Pre- and early postnatal enriched environmental experiences prevent neonatal hypoxia-ischemia late neurodegeneration via metabolic and neuroplastic mechanisms.

Prenatal and early postnatal periods are important for brain development and neural function. Neonatal insults such as hypoxia-ischemia (HI) causes prolonged neural and metabolic dysregulation, affecting central nervous system maturation. There is evidence that brain hypometabolism could increase the risk of adult-onset neurodegenerative diseases. However, the impact of non-pharmacologic strategies to attenuate HI-induced brain glucose dysfunction is still underexplored. This study investigated the long-term effects of early environmental enrichment in metabolic, cell, and functional responses after neonatal HI. Thereby, male Wistar rats were divided according to surgical procedure, sham, and HI (performed at postnatal day 3), and the allocation to standard (SC) or enriched condition (EC) during gestation and lactation periods. In-vivo cerebral metabolism was assessed by means of [18 F]-FDG micro-positron emission tomography, and cognitive, biochemical, and histological analyses were performed in adulthood. Our findings reveal that HI causes a reduction in glucose metabolism and glucose transporter levels as well as hyposynchronicity in metabolic brain networks. However, EC during prenatal or early postnatal period attenuated these metabolic disturbances. A positive correlation was observed between [18 F]-FDG values and volume ratios in adulthood, indicating that preserved tissue by EC is metabolically active. EC promotes better cognitive scores, as well as down-regulation of amyloid precursor protein in the parietal cortex and hippocampus of HI animals. Furthermore, growth-associated protein 43 was up-regulated in the cortex of EC animals. Altogether, results presented support that EC during gestation and lactation period can reduce HI-induced impairments that may contribute to functional decline and progressive late neurodegeneration.

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

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.

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.

Effect of carbamylated erythropoietin on neuronal apoptosis in fetal rats during intrauterine hypoxic-ischemic encephalopathy.

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) is a common disease that occurs during the perinatal period. The primary cause of neonatal HIE is related to fetal intrauterine anoxia. Carbamylated erythropoietin (CEPO), a derivative of erythropoietin (EPO), does not exert any erythropoietic effect; however, the neuroprotective effects resemble those of EPO. Previous studies have shown the potential benefits of CEPO on the central nervous system. The present study aimed to investigate the role of CEPO in neuronal apoptosis during intrauterine HIE and the underlying mechanisms. RESULTS: To validate our hypothesis, we established an intrauterine HIE model by occluding the bilateral utero-ovarian arteries of pregnant Sprague-Dawley rats. Compared to the I/R group, neuronal apoptosis in the CEPO group was significantly lower at 4, 12, 24, and 48 h (P < 0.05). CEPO significantly inhibited CC3 expression (P < 0.05) during the early-stages after ischemia-reperfusion (0.5, 4, 8, 12 and 24 h), upregulated Bcl-2 expression, and downregulated Bax expression at 4, 8, 12, and 24 h (P < 0.05). CONCLUSIONS: Carbamylated erythropoietin pretreatment inhibited the expression of proapoptotic protein CC3 in brain and regulated the Bcl-2/Bax ratio, resulting in reduced neuronal apoptosis and thus resulting in a protective effect on intrauterine HIE.

Effect of carbamylated erythropoietin on neuronal apoptosis in fetal rats during intrauterine hypoxic-ischemic encephalopathy

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) is a common disease that occurs during the perinatal period. The primary cause of neonatal HIE is related to fetal intrauterine anoxia. Carbamylated erythropoietin (CEPO), a derivative of erythropoietin (EPO), does not exert any erythropoietic effect; however, the neuroprotective effects resemble those of EPO. Previous studies have shown the potential benefits of CEPO on the central nervous system. The present study aimed to investigate the role of CEPO in neuronal apoptosis during intrauterine HIE and the underlying mechanisms. RESULTS: To validate our hypothesis, we established an intrauterine HIE model by occluding the bilateral uteroovarian arteries of pregnant Sprague-Dawley rats. Compared to the I/R group, neuronal apoptosis in the CEPO group was significantly lower at 4, 12, 24, and 48 h (P < 0.05). CEPO significantly inhibited CC3 expression (P < 0.05) during the early-stages after ischemia-reperfusion (0.5, 4, 8, 12 and 24 h), upregulated Bcl-2 expression, and downregulated Bax expression at 4, 8, 12, and 24 h (P < 0.05). CONCLUSIONS: Carbamylated erythropoietin pretreatment inhibited the expression of proapoptotic protein CC3 in brain and regulated the Bcl-2/Bax ratio, resulting in reduced neuronal apoptosis and thus resulting in a protective effect on intrauterine HIE.

