Effect of operative trauma and multiple propofol anesthesia on neurodevelopment and cognitive function in developmental rats / 浙江大学学报·医学版

To investigate the effect of multiple propofol anesthesia and operative trauma on neuroinflammation and cognitive function in development rats and its mechanism. A total of 104 13-day-old neonatal Sprague-Dawley rats were randomly divided into 4 groups with 26 rats in each group: control group was treated with saline q.d for propofol group was treated with propofol q.d for surgery group received abdominal surgery under local anesthesia and then treated with saline q.d for surgery with propofol group received propofol anesthesia plus abdominal surgery under local anesthesia with ropivacaine at d1, then treated with propofol q.d for At d2 of experiment, 13 rats from each group were sacrificed and brain tissue samples were taken, the concentration of TNF-α in hippocampus was detected with ELISA, the expression of caspase-3 and c-fos in hippocampal tissue was determined with immunohistochemical method, the number of apoptotic neurons in hippocampus was examined with TUNEL assay. Morris water maze test was used to examine the cognitive function of the rest rats at the age of 60 d, and the TNF-α concentration, caspase-3, c-fos expressions and the number of apoptotic neurons in hippocampus were also detected. Compared with control group, TNF-α concentration, caspase-3, c-fos expression and the neuroapoptosis in hippocampus increased significantly in other three groups (all 0.05). Morris water maze test showed that there were no significant differences in swimming speed, escape latency, target quadrant residence time and crossing times among groups (all >0.05). TNF-α level, expressions of caspase-3 and c-fos and apoptotic cell numbers in hippocampus had no significant differences among the 4 adult rats groups (all >0.05). Abdominal surgery and multiple propofol treatment can induce neuroinflammation and neuroapoptosis in hippocampus of neonatal rats, however, which may not cause adverse effects on neurodevelopment and cognitive function when they grown up.

Consequential exposure to hypothermia in gestational diabetic rats induces oxidative changes in the brain of offspring

Background: Prenatal stress is unique due to range of problems and can affect the embryo/fetus beginning with conception. Gestational diabetes mellitus is the concern for expectant-mothers wherein glucose intolerance with consistent hyperglycemia is a threatening factor during pregnancy. Objectives: In the event of multiple stressors posing their effects on intrauterine life and placenta being the target of increased sympathetic tone during gestation, there is a possibility of functional vulnerabilities that may contribute to the pathogenesis in post-natal life. Studying brain regional discrepancies in offspring might help to know the prenatal stress-induced variation in the antioxidant barrier and promoted oxidative stress. Materials and Methods: The changes occurring in oxidative stress indices in discrete brain regions of rat offspring born as a consequential exposure to gestational diabetes (streptozotocin induction) and cold stress (15 and 20°C) are assessed in this study. Results: The findings specify the involvement of cold-stress provoked induction of higher degree oxidative stress within brain compartments as evidenced by a decrease in antioxidant enzymes, namely, superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase, and GSH as well as increase in the concentration of malondialdehyde. Results highlight the synergistic actions of stressors due to the increased generation of free radicals. Cold stress at 15°C found to cause exacerbatory actions by depleting antioxidant enzymes in diabetic subjects than the exposures made at 20°C. Conclusion: The findings prove that cold stress is a crucial stimulus to a fetus during gestation and acts as a trigger of oxidative stress especially in diabetic subjects and can pose an adverse impact. These changes could partly explain the increased vulnerability of prenatally stressed subjects to functional disorders including deficits in memory and cognitive processes in later life.

Research Progress of Developmental Neurotoxicity Induced by General Anesthetics / 中山大学学报(医学科学版)

@#With the rapid development of surgery and the expansion of indications for surgical treatment ，the number of non-obstetric operations during pregnancy and infant operations has been increasing. Most of these operations need to be performed under general anesthesia，and the developing brain of fetus and infants are inevitably exposed to general anesthetics. Therefore，in recent years，the neurotoxicity effects of general anesthetics on the developing brain have become the focus and controversy in the medical sciences. Especially in 2016，US Food and Drug Administration（FDA）added black box for warning of general anesthetics commonly used in clinic，which caused confusion among doctors，patients and staffs in the related fields. Therefore，we will elaborate the preclinical and clinical studies of neurotoxicity of general anesthetics in combination with the characteristics of developing brain.

