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1.
Rev. bras. ter. intensiva ; 33(3): 469-476, jul.-set. 2021. graf
Article in English, Portuguese | LILACS | ID: biblio-1347303

ABSTRACT

RESUMO Desde a instituição da circulação extracorpórea, há cinco décadas, a lesão cerebral decorrente desse procedimento durante cirurgias cardiovasculares tem sido uma complicação frequente. Não existe uma causa única de lesão cerebral pelo uso de circulação extracorpórea, porém se sabe que acomete cerca de 70% dos pacientes submetidos a esse procedimento. A avaliação da pressão intracraniana é um dos métodos que podem orientar os cuidados com os pacientes submetidos a procedimentos associados com distúrbios neurológicos. Este artigo descreve dois casos de pacientes submetidos à cirurgia cardiovascular com circulação extracorpórea, para os quais os procedimentos de neuroproteção na fase pós-operatória foram guiados pelos achados relacionados ao formato das ondas de pressão intracraniana, obtidos por meio de um método não invasivo de monitoramento.


ABSTRACT Brain injury caused by extracorporeal circulation during cardiovascular surgical procedures has been a recurring complication since the implementation of extracorporeal circulation five decades ago. There is no unique cause of brain injury due to the use of extracorporeal circulation, but it is known that brain injury affects about 70% of patients who undergo this procedure. Intracranial pressure assessment is one method that can guide the management of patients undergoing procedures associated with neurological disturbances. This study describes two cases of patients who underwent cardiovascular surgery with extracorporeal circulation in whom clinical protocols for neuroprotection in the postoperative phase were guided by intracranial pressure waveform findings obtained with a novel noninvasive intracranial pressure monitoring method.


Subject(s)
Humans , Intracranial Pressure , Cardiac Surgical Procedures/adverse effects , Extracorporeal Circulation , Neuroprotection , Intensive Care Units
3.
Neuroscience Bulletin ; (6): 1412-1426, 2021.
Article in English | WPRIM | ID: wpr-922631

ABSTRACT

Endogenously eliminating the hematoma is a favorable strategy in addressing intracerebral hemorrhage (ICH). This study sought to determine the role of retinoid X receptor-α (RXR-α) in the context of hematoma absorption after ICH. Our results showed that pharmacologically activating RXR-α with bexarotene significantly accelerated hematoma clearance and alleviated neurological dysfunction after ICH. RXR-α was expressed in microglia/macrophages, neurons, and astrocytes. Mechanistically, bexarotene promoted the nuclear translocation of RXR-α and PPAR-γ, as well as reducing neuroinflammation by modulating microglia/macrophage reprograming from the M1 into the M2 phenotype. Furthermore, all the beneficial effects of RXR-α in ICH were reversed by the PPAR-γ inhibitor GW9662. In conclusion, the pharmacological activation of RXR-α confers robust neuroprotection against ICH by accelerating hematoma clearance and repolarizing microglia/macrophages towards the M2 phenotype through PPAR-γ-related mechanisms. Our data support the notion that RXR-α might be a promising therapeutic target for ICH.


Subject(s)
Anilides/pharmacology , Cerebral Hemorrhage/drug therapy , Hematoma/drug therapy , Humans , Macrophages , Microglia , Neuroprotection , PPAR gamma , Retinoid X Receptor alpha
4.
Acta Medica Philippina ; : 109-116, 2021.
Article in English | WPRIM | ID: wpr-877177

ABSTRACT

@#Background and Objectives. Neuroprotection agents may help improve the outcomes of large vessel ischemic stroke. This study aims to explore the role of Virgin Coconut Oil (VCO), with its well-documented anti-oxidant properties, in neuroprotection after transient occlusion of the extracranial internal carotid artery in a rat model of stroke. Methods. Twenty-three Sprague-Dawley rats were randomized into two groups: 1) control group (n=11) given distilled water, and 2) treatment group (n=12) given virgin coconut oil at 5.15 ml/kg body weight for seven days. Subsequently, the rats underwent transient right extracranial internal carotid artery occlusion (EICAO) for 5 minutes using non-traumatic aneurysm clips. At 4 and 24 hours after EICAO, the animals were examined for neurologic deficits by an observer blinded to treatment groups, then sacrificed. Eight brain specimens (4 from each group) were subjected to histopathologic examination (H & E staining) while the rest of the specimens were processed using triphenyltetrazolium chloride (TTC) staining to determine infarct size and area of hemispheric edema. Results. VCO treatment significantly improved the severity of neurologic deficit (1.42 ± 2.31) compared to the control distilled water group (4.09 ± 2.59) 24 hours after EICAO. Whereas, infarct size and percent hemispheric edema did not significantly differ between the two groups. Conclusion. Prophylactic treatment of VCO is protective against EICAO-induced neurologic deficits in a rat model. VCO shows great potential as a neuroprotective agent for large vessel ischemic stroke. However, more studies are necessary to elucidate the neuroprotective mechanisms of VCO therapy in ischemic stroke.


Subject(s)
Palm Oil , Oxidants , Antioxidants , Neuroprotection , Ischemia , Stroke
5.
J. venom. anim. toxins incl. trop. dis ; 27: e20200171, 2021. tab, graf
Article in English | LILACS, VETINDEX | ID: biblio-1279405

