Cuidado desenvolvimental para recém-nascidos pré-termos: revisão de escopo / Atención del desarrollo de los recién nacidos pretérmino: revisión del alcance / Developmental care for preterm newborns: a scoping review

Objetivo: mapear como o cuidado desenvolvimental prestado aos recém nascidos pré-termos tem sido desenvolvido nas unidades de terapia intensiva neonatal com a finalidade de sintetizar as evidências científicas atuais. Métodos: revisão de escopo com busca realizada em novembro de 2022 nas bases MEDLINE, Biblioteca Virtual em Saúde, CINAHL, Embase e Web of Science. Foram incluídos estudos que retratavam o cuidado desenvolvimental nas unidades neonatais, nos últimos cinco anos, sem restrição de idioma. Resultados: incluíram-se sete artigos e os principais temas foram: contato pele a pele, controle do ruído e luminosidade, participação da família e sensibilização e treinamento da equipe. Conclusão: esses cuidados contribuem para o desenvolvimento neuropsicomotor do prematuro, melhoram a assistência e reduzem a morbimortalidade e o tempo de internação.

Objective: To map the evolution of developmental care provided to preterm newborns in Neonatal Intensive Care Units to synthesize current scientific evidence. Methods: Bibliographic search for a scoping review was conducted in November 2022 on the MEDLINE, Virtual Health Library, CINAHL, Embase and Web of Science databases. Studies discussing developmental care in neonatal units in the past five years, without language restriction, were included. Results: The scoping review included articles, whose main topics were skin-to-skin contact, noise and light control, family participation, and team awareness and training. Conclusion: Developmental care practices contribute to the neuropsychomotor development of preterm infants, improve care, reduce morbidity and mortality, and the length of hospitalization.

Objetivo: mapear cómo se ha desarrollado la atención del desarrollo brindada a los recién nacidos pretérmino en las unidades de cuidados intensivos neonatales para sintetizar la evidencia científica actual. Métodos: revisión de alcance realizada en noviembre de 2022 mediante búsquedas en las bases de datos MEDLINE, Biblioteca Virtual en Salud, CINAHL, Embase y Web of Science. Se incluyeron estudios que trataron la atención del desarrollo en unidades neonatales, en los últimos cinco años, sin restricción de idioma. Resultados: se incluyeron siete artículos y los temas principales fueron contacto piel con piel, control de luz y ruido, participación familiar y sensibilización y entrenamiento del equipo. Conclusión: estos cuidados contribuyen al desarrollo neuropsicomotor de los prematuros, mejoran la asistencia y reducen la morbimortalidad y la estancia hospitalaria.

Piracetam-induced neuroprotection in lipopolysaccharides-challenged EOC-20 cells and mouse brain via attenuating oxidative stress

Abstract Therapeutically, piracetam has been used for decades as a cognitive enhancer for memory- related neuronal disorders. The present study aimed to investigate the neuroprotective potential of piracetam on lipopolysaccharides (LPS)-induced neuronal deficit using both in-vitro and in-vivo experimental models. For the in-vitro analysis, EOC-20 murine microglial cells were induced with a neuronal toxicity of 100 µg/ml of LPS, and the formation of intracellular reactive oxygen species (ROS) and nitric oxide (NO) productions were determined. For in-vivo neuroprotective analysis, groups of mice were treated orally with two doses of piracetam (200 and 400 mg/kg) for 30 days. Neuronal toxicity was induced by four intraperitoneal injections of LPS (250 µg/kg/day). The malondialdehyde (MDA) level was measured for oxidative stress, and catalase reduced glutathione (GSH), glutathione reductase (GRD), and superoxide dismutase (SOD) levels were determined as the antioxidant parameters. The result of the cell viability study was that pre-treatment with piracetam significantly protected the LPS-induced cell loss, and attenuated the ROS generation and NO production in LPS-induced EOC-20 cells. Moreover, the treatment of piracetam significantly reduced the MDA levels and improved catalase, GSH, GRD, and SOD activities in LPS-induced mice brains. The overall results from this study supported the neuroprotective effects of piracetam against LPS-induced neuronal toxicity.

