observations may form the basis to help in prevent and manage the diabetic encephalopathy.


Assuntos
Encefalopatias/etiologia , Neuropatias Diabéticas/prevenção & controle , Ácidos Graxos Ômega-3/uso terapêutico , Masoprocol/uso terapêutico , Animais , Glicemia/análise , Encéfalo/patologia , Encefalopatias/patologia , Encefalopatias/prevenção & controle , Neuropatias Diabéticas/patologia , Suplementos Nutricionais , Modelos Animais de Doenças , Teste de Tolerância a Glucose , Hipocampo/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
17.
Br J Anaesth ; 122(3): 350-360, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30770053

RESUMO

BACKGROUND: Resolution of inflammation is an active and dynamic process after surgery. Maresin 1 (MaR1) is one of a growing number of specialised pro-resolving lipids biosynthesised by macrophages that regulates acute inflammation. We investigated the effects of MaR1 on postoperative neuroinflammation, macrophage activity, and cognitive function in mice. METHODS: Adult male C57BL/6 (n=111) and Ccr2RFP/+Cx3cr1GFP/+ (n=54) mice were treated with MaR1 before undergoing anaesthesia and orthopaedic surgery. Systemic inflammatory changes, bone healing, neuroinflammation, and cognition were assessed at different time points. MaR1 protective effects were also evaluated using bone marrow derived macrophage cultures. RESULTS: MaR1 exerted potent systemic anti-inflammatory effects without impairing fracture healing. Prophylaxis with MaR1 prevented surgery-induced glial activation and opening of the blood-brain barrier. In Ccr2RFP/+Cx3cr1GFP/+ mice, fewer infiltrating macrophages were detected in the hippocampus after surgery with MaR1 prophylaxis, which resulted in improved memory function. MaR1 treatment also reduced expression of pro-inflammatory cell surface markers and cytokines by in vitro cultured macrophages. MaR1 was detectable in the cerebrospinal fluid of older adults before and after surgery. CONCLUSIONS: MaR1 exerts distinct anti-inflammatory and pro-resolving effects through regulation of macrophage infiltration, NF-κB signalling, and cytokine release after surgery. Future studies on the use of pro-resolving lipid mediators may inform novel approaches to treat neuroinflammation and postoperative neurocognitive disorders.


Assuntos
Encefalopatias/prevenção & controle , Ácidos Docosa-Hexaenoicos/farmacologia , Fraturas Ósseas/cirurgia , Inflamação/prevenção & controle , Transtornos Neurocognitivos/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Animais , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Período Perioperatório
18.
Am J Health Behav ; 43(2): 300-310, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30808470

RESUMO

Objective: In this study, we assessed patient knowledge, beliefs, and attitudes about brain health and strategies for Alzheimer's disease and related dementias (ADRD) prevention. Methods: We administered a Web-based survey consisting of 17 questions about brain health and strategies for ADRD prevention in a convenience sample of 1661 patients in an integrated healthcare delivery system in Washington state between February and March 2018. We calculated frequency distributions of the quantitative data and conducted inductive content analysis of qualitative data. Results: Most respondents were female (77%), 51-70 years of age (64%), and white (89%). Although most agreed it is possible to improve brain health and reduce personal ADRD risk, one- third lacked confidence that they could take action to reduce personal ADRD risk. Participants' responses to open-ended questions revealed 10 themes grouped into 3 organizing categories regarding their perceptions about how to prevent ADRD onset: (1) understand ADRD; (2) stay engaged; and (3) manage one's own health and healthcare. Conclusions: Survey respondents were engaged and aware of dementia prevention, but they lacked access to personally action- able evidence..


Assuntos
Envelhecimento , Encefalopatias/prevenção & controle , Demência/prevenção & controle , Conhecimentos, Atitudes e Prática em Saúde , Idoso , Doença de Alzheimer/prevenção & controle , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , Pessoa de Meia-Idade , Washington
19.
Ann Thorac Surg ; 108(1): 283-291, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30682350