ABSTRACT

Background Solitary wasp venoms may be a rich source of neuroactive substances, since their venoms are used for paralyzing preys. We have been exploring bioactive constituents of solitary wasp venoms and, in this study, the component profile of the venom from a solitary scoliid wasp, Scolia decorata ventralis, was investigated through a comprehensive analysis using LC-MS. Two peptides were synthesized, and their neuroprotective properties were evaluated. Methods A reverse-phase HPLC connected to ESI-MS was used for LC-MS analyses. Online mass fingerprinting was performed from TIC, and data-dependent tandem mass spectrometry gave the MS/MS spectra. The sequences of two major peptide components were determined by MALDI-TOF/TOF MS analysis, confirmed by solid phase synthesis. Using the synthetic peptides, biological activities were assessed. Cell integrity tests and neuroprotection analyzes using H2O2 as an oxidative stress inducer were performed for both peptides. Results Online mass fingerprinting revealed that the venom contains 123 components, and the MS/MS analysis resulted in 33 full sequences of peptide components. The two main peptides, α-scoliidine (DYVTVKGFSPLR) and β-scoliidine (DYVTVKGFSPLRKA), present homology with the bradykinin C-terminal. Despite this, both peptides did not behave as substrates or inhibitors of ACE, indicating that they do not interact with this metallopeptidase. In further studies, β-scoliidine, but not α -scoliidine, showed protective effects against oxidative stress-induced neurotoxicity in PC12 cells through integrity and metabolism cell assays. Interestingly, β-scoliidine has the extension of the KA dipeptide at the C-terminal in comparison with α-scoliidine. Conclusion Comprehensive LC-MS and MS/MS analyses from the Scolia decorata ventralis venom displayed the component profile of this venom. β-scoliidine showed an effective cytoprotective effect, probably due to the observed increase in the number of cells. This is the first report of solitary wasp venom peptides showing neuroprotective activity.(AU)


Subject(s)
Animals , Peptides/classification , Wasp Venoms , Wasps/metabolism , Neuroprotection , Oxidative Stress , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
6.
Rev. méd. Minas Gerais ; 31: 30211, 2021.
Article in Portuguese | LILACS | ID: biblio-1291269

ABSTRACT

O sulfato de magnésio tem sido utilizado em obstetrícia por décadas e milhares de mulheres já foram incluídas em ensaios clínicos que estudaram sua eficácia em uma variedade de condições gestacionais. Os principais usos do medicamento na atual prática obstétrica incluem prevenção e tratamento de convulsões eclâmpticas, prolongamento da gravidez para administração antenatal de corticosteroides e neuroproteção fetal na iminência de interrupção prematura da gravidez. Em função da alta qualidade e da consistência dos resultados de importantes ensaios clínicos, a indicação do sulfato de magnésio para profilaxia e terapia das convulsões eclâmpticas está bem estabelecida. Entretanto, tal unanimidade não ocorre com relação ao seu emprego como tocolítico, tanto pela discussão sobre sua efetividade quanto pelas doses mais altas usualmente utilizadas para esse fim. Em relação à importância do sulfato de magnésio como agente neuroprotetor fetal, a paralisia cerebral é a causa mais comum de deficiência motora na infância e tem como fator de risco mais importante a prematuridade, cuja incidência tem aumentado significativamente. Diretrizes nacionais e internacionais mais recentes, baseadas em resultados de ensaios clínicos randomizados e metanálises de boa qualidade, mostraram que a administração antenatal de sulfato de magnésio na iminência de parto pré-termo precoce é uma intervenção eficiente, viável, segura, com boa relação custo-benefício e pode contribuir para a melhoria dos desfechos neurológicos neonatais.


Magnesium sulfate has been used in obstetrics for decades and thousands of women have already been included in clinical trials that have studied its effectiveness in a variety of gestational conditions. The main uses of the drug in current obstetrical practice include prevention and treatment of eclamptic seizures, prolongation of pregnancy for antenatal administration of corticosteroids, and fetal neuroprotection in the imminence of premature termination of pregnancy. Because of the high quality and consistency of the results of important clinical trials, the indication of magnesium sulfate for prophylaxis and therapy of eclamptic seizures is well established. However, such unanimity does not occur regarding its use as tocolytic, either by the discussion of its effectiveness or by the higher doses usually used for this purpose. Regarding the importance of magnesium sulfate as a fetal neuroprotective agent, cerebral palsy is the most common cause of motor deficits in childhood and has a significantly higher incidence of prematurity as a major risk factor. More recent national and international guidelines, based on results from randomized controlled trials and good quality meta-analyzes, have shown that the antenatal administration of magnesium sulfate at the imminence of early preterm delivery is a cost-effective, viable, efficient intervention and safe and can contribute to the improvement of neonatal neurological outcomes.


Subject(s)
Humans , Female , Pregnancy , Magnesium Sulfate/therapeutic use , Obstetrics , Tocolysis , Cerebral Palsy , Eclampsia/drug therapy , Neuroprotection , Obstetric Labor, Premature , Magnesium
7.
Arq. bras. med. vet. zootec. (Online) ; 72(6): 2223-2232, Nov.-Dec. 2020. tab, graf, ilus
Article in Portuguese | LILACS, VETINDEX | ID: biblio-1142318

ABSTRACT

O objetivo deste estudo foi avaliar o efeito da ω-conotoxina MVIIC e das células-tronco mesenquimais (CTM) de forma isolada e sua associação nos ratos submetidos ao trauma medular agudo (TMA). Trinta Rattus novergicus, linhagem Wistar, três meses de idade, foram distribuídos igualmente em cinco grupos experimentais: controle negativo (CN), controle positivo (CP), ω-conotoxina MVIIC (MVIIC), células-tronco mesenquimais da medula óssea (CTM-MO) e associação (MVIIC + CTM-MO). O grupo CN foi submetido à laminectomia sem trauma medular, e os grupos CP, MVIIC, CTM-MO e MVIIC + CTM-MO foram submetidos ao trauma medular contusivo. O grupo CP recebeu, uma hora após o TMA, 10µL de PBS estéril, e os grupos MVIIC e MVIIC + CTM-MO receberam 10µL de PBS contendo 20pmol da ω-conotoxina MVIIC, todos por via intratecal. Os grupos CTM-MO e MVIIC + CTM-MO receberam, 24 horas após, 1x106 de CTM via intravenosa. Avaliou-se a recuperação da função locomotora até o sétimo dia pós-trauma. Os animais tratados com MVIIC + CTM-MO obtiveram recuperação motora após o trauma medular agudo (P<0,05). Conclui-se que essa associação apresentou efeito neuroprotetor com melhora na função locomotora em ratos Wistar.(AU)