The Relationship Between Neuroprotective Activity and Antigenotoxic and Acetylcholinesterase Inhibitory Effects of Glaucium corniculatum Extracts

Abstract The purpose of this study was to investigate the relationship between the acetylcholinesterase (AChE) inhibitory and antigenotoxic effect with the neuroprotective activity of Glaucium corniculatum methanol and water extracts rich in rutin and quercetin flavonoids. Neuroprotective activity in terms of cell survival and development against oxidative damage was measured by MTT assay and microscopic analysis in H2O2-induced NGF-differentiated PC12 (dPC12) cells. QRT-PCR and western blot hybridization method was employed for the determination of AChE inhibition of the extracts in the same cell model, and the genotoxic and antigenotoxic effects were identified with Comet assay with human lymphocytes. H2O2-induced vitality loss in dPC12 cells was inhibited in pre-treated cells with these plant extracts. Moreover, extracts stimulated neurite formation and prevented the oxidative stress-induced reduction in neurite growth. In general, it was determined that G. corniculatum methanol extract containing higher amounts of rutin and quercetin was more effective than water extract in terms of AChE inhibitory, antigenotoxic and also neuroprotective effect. In this study, it was shown for the first time that both AChE inhibitory and antigenotoxic effects of G. corniculatum may be effective in neuroprotection and it's protective and therapeutic effects against neurodegeneration may be related to the flavonoid content.

Uso de um método não invasivo no monitoramento da pressão intracraniana em unidade de terapia intensiva para melhorar a neuroproteção em pacientes no pós-operatório de cirurgia cardíaca após circulação extracorpórea / The use of a noninvasive intracranial pressure monitoring method in the intensive care unit to improve neuroprotection in postoperative cardiac surgery patients after extracorporeal circulation

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.

Facilitating the gut brain axis by probiotic bacteria to modulate neuroimmune response on lead exposed zebra fish models

Unravelling the efficacy of gut biome has a major impact on health. An unbalanced microbiome composition is linked to many common illnesses such as gut dysbiosis, mental deformities and immunological imbalance. An optimistic influence on the gut biome can be made by consumingprobiotics. This would stimulate neuroprotection and immunomodulation intended by heavy metals pollution. Lead is a major source of neurotoxin that can induce neural deformities. Lactobacillusspecies isolated from curd were characterized to confirm its specificity. Zebra fish was reared at standard conditions and preclinical assessment on the intensity of induced neurotoxin lead was performed. The embryo toxic assay, immunomodulation effects and animal behavioural models endorsed the consequence of neurotoxicity. Different concentrations of bacterial isolate with standard antidepressant was considered for analysing the vigour of toxicity and its influence on cognitive behaviour by novel tank diving method. The restrain in the animal behaviour was also conferred by all the test samples with a decreased bottom dwelling time which was authenticated with haematology and histopathological studies. The alterations in morphology of the lymphocytes were balanced by the treated test samples. This study paves a twofold potential of probiotic as neuroprotectant and immune modulator against heavy metal toxicity.

Traumatismo raquimedular / Spinal cord injury

According to different publications, the neurological level most frequently involved in traumatic spinal cord injury is cervical (16%-75%), followed by thoracic (16%-36%) and lumbar (9%-17%). The abrupt interruption of nerve conduction at the spinal level causes spinal shock, characterized by an acute neurological, hemodynamic, respiratory and urinary compromise, which associates with thermoregulation problems. Neurological repercussions are characterized by a motor compromise, evidenced as flaccid paralysis with areflexia, sensory damage, abolition of sympathetic activity and loss of adaptive reflexes in the territory located below the lesion. The management of traumatic spinal cord, both, isolated or associated with multiple trauma, must begin at the scene of the accident. The current trend is towards a selective immobilization identifiying the group of patients in whom it will have a real benefit. Clinical features of spinal shock and other clinical aspects of the spinal cord injury are described in detail. Diagnosis should include a complete neurological examination including imaging studies. The type of image of choice is computerized axial tomography (CT). Different treatment alternatives are analyzed, including early or delayed descompressive surgery, methylprednisolone, neuroprotection and neuroregeneration. Finally, anesthetic management is described, the objective of which should be to reduce the movement of the lesion area (especially during positioning and the laryngoscopy and intubation maneuver) and to maintain the medullary perfusion pressure within normal limits. Postoperative care should focus on pain management, prevention of thromboembolic events and weaning from mechanical ventilation.