Progress of ameliorating the neurotoxicity of anaesthetics on developing brain / 复旦学报（医学版）

General anesthetics are widely used in pregnant women,gravidas and infants.In the basic studies of rodents,mammals and non-human primate,general anesthetics can cause neurotoxicity,neuroapoptosis and damage neurodevelopment on the developing brain.Therefore,To explore protective measures and mechanism of anesthetic neurotoxicity is of great significance for formulating clinical anesthesia plan,guiding clinical obstetrics and pediatric anesthesia.This article reviewed the progress of ameliorating the neurotoxicity of general anaesthetics on developing brain including anesthetic assistants,hormone drugs,plant extracts,nutritional components and others.

Neonatal Administration of Memantine Enhances Social Cognition in Adult Rats Subjected to Early Maternal Deprivation

Schizophrenia is considered a neurodevelopmental disorder; however, all the available treatment options are used when the disease becomes clinically significant in adolescence or early adulthood. Using a developmental rat model of schizophrenia, we examined whether neonatal treatment with memantine, an NMDA receptor modulator, can improve schizophrenic-like symptoms in adulthood. Early maternal deprivation in rats produces deficits in social interaction behaviors in adulthood. In contrast, memantine administrated in neonatal rats subjected to early maternal deprivation significantly reduces deficits in social interaction behaviors in adulthood. These results raise the possibility that pharmacological treatment with memantine at the early developmental stage helps people with a risk to develop schizophrenic-like symptoms.

Effects of different doses of remifentanil on short-term learning and memory ability in the developing rats / 临床麻醉学杂志

Objective To investigate the effects of different doses of remifentanil on learning and memory ability,the expression of hippocampal tissue phosphorylation of cAMP response element binding protein (p-CREB)in developing rats.Methods A total of 72 Sprague-Dawley rats (1 9-23 g) were randomly divided into 4 groups (n =18 each):Group C:normal saline control group;R1,R2, R3 group received continuous intraperitoneal remifentanil 1,5,10 μg·kg-1 ·min-1 for 2 hours re-spectively.Both total volume of remifentanil and saline were 2 ml.The SpO 2 and pulse rates were mo-nitored during the experiment.Step-down test was used to evaluate the learning and memory ability, while Western blot analysis was performed to measure the expression of hippocampal p-CREB protein in 4 h,24 h,1 week when the rats were awake.Results Compared with group C,group R1 and R2, pulse rates of group R3 decreased significantly (P <0.05 ),but the changes of SpO 2 in each group were not statistically significant.At 4 h point:compared with group C and group R1,the error times in step-down test were increased in both group R2 and R3,the latencies were shortened (P <0.05);Compared with group R2,the error times were increased in group R3,latency was shortened (P <0.05).At 24 h point,compared with group C and group R1,the error times were increased in group R2,R3,latencies were shortened (P < 0.05 );Compared with group R2,the error times were in-creased in group R3,latency was shortened (P <0.05 ).The error times and latency of each group had not statistical significance in one week.At 4 h point,the expression of p-CREB protein in hippo-campus of group R3 downregulated compared with group C and group R1,R2,respectively (P <0.05).At 24 h point,the expression of p-CREB protein in hippocampus of group R2,R3 decreased compared with group C and group R1 respectively(P <0.05);The expression of p-CREB protein in each group had no statistical significance in one week.Conclusion 5-10 μg · kg-1 · min-1 dose of remifentanil can result in a decline of learning and memory ability in the developing rats in short-term,and the mechanism may relate to the inhibition of p-CREB protein expression in hippocampus.

Role of TNF-αin propofol-induced neuronal apoptosis and long-term cognitive impairment in neonatal rats / 中国药理学通报