The objective of this study was to evaluate the effect of isolated ω-conotoxin MVIIC and mesenchymal stem cells (MSCs) and its association in rats submitted to acute spinal cord injury (SCI). Thirty Rattus norvegicus, Wistar strain, three-month-old rats were randomly distributed in five experimental groups with six animals: negative control (CN), positive control (CP), ω-conotoxin MVIIC (MVIIC), bone marrow mesenchymal stem cells (CTM-MO) and the association (MVIIC + CTM-MO). The CN group underwent laminectomy without spinal cord trauma, and groups CP, MVIIC, CTM-MO and MVIIC + CTM-MO were submitted to contusive spinal cord trauma. The CP group received 10µl of PBS one hour after SCI, and groups MVIIC and MVIIC + CTM-MO received 10µl of PBS containing 20pmol of ω-conotoxin MVIIC, both intrathecally. Groups CTM-MO and MVIIC + CTM-MO received 1x106 of MSCs intravenously 24 hours later. The recovery of locomotor function was evaluated up to seven days post-injury. The animals treated with MVIIC + CTM-MO obtained motor recovery after SCI (P<0.05). It is concluded that this association showed neuroprotective effect with improvements in locomotor function in Wistar rats.(AU)


Subject(s)
Animals , Rats , Spinal Cord Injuries/rehabilitation , Calcium Channel Blockers , omega-Conotoxins/therapeutic use , Mesenchymal Stem Cells , Cell- and Tissue-Based Therapy/veterinary , Neuroprotection , Rats, Wistar
8.
Arq. neuropsiquiatr ; 78(5): 269-276, May 2020. tab
Article in English | LILACS | ID: biblio-1131707

ABSTRACT

ABSTRACT Background: Malfunctioning or damaged mitochondria result in altered energy metabolism, redox equilibrium, and cellular dynamics and is a central point in the pathogenesis of neurological disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic Lateral Sclerosis. Therefore, it is of utmost importance to identify mitochondrial genetic susceptibility markers for neurodegenerative diseases. Potential markers include the respiratory chain enzymes Riboflavin kinase (RFK), Flavin adenine dinucleotide synthetase (FAD), Succinate dehydrogenase B subunit (SDHB), and Cytochrome C1 (CYC1). These enzymes are associated with neuroprotection and neurodegeneration. Objective: To test if variants in genes RFK, FAD, SDHB and CYC1 deviate from Hardy-Weinberg Equilibrium (HWE) in different human mitochondrial haplogroups. Methods: Sequence variants in genes RFK, FAD, SDHB and CYC1 of 2,504 non-affected individuals of the 1,000 genomes project were used for mitochondrial haplogroup assessment and HWE calculations in different mitochondrial haplogroups. Results: We show that RFK variants deviate from HWE in haplogroups G, H, L, V and W, variants of FAD in haplogroups B, J, L, U, and C, variants of SDHB in relation to the C, W, and A and CYC1 variants in B, L, U, D, and T. HWE deviation indicates action of selective pressures and genetic drift. Conclusions: HWE deviation of particular variants in relation to global populational HWE, could be, at least in part, associated with the differential susceptibility of specific populations and ethnicities to neurodegenerative diseases. Our data might contribute to the epidemiology and diagnostic/prognostic methods for neurodegenerative diseases.


RESUMO Introdução: Mitocôndrias defeituosas ou danificadas resultam em alterações do metabolismo energético, equilíbrio redox e dinâmica celular e são, portanto, identificadas como o ponto central da patogênese em muitos distúrbios neurológicos, como a doença de Alzheimer, a doença de Parkinson, a doença de Huntington e a Esclerose Lateral Amiotrófica. Portanto, é de fundamental importância identificar marcadores de susceptibilidade genética mitocondrial para doenças neurodegenerativas. Entre os potenciais marcadores relevantes estão as enzimas da cadeia respiratória riboflavina quinase (RFK), flavina adenina dinucleotídeo sintetase (FAD), succinato desidrogenase subunidade B (SDHB) e citocromo C1 (CYC1). Estas enzimas estão associadas à neuroproteção e à neurodegeneração. Objetivo: Testar se variantes nas sequências dos genes RFK, FAD, SDHB e CYC1 desviam do Equilíbrio de Hardy-Weinberg (HWE) em diferentes haplogrupos mitocondriais humanos. Métodos: Neste trabalho utilizamos os variantes nos genes RFK, FAD, SDHB e CYC1 de sequências de 2.504 indivíduos não afetados do projeto de 1.000 genomas para o cálculo dos valores de HWE em diferentes haplogrupos mitocondriais. Resultados: As variantes de RFK desviam de HWE nos haplogrupos G, H, L, V e W, variantes de FAD nos haplogrupos B, J, L, U e C, variantes de SDHB em relação às variantes C, W e A e CYC1 em B, L, U, D e T. O desvio de HWE indica a ação de pressões seletivas e desvio genético. Conclusões: O desvio do HWE de variantes particulares em relação ao HWE populacional global poderia estar, pelo menos em parte, associado à suscetibilidade diferencial de populações e etnias específicas a doenças neurodegenerativas. Nossos dados podem contribuir para a epidemiologia e métodos diagnósticos/prognósticos para doenças neurodegenerativas.