El nivel neurológico más frecuentemente comprometido en las lesiones raquimedulares por trauma es el cervical (16%-75%), seguido del torácico (16%-36%) y lumbar (9%-17%) según diferentes publicaciones. La brusca interrupción de la conducción nerviosa a nivel medular origina el cuadro de medular, caracterizado por un agudo compromiso neurológico, hemodinámico, respiratorio y urinario, asociado a problemas de termorregulación, con repercusiones neurológicas caracterizadas por un compromiso motor que se manifiesta como una parálisis fláccida con arreflexia, daño sensitivo, desaparición de la actividad simpática y pérdida de reflejos de adaptación en el territorio ubicado por debajo de la lesión. El manejo del trauna raquimedular asociado o no a politraumatismo debe inicirse en la escena del accidente; la tendencia actual es hacia una inmovilización selectiva, haciendo una identificación del grupo de pacientes en los que tendrá un real beneficio. Se describe detalladamente el cuadro de medular o espinal y otros aspectos clínicos de la sección medular. El diagnóstico debe incluir un examen neurológico completo y estudios de imagenología; el tipo de imagen de elección es la tomografía axial computarizada (TAC). Se analizan las diferentes alternativas de tratamiento: cirugía descompresiva precoz o diferida, metilprednisolona, neuroprotección y neurorregeneración. Finalmente se detalla el manejo anestésico, cuyo objetivo debe perseguir el menor movimiento de la zona de la lesión (especialmente durante el posicionamiento y la maniobra de laringoscopía e intubación) y el mantenimiento de la presión de perfusión medular dentro de los límites más estables posilbes. Los cuidados posoperatorios deben estar dirigidos especialmente al manejo de la analgesia, la prevención de la enfermedad tromboembólica y la desconexión de la ventilación mecánica.

¿Anestesia halogenada o anestesia total endovenosa en neurocirugía? / Volatile or total intravenous anesthesia for neurosurgery?

Total intravenous anesthesia (TIVA) with propofol/remifentanil appears in the literatura as a good option for neurosurgical patients who have increased intracranial pressure (ICP),risk of postoperative nausea and vomiting (PONV), need for neuromonitoring, and in those with impaired brain self-regulation. On the other hand, in patients with normal neurological status, normal ICP, a technique with volatile (halogenated) agents plus an opiiid can be used. This review describes two anesthetic techniques available for use in neurosurgery, highlighting the neurophysiological changes, advantages and disadvantages of each technique. MATERIAL AND METHOD: PubMed search engine was used for bibliographic search. DISCUSSION: The search for an ideal anesthetic in neurosurgery is still a matter of debate. There are numerous investigations aimed at finding an optimal agent that ensure the coupling between cerebral flow (CBF) and metabolism, keeping self-regulation intact without increasing the CBF and intracerebral pressure (ICP). CONCLUSIONS: Both anesthetic techniques, TIVA and volatile agents (halogenated), can be used in neurosurgical procedures and should provide neuroprotection, brain relaxation and a rapid awakening.

La anestesia total endovenosa (TIVA) con propofol/remifentanilo aparece en la literatura como una buena opción para pacientes neuroquirúrgicos que tienen aumento de la presión intracraneana (PIC), riesgo de náuseas y vómitos posoperatorios (NVPO), necesidad de neuromonitoreo, y en aquellos con alteración de la autorregulación cerebral. Por otra parte, en pacientes con estado neurológico normal, PIC normal puede usarse una técnica con agentes volátiles (halogenados) más un opioide. Esta revisión describe dos técnicas anestésicas disponibles para su uso en neurocirugía, destaca los cambios neurofisiológicos, ventajas y desventajas de cada técnica. MATERIAL Y MÉTODO: Para búsqueda bibliográfica se usó buscador PubMed. DISCUSIÓN: La búsqueda de un anestésico ideal en neurocirugía sigue siendo tema de debate. Existen numerosas investigaciones destinadas a buscar un agente óptimo que asegure el acoplamiento entre flujo sanguíneo cerebral (FSC) y metabolismo, manteniendo la autorregulación intacta sin aumentar el FSC y presión intracerebral (PIC). CONCLUSIONES: Ambas técnicas anestésicas, TIVA y agentes volátiles (halogenados), pueden ser usadas en procedimientos neuroquirúrgicos y deben brindar neuroprotección, relajación cerebral y un despertar rápido.