Pregnancy swimming causes short- and long-term neuroprotection against hypoxia-ischemia in very immature rats.

BackgroundHypoxia-ischemia (HI) is a major cause of neurological damage in preterm newborn. Swimming during pregnancy alters the offspring's brain development. We tested the effects of swimming during pregnancy in the very immature rat brain.MethodsFemale Wistar rats (n=12) were assigned to the sedentary (SE, n=6) or the swimming (SW, n=6) group. From gestational day 0 (GD0) to GD21 the rats in the SW group were made to swim for 20 min/day. HI on postnatal day (PND) 3 rats caused sensorimotor and cognitive impairments. Animals were distributed into SE sham (SESH), sedentary HIP3 (SEHI), swimming sham (SWSH), and swimming HIP3 (SWHI) groups. At PND4 and PND5, Na+/K+-ATPase activity and brain-derived neurotrophic factor (BDNF) levels were assessed. During lactation and adulthood, neurological reflexes, sensorimotor, anxiety-related, and cognitive evaluations were made, followed by histological assessment at PND60.ResultsAt early stages, swimming caused an increase in hippocampal BDNF levels and in the maintenance of Na+/K+-ATPase function in the SWHI group. The SWHI group showed smaller lesions and the preservation of white matter tracts. SEHI animals showed a delay in reflex maturation, which was reverted in the SWHI group. HIP3 induced spatial memory deficits and hypomyelination in SEHI rats, which was reverted in the SWHI group.ConclusionSwimming during pregnancy neuroprotected the brains against HI in very immature neonatal rats.

¿Es posible disminuir la incidencia de encefalopatía hipóxico isquémica? / Is it possible to reduce the incidence of hypoxic-ischemic encephalopathy?

Objetivo: Determinar si una política local, establecida en la Maternidad del Hospital Padre Hurtado (HPH), para bajar la incidencia de Encefalopatía Hipóxico Isquémica es efectiva, sin incrementar en forma relevante la tasa de cesáreas. Diseño: Estudio de cohorte. Escenario: Unidad de Gestión Clínica de la Mujer y el Recién Nacido del Hospital Padre Hurtado. Población: Neonatos mayores de 33 semanas de edad gestacional, nacidos en el Hospital Padre Hurtado durante los años 1999 y 2015. Método: Se revisaron los resultados de una política de intervención para prevención de asfixia neonatal establecida en la Maternidad del Hospital Padre Hurtado durante un periodo de 14 años. Resultados: Al analizar los datos de un total de 102.612 nacidos vivos, se constató una disminución en la incidencia de EHI en sus 3 grados de una tasa de 4.75/1.000 nacidos vivos previo a la intervención (grupo control) a una tasa de 1.46 por 1.000 nacidos vivos post intervenciones, con alta significancia estadística (p=0,008), llegando en los últimos 6 años a tasa promedio de 0.87/1.000 nacidos vivos. La tasa de EHI moderada y severa bajó de 1.15 por mil nacidos vivos a 0.62, también con alta significancia estadística (p=0.02). La tasa de cesáreas oscilo entre 26-29 % en estos años. Conclusión: La introducción de intervenciones protocolizadas y sistematizadas por medio de la implementación de guías de manejo del trabajo de parto, la capacitación del equipo de profesionales y la auditoría continua de los casos de EHI en el Servicio de Maternidad del Hospital Padre Hurtado se asoció a una disminución significativa de EHI, manteniendo la tasa de cesáreas bajo 30%.

Objectives: Determine whether a local policy to reduce the incidence of neonatal hypoxic-ischemic encephalopathy (HIE), established at the Maternity Unit of Hospital Padre Hurtado (HPH), is effective without significantly increasing the cesarean rate. Design: Cohort study. Setting: Maternity unit of Hospital Padre Hurtado. Population: Newborns older than 33 weeks born at Hospital Padre Hurtado between 1999 and 2015. Methods: The results of a training policy to prevent HIE and perinatal asphyxia established at the Maternity unit of Hospital Padre Hurtado were reviewed during a period of 14 years. Results: From a total of 102.612 newborns analyzed, results showed a decrease in all grades of HIE incidence, from a rate of 4.75 / 1,000 live births prior to intervention (control group) to a rate of 1.46 per 1,000 live births after interventions, with high statistically significance (p=0.008), it reached an average rate of 0.87/1000 for the last 6 years. The moderate and severe HIE rate decreased from 1.15/1000 to 0.62/1000, also with high statistically significance (p=0.02). During the same period of time, the cesarean rate varied between 26-29%. Conclusion: The introduction of protocolized and systematized interventions trough the implantation of Management guides, obstetrics emergency trainings to the professional team and continues audit of the HIE cases at the Maternity unit Hospital Padre Hurtado was associated to a significant decrease of HIE, maintaining the rate of cesareans below 30%.