Subject(s)
Humans , Neurodegenerative Diseases , Amyotrophic Lateral Sclerosis , Energy Metabolism , Neuroprotection , Mitochondria/chemistry
9.
Article in English | WPRIM | ID: wpr-787143

ABSTRACT

The present study was aimed to explore the neuroprotective role of imatinib in global ischemia-reperfusion-induced cerebral injury along with possible mechanisms. Global ischemia was induced in mice by bilateral carotid artery occlusion for 20 min, which was followed by reperfusion for 24 h by restoring the blood flow to the brain. The extent of cerebral injury was assessed after 24 h of global ischemia by measuring the locomotor activity (actophotometer test), motor coordination (inclined beam walking test), neurological severity score, learning and memory (object recognition test) and cerebral infarction (triphenyl tetrazolium chloride stain). Ischemia-reperfusion injury produced significant cerebral infarction, impaired the behavioral parameters and decreased the expression of connexin 43 and phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in the brain. A single dose administration of imatinib (20 and 40 mg/kg) attenuated ischemia-reperfusion-induced behavioral deficits and the extent of cerebral infarction along with the restoration of connexin 43 and p-STAT3 levels. However, administration of AG490, a selective Janus-activated kinase 2 (JAK2)/STAT3 inhibitor, abolished the neuroprotective actions of imatinib and decreased the expression of connexin 43 and p-STAT3. It is concluded that imatinib has the potential of attenuating global ischemia-reperfusion-induced cerebral injury, which may be possibly attributed to activation of JAK2/STAT3 signaling pathway along with the increase in the expression of connexin 43.


Subject(s)
Animals , Brain , Carotid Arteries , Cerebral Infarction , Connexin 43 , Imatinib Mesylate , Ischemia , Learning , Memory , Mice , Motor Activity , Neuroprotection , Phosphotransferases , Reperfusion , Reperfusion Injury , STAT3 Transcription Factor , Transducers , Walking
10.
J. venom. anim. toxins incl. trop. dis ; 26: e20190093, 2020. ilus, tab, graf
Article in English | LILACS, VETINDEX | ID: biblio-1135141

ABSTRACT

Ventral root avulsion (VRA) is an experimental approach in which there is an abrupt separation of the motor roots from the surface of the spinal cord. As a result, most of the axotomized motoneurons degenerate by the second week after injury, and the significant loss of synapses and increased glial reaction triggers a chronic inflammatory state. Pharmacological treatment associated with root reimplantation is thought to overcome the degenerative effects of VRA. Therefore, treatment with dimethyl fumarate (DMF), a drug with neuroprotective and immunomodulatory effects, in combination with a heterologous fibrin sealant/biopolymer (FS), a biological glue, may improve the regenerative response. Methods: Adult female Lewis rats were subjected to VRA of L4-L6 roots followed by reimplantation and daily treatment with DMF for four weeks. Survival times were evaluated 1, 4 or 12 weeks after surgery. Neuronal survival assessed by Nissl staining, glial reactivity (anti-GFAP for astrocytes and anti-Iba-1 for microglia) and synapse preservation (anti-VGLUT1 for glutamatergic inputs and anti-GAD65 for GABAergic inputs) evaluated by immunofluorescence, gene expression (pro- and anti-inflammatory molecules) and motor function recovery were measured. Results: Treatment with DMF at a dose of 15 mg/kg was found to be neuroprotective and immunomodulatory because it preserved motoneurons and synapses and decreased astrogliosis and microglial reactions, as well as downregulated the expression of pro-inflammatory gene transcripts. Conclusion: The pharmacological benefit was further enhanced when associated with root reimplantation with FS, in which animals recovered at least 50% of motor function, showing the efficacy of employing multiple regenerative approaches following spinal cord root injury.(AU)


Subject(s)
Animals , Biological Products , Biopolymers , Fibrin , Immunomodulation , Dimethyl Fumarate , Neuroprotection , Gene Expression
11.
Rev. Assoc. Med. Bras. (1992) ; 65(8): 1116-1121, Aug. 2019. tab, graf
Article in English | LILACS | ID: biblio-1041063

ABSTRACT

SUMMARY INTRODUCTION The possibility that hypothermia has a therapeutic role during or after resuscitation from severe perinatal asphyxia has been a longstanding focus of research. Studies designed around this fact have shown that moderate cerebral hypothermia, initiated as early as possible, has been associated with potent, long-lasting neuroprotection in perinatal patients. OBJECTIVES To review the benefits of hypothermia in improving cellular function, based on the cellular characteristics of hypoxic-ischemic cerebral injury and compare the results of two different methods of cooling the brain parenchyma. METHODS Medline, Lilacs, Scielo, and PubMed were searched for articles registered between 1990 and 2019 in Portuguese and English, focused on trials comparing the safety and effectiveness of total body cooling with selective head cooling with HIE. RESULTS We found that full-body cooling provides homogenous cooling to all brain structures, including the peripheral and central regions of the brain. Selective head cooling provides a more extensive cooling to the cortical region of the brain than to the central structures. CONCLUSIONS Both methods demonstrated to have neuroprotective properties, although full-body cooling provides a broader area of protection. Recently, head cooling combined with some body cooling has been applied, which is the most promising approach. The challenge for the future is to find ways of improving the effectiveness of the treatment.


RESUMO INTRODUÇÃO A possibilidade de a hipotermia ter um papel terapêutico durante ou após a reanimação da asfixia perinatal grave tem sido um foco de pesquisa de longa data. Estudos desenhados em torno desse fato mostraram que a hipotermia cerebral moderada, iniciada o mais cedo possível, tem sido associada à neuroproteção potente e duradoura em espécies perinatais. OBJETIVOS Resumidamente, analisar os benefícios da hipotermia na melhoria da função celular, com base nas características celulares da lesão cerebral hipóxico-isquêmica e comparar os resultados de dois métodos diferentes de resfriamento do parênquima cerebral. MATERIAL E MÉTODOS Medline, Lilacs, SciELO e PubMed foram pesquisados para artigos registrados entre 1990 e 2019 nos idiomas português e inglês, com foco em estudos comparando segurança e eficácia do resfriamento corporal total com o resfriamento seletivo da cabeça com EHI. RESULTADOS Descobrimos que o resfriamento de corpo inteiro fornece resfriamento homogêneo para todas as estruturas cerebrais, incluindo as regiões periférica e central do cérebro. O resfriamento seletivo da cabeça fornece um resfriamento mais amplo para a região cortical do cérebro do que para as estruturas centrais. CONCLUSÕES Ambos os métodos demonstraram ter propriedades neuroprotetoras, embora o resfriamento de corpo inteiro forneça uma área mais ampla de proteção. Recentemente, o resfriamento da cabeça combinado com algum resfriamento corporal foi aplicado e essa é a maneira mais promissora. O desafio para o futuro é encontrar formas de melhorar a eficácia do tratamento.