Aim To investigate the role of TNF-αin propofol-induced neuronal apoptosis and long-term cog-nitive impairment in neonatal rats .Methods Seven-day-old SD rats were randomly divided into 3 groups:Control group ( n =12 ) , P ( single ) group ( n =6 ):propofol 50 mg · kg -1 was injected intraperitoneally (ip.)once;P(repeated) group(n=6):propofol 50 mg · kg -1 was injected ip.once daily, and for seven times. Hippocampal TNF-αlevel was measured 2 hours after propofol anesthesia , there were two time points(n=6) in Control group as control levels (post-natal day 7 for P ( single ) group and postnatal day 13 for P ( repeated ) group ) .In another experiment , 7-day-old rats were randomly divided into 5 groups:Con-trol group; P ( single ) group; P ( repeated ) group; P ( single ) +ETN group: ETN ( etanercept ) 0.4 mg · kg -1 was injected intracerebroventricularly 30 min be-fore propofol administration; P ( repeated ) +ETN group:ETN 0.4 mg· kg -1 was injected intracerebrov-entricularly 30 min before the 1st and 4th administration of propofol , which was injected ip .for seven times , once daily .Hippocampal neuronal apoptosis was detec-ted at postnatal day 7 [ P ( repeated ) and P ( repeated )+ETN groups not involved at this time point ] , 13, 21 and 35 , cognitive function was measured at postnatal day 36 to 41 using Morris water maze test .Results Propofol with different exposure times could increase hippocampal TNF-αlevels(P0.05 );in P ( repeated ) group, active caspase-3 positive neurons were more significantly increased at postnatal day 13, 21 and 35 than those in control group ( P0.05 ) .Con-clusion TNF-αmediates hippocampal neuronal apop-tosis and long-term cognitive impairment induced by propofol in neonatal rats , and long-term cognitive im-pairment may be related with persistent neuronal apop-tosis.

Therapeutic effects of intravenous administration of bone marrow stromal cells on sevoflurane-induced neuronal apoptosis and neuroinflammation in neonatal rats / 대한마취과학회지

BACKGROUND: Sevoflurane exposure during the early postnatal period causes neuroinflammation and neuronal apoptosis in rodents. Bone marrow stromal cells (BMSCs) have been shown to protect and repair the damaged central nervous system, for example in ischemic stroke models. In this study, we investigated whether intravenous administration of BMSCs ameliorated neurodegeneration, induced by sevoflurane exposure, in neonatal rats. METHODS: Sprague-Dawley rat pups (postnatal day 7) were exposed to 2% sevoflurane for 6 h (vehicle group, n = 7). BMSCs were administered 30 min after induction of sevoflurane anesthesia (BMSCs group, n = 7). The pups were exposed to carrier gas only, as a negative control (mock anesthesia group, n = 4). We assessed the therapeutic effects of BMSC treatment by measuring expression of the pro-inflammatory cytokine interleukin-6 (IL-6), and levels of cleaved caspase-3, in brain tissues immediately following sevoflurane anesthesia. RESULTS: Analysis of the cleaved caspase-3 bands revealed that levels of activated caspase-3 were elevated in the vehicle group compared with the mock anesthesia group, indicating that a single exposure to sevoflurane at subclinical concentrations can precipitate neuronal apoptosis. BMSC treatment did not suppress apoptosis induced by sevoflurane exposure (compared with the vehicle group). The vehicle group had higher proinflammatory cytokine IL-6 protein levels compared with the mock anesthesia group, indicating that sevoflurane exposure induces IL-6 expression. BMSC treatment suppressed sevoflurane-induced increases in IL-6 expression, indicating that these cells can inhibit the neuroinflammation induced by sevoflurane exposure (vehicle group vs. BMSC group). CONCLUSIONS: Intravenous administration of BMSCs reduces neuroinflammation, but does not attenuate apoptosis induced by sevoflurane exposure.

Efeitos da epilepsia e da desnutrição no sistema nervoso central em desenvolvimento: aspectos clínicos e evidências experimentais / Effects of epilepsy and malnutrition in the developing central nervous system: clinical aspects and experimental evidences

INTRODUÇÃO: A desnutrição e epilepsia são problemas prevalentes em países em desenvolvimento, principalmente na faixa etária pediátrica. OBJETIVOS: Tendo em vista o impacto que insultos como as crises convulsivas e a desnutrição geram no sistema nervoso central (SNC) de crianças, nosso estudo visa revisar a literatura atual sobre a relação entre desnutrição precoce e epilepsia em estudos clínicos e experimentais em ratos. METODOLOGIA: Revisão de literatura em revistas indexadas no Medline, no período de janeiro de 2000 até dezembro de 2008. RESULTADOS: Foram utilizados os unitermos epilepsy e malnutrition para a busca, sendo encontrados 1044 artigos, dos quais 56 foram selecionados para esta revisão. Procuramos resumir os principais achados referentes às alterações influenciadas pelas crises convulsivas e desnutrição no desenvolvimento do SNC. CONCLUSÕES: A análise desses artigos indicou que a desnutrição precoce acarreta déficit neuronal, com alterações cognitivas e modificações no desenvolvimento e crescimento em modelos experimentais, podendo haver maior suscetibilidade a crises convulsivas. Aparentemente, a desnutrição não é uma causa direta de epilepsia, mas pode diminuir o limiar para as crises epiléticas, havendo um efeito aditivo entre ambas.