Sulfato de magnésio: principais utilizações na obstetrícia contemporânea / Magnesium sulphate: main uses in contemporary obstetrics

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.

Novel neuroprotective peptides in the venom of the solitary scoliid wasp Scolia decorata ventralis

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)

The neuroprotection of cerebrolysin after spontaneous intracerebral hemorrhage through regulates necroptosis via Akt/ GSK3B signaling pathway

ABSTRACT Purpose: Spontaneous intracerebral hemorrhage (ICH) is a major cause of death and disability with a huge economic burden worldwide. Cerebrolysin (CBL) has been previously used as a nootropic drug. Necroptosis is a programmed cell death mechanism that plays a vital role in neuronal cell death after ICH. However, the precise role of necroptosis in CBL neuroprotection following ICH has not been confirmed. Methods: In the present study, we aimed to investigate the neuroprotective effects and potential molecular mechanisms of CBL in ICH-induced early brain injury (EBI) by regulating neural necroptosis in the C57BL/6 mice model. Mortality, neurological score, brain water content, and neuronal death were evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, Evans blue extravasation, Western blotting, and quantitative real-time polymerase chain reaction (PCR). Results: The results show that CBL treatment markedly increased the survival rate, neurological score, and neuron survival, and downregulated the protein expression of RIP1 and RIP3, which indicated that CBL-mediated inhibition of necroptosis, and ameliorated neuronal death after ICH. The neuroprotective capacity of CBL is partly dependent on the Akt/GSK3β signaling pathway. Conclusions: CBL improves neurological outcomes in mice and reduces neuronal death by protecting against neural necroptosis.

Ethanolic Extract of the Red Algae Meristiella echinocarpa (Areschoug) Confers Neuroprotection in Mice / Extrato Etanólico da Alga Vermelha Meristiella echinocarpa (Areschoug) Confere Neuroproteção em Camundongos

Objectives: This study aimed to investigate the neuroprotective effects of the ethanolic extract obtained from red algae marine Meristiella echinocarpa (Areschougiaceae) ­ EEMe. Methods: EEMe was used in doses ranging from 10 to 40 mg/kg, administered intraperitoneally in mice. Behavioral tests were performed to assess locomotor activity (open field), anxiety (elevated plus maze), depression (tail suspension), and motor coordination (rota-rod). The anticonvulsant effect of the algae extract was evaluated in two models of seizures induced by strychnine and pentylenetetrazol. The level of oxidative stress was also evaluated in the following brain areas: the prefrontal cortex, hippocampus, and striatum. Statistical analysis was performed applying ANOVA followed by the Bonferroni test. Results: EEMe reduced significantly the number of crossing (36%) and rearing (54%) in the open field test and increased 1.3x the immobility time in the tail suspension test. In brain areas EEMe also reduced significantly malondialdehyde levels (striatum: 45%, hippocampus: 38%, prefrontal cortex: 37%) and nitrite levels (striatum: 72%, hippocampus: 79%, prefrontal cortex: 63%), and increased the reduced-glutathione levels (striatum: 72%, hippocampus: 73%, prefrontal cortex: 42%). In addition, the extract significantly prolonged the latency of seizures induced by strychnine (38%) or pentylenetetrazol (57%), and the latency of death induced by pentylenetetrazol (6.1x). Conclusion: EEMe exhibits antioxidant and anticonvulsant effects, probably involving GABAergic and glycinergic pathways.