RESUMO

BACKGROUND: The increasing use of antegrade cerebral perfusion (ACP) during aortic arch surgery has corresponded with a trend toward warmer target temperatures for hypothermic circulatory arrest. This meta-analysis examined the clinical outcomes using colder or warmer circulatory arrest targets with ACP. METHODS: Electronic searches were performed using four databases from their inception to February 2017. Comparative studies of adult patients who underwent aortic arch operations using ACP at different circulatory arrest temperatures were included. Data were extracted by 2 independent researchers and analyzed according to predefined end points using a random-effects model. RESULTS: The literature search identified 18 comparative studies, with 1,215 patients in the "cold" cohort and 1,417 in the "warm" cohort. Mean hypothermic circulatory arrest temperatures were 20.3°C and 26.5°C in the cold and warm groups, respectively. A trend existed for increased permanent neurologic deficit overall when colder targets were used (odds ratio, 1.45; 95% confidence interval, 0.98 to 2.13; p = 0.06); this became significant when adjusted estimates were aggregated (odds ratio, 1.65; 95% confidence interval, 1.06 to 2.55; p = 0.03). No difference in the mortality rate was seen when adjusted effects were aggregated. Temporary neurologic deficit, postoperative dialysis, ventilator time, and intensive care unit stay were significantly reduced in the warm cohort overall. No significant differences in reexploration for bleeding were found. CONCLUSIONS: ACP with warmer circulatory arrest temperatures may reduce the incidence of permanent neurologic deficit as well as potentially other clinical outcomes. Further studies are required to determine the safe circulatory arrest durations for visceral organs at warmer temperatures.


Assuntos
Aorta Torácica/cirurgia , Parada Cardíaca Induzida/métodos , Perfusão , Temperatura , Encéfalo/irrigação sanguínea , Encefalopatias/prevenção & controle , Procedimentos Cirúrgicos Cardiovasculares/mortalidade , Parada Circulatória Induzida por Hipotermia Profunda/efeitos adversos , Feminino , Parada Cardíaca Induzida/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/prevenção & controle
20.
Crit Care Med ; 47(3): 419-427, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30608279

RESUMO

OBJECTIVES: Implementation of delirium guidelines at ICUs is suboptimal. The aim was to evaluate the impact of a tailored multifaceted implementation program of ICU delirium guidelines on processes of care and clinical outcomes and draw lessons regarding guideline implementation. DESIGN: A prospective multicenter, pre-post, intervention study. SETTING: ICUs in one university hospital and five community hospitals. PATIENTS: Consecutive medical and surgical critically ill patients were enrolled between April 1, 2012, and February 1, 2015. INTERVENTIONS: Multifaceted, three-phase (baseline, delirium screening, and guideline) implementation program of delirium guidelines in adult ICUs. MEASUREMENTS AND MAIN RESULTS: The primary outcome was adherence changes to delirium guidelines recommendations, based on the Pain, Agitation and Delirium guidelines. Secondary outcomes were brain dysfunction (delirium or coma), length of ICU stay, and hospital mortality. A total of 3,930 patients were included. Improvements after the implementation pertained to delirium screening (from 35% to 96%; p < 0.001), use of benzodiazepines for continuous sedation (from 36% to 17%; p < 0.001), light sedation of ventilated patients (from 55% to 61%; p < 0.001), physiotherapy (from 21% to 48%; p < 0.001), and early mobilization (from 10% to 19%; p < 0.001). Brain dysfunction improved: the mean delirium duration decreased from 5.6 to 3.3 days (-2.2 d; 95% CI, -3.2 to -1.3; p < 0.001), and coma days decreased from 14% to 9% (risk ratio, 0.5; 95% CI, 0.4-0.6; p < 0.001). Other clinical outcome measures, such as length of mechanical ventilation, length of ICU stay, and hospital mortality, did not change. CONCLUSIONS: This large pre-post implementation study of delirium-oriented measures based on the 2013 Pain, Agitation, and Delirium guidelines showed improved health professionals' adherence to delirium guidelines and reduced brain dysfunction. Our findings provide empirical support for the differential efficacy of the guideline bundle elements in a real-life setting and provide lessons for optimization of guideline implementation programs.


Assuntos
Encefalopatias/etiologia , Delírio/terapia , Fidelidade a Diretrizes , Idoso , Encefalopatias/epidemiologia , Encefalopatias/prevenção & controle , Estudos Controlados Antes e Depois , Delírio/complicações , Delírio/diagnóstico , Feminino , Fidelidade a Diretrizes/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Estudos Prospectivos , Resultado do Tratamento
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