Subject(s)
Humans , Asphyxia Neonatorum/therapy , Hypoxia-Ischemia, Brain/prevention & control , Hypothermia, Induced/methods , Severity of Illness Index , Clinical Studies as Topic , Neuroprotection
12.
Femina ; 47(2): 114-121, 20190228. ilus
Article in Portuguese | LILACS | ID: biblio-1046500

ABSTRACT

Os principais usos contemporâneos do sulfato de magnésio na prática obstétrica incluem a prevenção e o tratamento de convulsões em portadoras de pré-eclâmpsia e eclâmpsia, o prolongamento da gravidez para administração antenatal de corticosteroides e a neuroproteção fetal na iminência de interrupção prematura da gestação, uma indicação mais recente. A paralisia cerebral é a causa mais comum de deficiência motora na infância e apresenta como fator de risco mais importante o nascimento pré-termo, cuja incidência tem aumentado significativamente. Como consequência, a ocorrência da paralisia cerebral também tem aumentado, a despeito da melhoria da sobrevida dos fetos pré-termos. No atual contexto de procura por estratégias que se mostrem efetivas na redução da paralisia cerebral nos recém-nascidos prematuros e que deveriam ser implementadas com o objetivo de diminuir os seus efeitos danosos nos indivíduos e suas famílias, nos serviços de saúde e na sociedade como um todo, o sulfato de magnésio tem se mostrado como o mais promissor agente neuroprotetor fetal. Desde a década de 1990, estudos resultantes das suas indicações para a prevenção das convulsões eclâmpticas ou para tocólise têm evidenciado redução nas taxas de paralisia cerebral e leucomalácia periventricular em prematuros. Diretrizes nacionais e internacionais mais recentes, baseando-se em resultados de ensaios randomizados controlados e metanálises de boa qualidade, têm avançado na recomendação sobre os regimes terapêuticos e na construção de algoritmos para utilização do sulfato de magnésio na neuroproteção fetal.(AU)


The main contemporary uses of magnesium sulfate in obstetric practice include the prevention and treatment of seizures in patients with preeclampsia and eclampsia, prolongation of pregnancy for antenatal administration of corticosteroids and fetal neuroprotection at the imminence of premature termination of pregnancy, a more recent indication. Cerebral palsy is the most common cause of motor deficits in childhood and has a significant increase in preterm birth as a major risk factor. As a result, the occurrence of cerebral palsy has also increased, despite the improvement in the survival of preterm fetuses. In the current context of search for strategies that are effective in reducing cerebral palsy in preterm newborns and that should be implemented with the aim of reducing their harmful effects on individuals and their families, health services and society as a whole, magnesium sulfate has been shown to be the most promising fetal neuroprotective agent. Since the 1990s, studies arising from its indications for prevention of eclamptic seizures or tocolysis have shown a reduction in the rates of cerebral palsy and periventricular leukomalacia in preterm infants. More recent national and international guidelines, based on results from randomized controlled trials and good quality meta-analyzes, have advanced the recommendation on therapeutic regimens and the construction of algorithms for the use of magnesium sulphate in fetal neuroprotection.(AU)


Subject(s)
Humans , Female , Pregnancy , Infant, Newborn , Infant, Premature , Cerebral Palsy/prevention & control , Neuroprotection/drug effects , Magnesium/adverse effects , Magnesium Sulfate/therapeutic use , Randomized Controlled Trials as Topic , Databases, Bibliographic , Neuroprotective Agents , Contraindications, Drug
13.
Campinas; s.n; 2019. ilus, graf, tab.
Thesis in Portuguese | LILACS | ID: biblio-1118162