Objetivos: este estudo teve como objetivo investigar os efeitos neuroprotetores do extrato etanólico da alga marinha vermelha Meristiella echinocarpa (Areschougiaceae) - EEMe. Métodos: EEMe foi utilizado em doses que variaram de 10 a 40 mg/kg, administrados via intraperitoneal em camundongos. Foram realizados testes comportamentais que avaliaram a atividade locomotora (campo aberto), a ansiedade (labirinto em cruz elevado), a depressão (suspensão em cauda) e a coordenação motora (rota-rod). O efeito anticonvulsivante do extrato da alga foi avaliado em dois modelos de convulsões por estricnina e pentilenotetrazol. Foi também realizada a avaliação do nível de estresse oxidativo nas seguintes áreas cerebrais: córtex pré-frontal, hipocampo e corpo estriado. A análise estatística foi realizada, aplicando a ANOVA seguida do teste de Bonferroni. Resultados: o EEMe reduziu, significativamente, o número de cruzamentos (36%) e o número de rearing (54%) no teste de campo aberto e aumentou, em 1,3x, o tempo de imobilidade no teste de suspensão pela cauda. Nas áreas cerebrais, o EEMe também reduziu, significativamente, os níveis de malondialdeído (estriado: 45%, hipocampo: 38%, córtex pré-frontal: 37%) e os níveis de nitrito (estriado: 72%, hipocampo: 79%, córtex pré-frontal: 63%) e aumentou a glutationa reduzida (estriado: 72%, hipocampo: 73%, córtex pré-frontal: 42%). Além disso, o EEMe prolongou, significativamente, a latência das convulsões induzidas por estricnina (38%) ou pentilenotetrazol (57%), e a latência da morte induzida por pentilenetetrazol (6,1x). Conclusão: o EEMe apresenta efeitos antioxidantes e anticonvulsivantes, provavelmente envolvendo as vias GABAérgica e glicinérgica.

ω-Conotoxina MVIIC e células-tronco mesenquimais promovem recuperação motora em ratos Wistar após trauma medular agudo / ω-Conotoxin MVIIC and mesenchymal stem cells promote motor recovery in Wistar rats after acute spinal cord injury]

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)

Hardy-Weinberg Equilibrium in different mitochondrial haplogroups of four genes associated with neuroprotection and neurodegeneration / Equilíbrio de Hardy-Weinberg em diferentes haplogrupos mitocondriais de quatro genes associados à neuroproteção e neurodegeneração

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.

Neuroprotection and immunomodulation by dimethyl fumarate and a heterologous fibrin biopolymer after ventral root avulsion and reimplantation

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)

Selective head cooling and whole body cooling as neuroprotective agents in severe perinatal asphyxia

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.

Neuroprotective effects of an Nrf2 agonist on high glucose-induced damage in HT22 cells

BACKGROUND: Oxidative stress is the hallmark of diabetic encephalopathy, which may be caused by hyperglycaemic toxicity. We aimed to discover pharmacologic targets to restore redox homeostasis. We identified the transcription factor Nrf2 as such a target. METHODS: HT22 cells were cultured in 25 or 50 mM D-glucose with various concentrations of sulforaphane (SFN) (from 1.25 to 5.0 µM). Cell viability was tested with the Cell Counting Kit-8 assay. Reactive oxygen species (ROS) production was detected with an inverted fluorescence microscope using the dichlorodihydrofluorescein-diacetate fluorescent probe. The expression of NF-E2-related factor 2 (Nrf2), haem oxygenase-1 (HO-1) and nuclear factor-κB (NF-κB) at the mRNA and protein levels was detected by reverse transcription quantitative polymerase chain reaction and western blotting. RESULT: We found that a high glucose concentration (50 mM) increased the generation of ROS, downregulated the expression of Nrf2/HO-1 and upregulated the expression of NF-κB. Moreover, HT22 cell viability significantly decreased after culture in high-glucose medium for 24, 48 and 72 h, whereas the activation of the Nrf2/HO-1 pathway using a pharmacological Nrf2 activator abrogated this high-glucose-induced toxicity. CONCLUSION: This study suggests that the activation of the Nrf2-ARE signalling pathway might be a therapeutic target for the treatment of diabetic encephalopathy.

Assessment of neuropharmacological potential of low molecular weight components extracted from Rhinella schneideri toad poison