INTRODUCTION: Malnutrition and epilepsy are main problems in developing countries, especially affecting children. PURPOSE: Considering the impact that insults like seizures and malnutrition have in the developing central nervous system (CNS), our study intends to review the current literature about the relation between epilepsy and early malnutrition in clinical and experimental studies in rats. METHODS: Literature review in Medline, during the period of January of 2000 to December 2008. RESULTS: Using the key words epilepsy and malnutrition, 1044 articles were found, from which we used 56 to this review. We intended to summarize the main findings that are refered to the alterations induced by seizures and malnutrition in the CNS development. CONCLUSION: The analysis of these articles indicated that early malnutrition lead to neuronal deficit, with cognitive alterations and growth and developmental disorders in experimental models, possibly causing more susceptibility to seizures. Apparently, malnutrition is not a direct cause of epilepsy, but it can decrease the threshold to seizures, suggesting an additive effect between these variables.

Modelos animales de lesión y reparación del cerebro en desarrollo / Animal models of injury and repair in developing brain

Gran parte de la morbilidad y mortalidad neonatal están determinadas por la lesión del cerebro en desarrollo. Un considerable número de los niños afectados presentarán secuelas neurológicas a largo plazo. A pesar de la importancia médica y social que presenta el problema, los avances alcanzados por la medicina neonatal no cuentan aún con una terapéutica eficaz para prevenir o aminorar las consecuencias de la lesión del cerebro en desarrollo. En la siguiente revisión nos proponemos actualizar las investigaciones más recientes en relación a los mecanismos de lesión y reparación del cerebro en desarrollo, basados en modelos animales que ilustran sobre los mecanismos plásticos de adaptación neuronal y funcional; el fin es un mejor conocimiento de los citados procesos que ayude al clínico en la práctica cotidiana de la neonatología.

Brain injury is a major contributor to neonatal morbidity and mortality, a considerable group of these children will develop long term neurological sequels. Despite the great clinical and social significance and the advances in neonatal medicine, no therapy yet does exist that prevent or decrease detrimental effects in cases of neonatal brain injury. Our objective was to review recent research in relation to the hypothesis for repair mechanism in the developing brain, based in animal models that show developmental compensatory mechanisms that promote neural and functional plasticity. A better understanding of these adaptive mechanisms will help clinicians to apply knowledge derived from animals to human clinical situations.

The Neuroprotective Effects of Phenytion on Ischemic-hypoxic Injury to the Developing Rat Brain

Phenytoin is an anticonvulsant compound which modulates the voltage-dependent sodium channels. It has a neuroprotective effect in vitro against hypoxic damage in hippocampal slices of adult rats. The authors studied the efficacy of phenytion on cerebral ischemia in an vivo model of hypoxic-ischemic brain injury in developing rat brain. To elicit injury, 7 days old(P7) Sprague-dawley rats subjected to right common carotid ligation followed by 8% O2 exposure(humidified, balanced with nitrogen) for 3 hours under the halothane anesthesia(control group, N=58). Body temperature of the rats was accurately controlled before and during hypoxia. Before hypoxia, pups received intraperitoneal phenytoin(30mg/kg)(phenytoin-treated group, N=17). The animals were sacrificed one week later and histopathological evaluation of ischemic neuronal damage were conducted employing hematoxylin-eosin staining and measurement of the hemispheric weight differences were performed. Phenytoin was found to be effective in reducing neuronal damage in terms of weight comparison(24+/-2.4% atrophy of control vs. 5+/-2.9% atrophy of phenytoin group, p<0.001) and ischemic changes in hippocampal region(p<0.05 in CA1, CA2, and CA3 area). These data suggest that compounds like phenytoin, which modulates voltage-dependent sodium channels, can reduce the degree of injury from hypoxic-ischemic insults to the developing rat brain.