ABSTRACT

Resumo: O veneno da aranha Phoneutria nigriventer (PNV) contém neuropeptídeos que afetam canais iônicos e a neurotransmissão, induzindo a quebra da barreira hematoencefálica (BHE) no hipocampo de ratos, o que ocorre paralelamente ao aumento do fator de crescimento endotelial vascular (VEGF). Sabe-se que a resposta biológica do VEGF é desencadeada através da regulação transcricional promovida pelo domínio tirosina-quinase de receptores transmembranares do VEGF, dos quais o VEGFR-2 (Flk-1) é considerado o principal mediador e ativador de várias vias de sinalização. O trabalho propõe investigar o possível papel neuroprotetor do VEGF após inibir sua ligação ao receptor Flk-1 pelo itraconazol (ITZ). Para isso, examinamos o status bioquímico do hipocampo por espectroscopia no Infravermelho com Transformada de Fourier (FT-IR), bem como avaliamos as proteínas envolvidas nas rotas paracelular e transcelular da BHE e quais vias de sinalização, relacionadas à neuroproteção do VEGF, foram ativadas. Os ratos receberam PNV ou foram pré-tratados com ITZ (30 min) seguido de PNV pela veia da cauda e depois sacrificados em 1 e 2 h (intervalos com maiores sinais de intoxicação), 5 h (intervalo com sinais incipientes de recuperação) e 24 h (intervalo sem sinal visual detectável de envenenamento), sendo comparados aos controles, salina e ITZ. O pré-tratamento com o antifúngico agravou os efeitos do veneno e aumentou danos à BHE. Os espectros FT-IR do veneno, hipocampo dos controles, PNV e ITZ-PNV mostraram as bandas de 1400 cm-1 (carboxilato) e de 1467 cm-1 (flexão de CH2: principalmente lipídios), que foram considerados bandas biomarcadora e referência, respectivamente. A inibição da ligação VEGF/Flk-1 produziu mudanças marcantes na estabilidade lipídios/proteínas em 1-2 h. As maiores diferenças ocorreram nas regiões espectrais atribuídas à lípides simétricos (2852 cm-1) e assimétricos (2924 e 2968 cm-1). As análises quantitativas mostraram maiores aumentos na razão 1400 cm-1/1467 cm-1 no período de intoxicação grave (1 h), e referem-se à região espectral de 3106 cm-1 a 687 cm-1. Ademais, a desativação da ligação VEGF/Flk-1 pelo itraconazol (ITZ) aumentou o fator indutor de hipóxia (H1F1-?), VEGF, Flk-1, Flt-1, Neu-N e caspase-3 às 5 horas após a injeção do PNV. No mesmo intervalo, a permeabilidade transcelular da BHE aumentou (caveolina-1?, dinamina-2 e família Src de não receptores tirosina-quinase (SKFs)), enquanto laminina e a via paracelular (occludina, ?-catenina) foram reforçadas e a proteína de efluxo glicoproteína-P (P-gp) aumentou. Ao mesmo tempo (5 h), ocorreu auto-fosforilação da via pró-proliferação celular (p38-fosforilada). Às 24 h, apesar da ausência de sinais de intoxicação, a via pró-sobrevivência celular (Akt-fosforilada) diminuiu nos animais pré-tratados com ITZ, enquanto aumentou nos tratados com PNV apenas. Os dados indicam ativação de mecanismos de neuroproteção relacionados ao VEGF envolvendo o receptor Flk-1 e principalmente à serina-treonina-quinase Akt, provavelmente via PI3K. ERK-fosforilada (2 h) e p38-fosforilada (5 h) sugerem interação entre as vias de sinalização com o objetivo de restabelecer a homeostase do hipocampo. O intervalo de 5 h parece ser o ponto de virada orquestrando respostas biológicas variadas. Os dados permitem concluir sobre o papel neuroprotetor do VEGF e que o mesmo pode ser explorado como possível alvo terapêutico no envenenamento por P. nigriventer.(AU)


Abstract: Phoneutria nigriventer spider venom (PNV) contains ion channels-acting neuropeptides that affect neurotransmission and induces transitory blood-brain barrier (BBB) breakdown in rat¿s hippocampus, which run in parallel with (vascular endothelial growth factor) VEGF upregulation. It is known that VEGF biological response is triggered through transcriptional regulation promoted by transmembrane tyrosine kinase receptors, being VEGFR-2 (Flk-1) considered the major mediator of VEGF effect through activation of a number of signaling pathways. The purpose of this work is to investigate a putative neuroprotective role of VEGF by inhibiting its binding to receptor Flk-1 by itraconazole (ITZ). To do this, we examined the biochemical status of the hippocampus by Infrared Spectroscopy and Fourier Transform (FT-IR), as well as evaluated the proteins involved in the BBB paracellular and transcellular routes and which signaling pathways related to VEGF neuroprotection were activated. Rats were administered PNV alone or were pre-treated with ITZ (30 min) followed by PNV through the tail vein, and then euthanized at 1 and 2 h (intervals with greatest signs of intoxication), 5 h (interval with incipient signs of animals¿ recovery) and 24 h (interval with no visually detectable envenomation sign) and compared to saline and ITZ controls. The antifungal pre-treatment aggravated PNV toxic effects and increased BBB damage. FT-IR spectra of venom and from hippocampi of controls, PNV and ITZ-PNV showed a 1400 cm-1 band linked to symmetric stretch of carboxylate and 1467 cm-1 band (CH2 bending: mainly lipids), which were considered biomarker and reference bands, respectively. Inhibition of VEGF/Flk-1 binding produced marked changes in lipid/protein stability at 1-2 h. The largest differences were observed in spectra regions assigned to lipids, both symmetric (2852 cm-1) and asymmetric (2924 and 2968 cm-1). Quantitative analyses showed greatest increases in the 1400 cm-1/1467 cm-1 ratio also at 1 h. Such changes at period of rats¿ severe intoxication referred to wavenumber region from 3106 cm-1 to 687 cm-1. Furthermore, the deactivation of Flk-1 receptor by VEGF through itraconazole (ITZ) showed increased hypoxia inducible factor (H1F-1?), VEGF, Flk-1, Flt-1, Neu-N and caspase-3 at 5 h after PNV injection. At same interval, BBB transcellular permeability increased (caveolin-1?, dynamin-2 and Src family of non-receptor tyrosine kinases (SKFs)), while laminin and paracellular route (occludin, ?-catenin) were reinforced and P-glycoprotein (P-gp) efflux protein was increased. Such effects were timely followed by upregulation of auto-phosphorylation of the pro-proliferation (phosphorylated-p38) pathway. At 24 h, despite absence of intoxication signs, the pro-survival (p-Akt) pathway was downregulated in animals underwent inhibition of VEGF-Flk-1 binding, whereas it was upregulated in PNV rats non-treated with ITZ. The data indicate triggering of VEGF-related mechanisms involving Flk-1 receptor and serine-threonine kinase Akt, probably via PI3K, as the main mechanism of neuroprotection. Phosphorylated ERK (2 h) and p-p38 (5 h) indicates interplay among transduction pathways likely aiming at re-establishment of hippocampal homeostasis. The findings suggest 5 h interval as the turning point that orchestrates varied biological responses. Taking together the data of the present study allow concluding that VEGF expression exerts neuroprotective role and can be explored as a possible therapeutic target in P. nigriventer envenomation.(AU)