Studies on toad poison are relevant since they are considered a good source of toxins that act on different biological systems. Among the molecules found in the toad poison, it can be highlighted the cardiotonic heterosides, which have a known mechanism that inhibit Na+/K+-ATPase enzyme. However, these poisons have many other molecules that may have important biological actions. Therefore, this work evaluated the action of the low molecular weight components from Rhinella schneideri toad poison on Na+/K+-ATPase and their anticonvulsive and / or neurotoxic effects, in order to detect molecules with actions of biotechnological interest. Methods: Rhinella schneideri toad (male and female) poison was collected by pressuring their parotoid glands and immediately dried and stored at -20 °C. The poison was dialysed and the water containing the low molecular mass molecules (< 8 kDa) that permeate the dialysis membrane was collected, frozen and lyophilized, resulting in the sample used in the assays, named low molecular weight fraction (LMWF). Na+/K+ ATPase was isolated from rabbit kidneys and enzyme activity assays performed by the quantification of phosphate released due to enzyme activity in the presence of LMWF (1.0; 10; 50 and 100 µg/mL) from Rhinella schneideri poison. Evaluation of the L-Glutamate (L-Glu) excitatory amino acid uptake in brain-cortical synaptosomes of Wistar rats was performed using [3H]L-glutamate and different concentration of LMWF (10-5 to 10 µg/µL). Anticonvulsant assays were performed using pentylenetetrazole (PTZ) and N-methyl-D-aspartate (NMDA) to induce seizures in Wistar rats (n= 6), which were cannulated in the lateral ventricle and treated with different concentration of LMWF (0.25; 0.5; 1.0; 2.0; 3.0 and 4.0 µg/µL) 15 min prior to the injection of the seizure agent. Results: LMWF induced a concentration-dependent inhibition of Na+/K+-ATPase (IC50% = 107.5 μg/mL). The poison induces an increased uptake of the amino acid L-glutamate in brain-cortical synaptosomes of Wistar rats. This increase in the L-glutamate uptake was observed mainly at the lowest concentrations tested (10-5 to 10-2 µg/µL). In addition, this fraction showed a very relevant central neuroprotection on seizures induced by PTZ and NMDA. Conclusions: LMWF from Rhinella schneideri poison has low molecular weight compounds, which were able to inhibit Na+/K+-ATPase activity, increase the L-glutamate uptake and reduced seizures induced by PTZ and NMDA. These results showed that LMWF is a rich source of components with biological functions of high medical and scientific interest.(AU)

Neuroprotective properties of RT10, a fraction isolated from Parawixia bistriata spider venom, against excitotoxicity injury in neuron-glia cultures

L-Glutamate (L-Glu), the major excitatory neurotransmitter in the mammalian Central Nervous System (CNS), is essential to cognitive functions. However, when L-Glu is accumulated in large concentrations at the synaptic cleft, it can induce excitotoxicity that results in secondary damage implicated in many neurological disorders. Current therapies for the treatment of neurological disorders are ineffective and have side effects associated with their use; therefore, there is a need to develop novel treatments. In this regard, previous studies have shown that neuroactive compounds obtained from the venom of the spider Parawixia bistriata have neuroprotective effects in vitro and in vivo. In this sense, this work aimed to evaluate potential neuroprotective effects of fraction RT10, obtained from this spider venom, on primary cultures of neuron and glial cells subjected to glutamate excitotoxicity insults. Methods: Primary cultures of neurons and glia were obtained from the cerebral tissue of 1-day-old postnatal Wistar rats. After 7 days in vitro (DIV), the cultures were incubated with fraction RT10 (0.002; 0.02; 0.2 and 2 µg/µL) or riluzole (100 µM) for 3-hours before application of 5 mM L-Glu. After 12 hours, the resazurin sodium salt (RSS) test was applied to measure metabolic activity and proliferation of living cells, whereas immunocytochemistry for MAP2 was performed to measure neuronal survival. In addition, the cells were immunolabeled with NeuN and GFAP in baseline conditions. Results: In the RSS tests, we observed that pre-incubation with RT10 before the excitotoxic insults from L-Glu resulted in neuroprotection, shown by a 10% reduction in the cell death level. RT10 was more effective than riluzole, which resulted in a cell-death reduction of 5%. Moreover, qualitative analysis of neuronal morphology (by MAP2 staining, expressed as fluorescence intensity (FI), an indirect measure of neuronal survival) indicate that RT10 reduced the toxic effects of L-Glu, as shown by a 38 % increase in MAP2 fluorescence when compared to L-Glu insult. On the other hand, the riluzole treatment resulted in 17% increase of MAP2 fluorescence; therefore, the neuroprotection from RT10 was more efficacious. Conclusion: RT10 fraction exhibits neuroprotective effects against L-Glu excitotoxicity in neuron-glia cultured in vitro.(AU)

Neuroproteção fetal: uma utilização contemporânea do sulfato de magnésio / Fetal neuroprotection: a contemporary use of magnesium sulfate

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)