Subject(s)
Rats , Spider Venoms , Blood-Brain Barrier , Vascular Endothelial Growth Factor A , Poisoning , Poisons/administration & dosage , Central Nervous System , Itraconazole , Neuroprotection , Ion Channels
14.
Article in English | WPRIM | ID: wpr-719639

ABSTRACT

Previous studies have shown that spinosin was implicated in the modulation of sedation and hypnosis, while its effects on learning and memory deficits were rarely reported. The aim of this study is to investigate the effects of spinosin on the improvement of cognitive impairment in model mice with Alzheimer’s disease (AD) induced by Aβ1–42 and determine the underlying mechanism. Spontaneous locomotion assessment and Morris water maze test were performed to investigate the impact of spinosin on behavioral activities, and the pathological changes were assayed by biochemical analyses and histological assay. After 7 days of intracerebroventricular (ICV) administration of spinosin (100 µg/kg/day), the cognitive impairment of mice induced by Aβ1–42 was significantly attenuated. Moreover, spinosin treatment effectively decreased the level of malondialdehyde (MDA) and Aβ1–42 accumulation in hippocampus. Aβ1–42 induced alterations in the expression of brain derived neurotrophic factor (BDNF) and B-cell lymphoma-2 (Bcl-2), as well as inflammatory response in brain were also reversed by spinosin treatment. These results indicated that the ameliorating effect of spinosin on cognitive impairment might be mediated through the regulation of oxidative stress, inflammatory process, apoptotic program and neurotrophic factor expression, suggesting that spinosin might be beneficial to treat learning and memory deficits in patients with AD via multi-targets.


Subject(s)
Alzheimer Disease , Animals , B-Lymphocytes , Brain , Brain-Derived Neurotrophic Factor , Cognition Disorders , Hippocampus , Humans , Hypnosis , Learning , Locomotion , Malondialdehyde , Memory Disorders , Memory , Mice , Neuroprotection , Neuroprotective Agents , Oxidative Stress , Water
15.
Article in English | WPRIM | ID: wpr-719412

ABSTRACT

Neural stem cells (NSCs) can proliferate and differentiate into multiple cell types that constitute the nervous system. NSCs can be derived from developing fetuses, embryonic stem cells, or induced pluripotent stem cells. NSCs provide a good platform to screen drugs for neurodegenerative diseases and also have potential applications in regenerative medicine. Natural products have long been used as compounds to develop new drugs. In this review, natural products that control NSC fate and induce their differentiation into neurons or glia are discussed. These phytochemicals enable promising advances to be made in the treatment of neurodegenerative diseases.


Subject(s)
Biological Products , Embryonic Stem Cells , Fetus , Induced Pluripotent Stem Cells , Nervous System , Neural Stem Cells , Neurodegenerative Diseases , Neurogenesis , Neuroglia , Neurons , Neuroprotection , Phytochemicals , Regenerative Medicine
16.
Article in English | WPRIM | ID: wpr-766354

ABSTRACT

Trigeminal nerve injury as a consequence of lower third molar surgery is a notorious complication and may affect the patient in long term. Inferior alveolar nerve (IAN) and lingual nerve (LN) injury result in different degree of neurosensory deficit and also other neurological symptoms. The long term effects may include persistent sensory loss, chronic pain and depression. It is crucial to understand the pathophysiology of the nerve injury from lower third molar surgery. Surgery remains the most promising treatment in moderate-to-severe nerve injuries. There are limitations in the current treatment methods and full recovery is not commonly achievable. It is better to prevent nerve injury than to treat with unpredictable results. Coronectomy has been proved to be effective in reducing IAN injury and carries minimal long-term morbidity. New technologies, like the roles of erythropoietin and stem cell therapy, are being investigated for neuroprotection and neural regeneration. Breakthroughs in basic and translational research are required to improve the clinical outcomes of the current treatment modalities of third molar surgery-related nerve injury.


Subject(s)
Chronic Pain , Depression , Erythropoietin , Humans , Lingual Nerve , Mandibular Nerve , Molar, Third , Neuroprotection , Postoperative Complications , Regeneration , Stem Cells , Translational Medical Research , Trigeminal Nerve Injuries , Trigeminal Nerve
17.
Journal of Stroke ; : 160-174, 2019.
Article in English | WPRIM | ID: wpr-766250

ABSTRACT

Tissue plasminogen activator (tPA) is the only therapeutic agent approved to treat patients with acute ischemic stroke. The clinical benefits of tPA manifest when the agent is administered within 4.5 hours of stroke onset. However, tPA administration, especially delayed administration, is associated with increased intracranial hemorrhage (ICH), hemorrhagic transformation (HT), and mortality. In the ischemic brain, vascular remodeling factors are upregulated and microvascular structures are destabilized. These factors disrupt the blood brain barrier (BBB). Delayed recanalization of the vessels in the presence of relatively matured infarction appears to damage the BBB, resulting in HT or ICH, also known as reperfusion injury. Moreover, tPA itself activates matrix metalloproteases, further aggravating BBB disruption. Therefore, attenuation of edema, HT, or ICH after tPA treatment is an important therapeutic strategy that may enable clinicians to extend therapeutic time and increase the probability of excellent outcomes. Recently, numerous agents with various mechanisms have been developed to interfere with various steps of ischemia/reperfusion injuries or BBB destabilization. These agents successfully reduce infarct volume and decrease the incidence of ICH and HT after delayed tPA treatment in various animal stroke models. However, only some have entered into clinical trials; the results have been intriguing yet unsatisfactory. In this narrative review, I describe such drugs and discuss the problems and future directions. These “tPA helpers” may be clinically used in the future to increase the efficacy of tPA in patients with acute ischemic stroke.


Subject(s)
Animals , Blood-Brain Barrier , Brain , Edema , Humans , Incidence , Infarction , Intracranial Hemorrhages , Metalloproteases , Mortality , Neuroprotection , Reperfusion Injury , Stroke , Tissue Plasminogen Activator , Vascular Remodeling
18.
Article in English | WPRIM | ID: wpr-765853

ABSTRACT

OBJECTIVE: In Parkinson's disease (PD), vitamin B12 levels are lower, and comorbid B12 deficiency has been associated with the development of neuropathy and early gait instability. Because little is known about B12 supplement use in PD, we sought to evaluate its use in a large PD cohort and, as an exploratory analysis, to determine whether baseline characteristics or disease progression differed according to B12 supplementation. METHODS: We utilized data collected as part of the National Institutes of Health Exploratory Trials in PD (NET-PD) Long-term Study (LS-1), a longitudinal study of 1,741 participants. We stratified subjects into 4 groups according to daily supplement use: no B12, multivitamin (MVI) containing < 100 μg B12, B12 ≥ 100 μg, and MVI + B12 ≥ 100 μg. Clinical outcomes were assessed at 3 years for each group using the Unified Parkinson's Disease Rating Scale (UPDRS), its subscores, and selected individual questions. RESULTS: Of the 1,147 participants who completed the 3-year visit, 41% took an MVI, 2% took B12, 3% took MVI + B12, and 54% reported taking no supplements. At 3 years, no significant differences in clinical outcomes were observed. However, there was a trend toward lower hazard ratios for developing sensory symptoms (UPDRS Item 17) in the MVI (p = 0.08) and B12 + MVI (p = 0.08) groups compared to that in the no supplement group. CONCLUSION: These results show that supplementation with vitamin B12 ≥ 100 μg is uncommon in early PD. The finding of a trend toward a lower hazard ratio for the development of sensory symptoms in those taking an MVI or B12 + MVI warrants further study.


Subject(s)
Cohort Studies , Disease Progression , Gait , Longitudinal Studies , Neuroprotection , Parkinson Disease , Vitamin B 12 , Vitamins
19.
Article in English | WPRIM | ID: wpr-763048

ABSTRACT

Brain aging is an inevitable process characterized by structural and functional changes and is a major risk factor for neurodegenerative diseases. Most brain aging studies are focused on neurons and less on astrocytes which are the most abundant cells in the brain known to be in charge of various functions including the maintenance of brain physical formation, ion homeostasis, and secretion of various extracellular matrix proteins. Altered mitochondrial dynamics, defective mitophagy or mitochondrial damages are causative factors of mitochondrial dysfunction, which is linked to age-related disorders. Etoposide is an anti-cancer reagent which can induce DNA stress and cellular senescence of cancer cell lines. In this study, we investigated whether etoposide induces senescence and functional alterations in cultured rat astrocytes. Senescence-associated β-galactosidase (SA-β-gal) activity was used as a cellular senescence marker. The results indicated that etoposide-treated astrocytes showed cellular senescence phenotypes including increased SA-β-gal-positive cells number, increased nuclear size and increased senescence-associated secretory phenotypes (SASP) such as IL-6. We also observed a decreased expression of cell cycle markers, including Phospho-Histone H3/Histone H3 and CDK2, and dysregulation of cellular functions based on wound-healing, neuronal protection, and phagocytosis assays. Finally, mitochondrial dysfunction was noted through the determination of mitochondrial membrane potential using tetramethylrhodamine methyl ester (TMRM) and the measurement of mitochondrial oxygen consumption rate (OCR). These data suggest that etoposide can induce cellular senescence and mitochondrial dysfunction in astrocytes which may have implications in brain aging and neurodegenerative conditions.


Subject(s)
Aging , Animals , Astrocytes , Brain , Cellular Senescence , Cell Cycle , Cell Line , DNA , Etoposide , Extracellular Matrix Proteins , Homeostasis , Interleukin-6 , Membrane Potential, Mitochondrial , Mitochondria , Mitophagy , Mitochondrial Dynamics , Neurodegenerative Diseases , Neurons , Neuroprotection , Oxygen Consumption , Phagocytosis , Phenotype , Rats , Risk Factors , Wound Healing
20.
Article in Korean | WPRIM | ID: wpr-764671

ABSTRACT

PURPOSE: The purpose of this study was to identify the effect of ghrelin on memory impairment in a rat model of vascular dementia induced by chronic cerebral hypoperfusion. METHODS: Randomized controlled groups and the posttest design were used. We established the representative animal model of vascular dementia caused by bilateral common carotid artery occlusion and administered 80 µg/kg ghrelin intraperitoneally for 4 weeks. First, behavioral studies were performed to evaluate spatial memory. Second, we used molecular biology techniques to determine whether ghrelin ameliorates the damage to the structure and function of the white matter and hippocampus, which are crucial to learning and memory. RESULTS: Ghrelin improved the spatial memory impairment in the Y-maze and Morris water maze test. In the white matter, demyelination and atrophy of the corpus callosum were significantly decreased in the ghrelin-treated group. In the hippocampus, ghrelin increased the length of hippocampal microvessels and reduced the microvessels pathology. Further, we confirmed angiogenesis enhancement through the fact that ghrelin treatment increased vascular endothelial growth factor (VEGF)-related protein levels, which are the most powerful mediators of angiogenesis in the hippocampus. CONCLUSION: We found that ghrelin affected the damaged myelin sheaths and microvessels by increasing angiogenesis, which then led to neuroprotection and improved memory function. We suggest that further studies continue to accumulate evidence of the effect of ghrelin. Further, we believe that the development of therapeutic interventions that increase ghrelin may contribute to memory improvement in patients with vascular dementia.


Subject(s)
Animals , Atrophy , Carotid Artery, Common , Corpus Callosum , Dementia , Dementia, Vascular , Demyelinating Diseases , Ghrelin , Hippocampus , Humans , Learning , Memory Disorders , Memory , Microvessels , Models, Animal , Molecular Biology , Myelin Sheath , Neuroprotection , Pathology , Rats , Spatial Memory , Vascular Endothelial Growth Factor A , Water , White Matter
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