Administration of Huperzia quadrifariata Extract, a Cholinesterase Inhibitory Alkaloid Mixture, has Neuroprotective Effects in a Rat Model of Cerebral Hypoxia-Ischemia.

Neonatal hypoxia-ischemia (HI) is an etiologic component of several neurologic pathologies associated to cognitive impairment. The mechanisms involved in HI-induced tissue damage start immediately after HI and extend for days. Acetylcholine is an important neurotransmitter in the central nervous system and exerts a protector effect on tissue damage by modulating inflammation, and cholinesterase inhibitors have shown neuroprotective properties and their action are often attributed to inhibition of the immune response. The administration of Huperzia quadrifariata alkaloid extract (HqAE), with potent and selective cholinesterase inhibitor properties, will reduce the HI induced behavioral deficits and tissue damage. A total of 84 newborn Wistar rat pups at post natal day 7 (PND7) were subjected to right carotid occlusion followed by 1 h of hypoxia (8% of O2) and i.p. injections of saline, vehicle or HqAE (10 mg/kg). Morris Water Maze and inhibitory avoidance tests were used to assess the cognitive function. Flow cytometry was performed at PND11. Histological analysis was performed at PND45. HqAE treatment was able to prevent the HI induced cognitive deficits in both tests and, at PND45, histological analysis showed that HqAE treatment reduced hippocampus tissue damage. Flow cytometry of the injured hippocampus revealed that the treatment was able to reduce cellular death and the number of infiltrating T cells. Altogether, these results show the therapeutic potential of the Huperzia quadrifariata alkaloid extract to prevent cognitive deficits and histological damage caused by neonatal hypoxia-ischemia, probably by reducing cellular death and T cell mobilization.

Flaxseed mitigates brain mass loss, improving motor hyperactivity and spatial memory, in a rodent model of neonatal hypoxic-ischemic encephalopathy.

Neonatal hypoxic-ischemic (HI) encephalopathy is a major cause of perinatal morbimortality. There is growing evidence that n-3 polyunsaturated fatty acids, especially docosahexaenoic acid (DHA), attenuate brain injury. This study aimed to investigate the possible neuroprotective effect of maternal intake of flaxseed, rich in DHA׳s precursor α-linolenic acid, in the young male offspring subjected to perinatal HI. Wistar rats were divided in six groups, according to maternal diet and offspring treatment at day 7: Control HI (CHI) and Flaxseed HI (FHI); Control Sham and Flaxseed Sham; Control Control and Flaxseed Control. Flaxseed diet increased offspring׳s hippocampal DHA content and lowered depressive behavior. CHI pups presented brain mass loss, motor hyperactivity and poor spatial memory, which were improved in FHI rats. Maternal flaxseed intake may prevent depressive symptoms in the offspring and promote neuroprotective effects, in the context of perinatal HI, improving brain injury and its cognitive and behavioral impairments.

Targeted temperature management in survivors of cardiac arrest.

Mild therapeutic hypothermia (MTH) results in a significant decrease in mortality and improvement of neurologic outcomes in cardiac arrest (CA) survivors. Cardiologists and intensivists must be acquainted with the indications and technique because MTH is the only proven neuroprotective therapy for CA survivors. CA involves reinstituting meaningful cardiac activity and minimizing secondary neurologic injuries. This article focuses on MTH as the main strategy for post-CA care.

Hypoxic preconditioning induces an AT2-R/VEGFR-2(Flk-1) interaction in the neonatal brain microvasculature for neuroprotection.

The angiotensin II receptor subtype 2 (AT2-R) has been proposed to mediate protective vascular actions after brain injury. In this study we investigated the participation of this peptide in the tolerance to cellular damage induced by preconditioning in a rat model of neonatal hypoxia-ischemia (HI). We found that injured animals present a decreased number of microvessels in the ipsilateral (IPLT) side of the brain while in the contralateral (CNLT) side the microvessel number is increased. On the contrary, in the preconditioned animals the microvessels maintained the same number as in control animals. However these vessels show a remarkable increase of the fluorescent signal when they are labeled with antiFlk-1 (VEGFR2), while the Flt-1 (VEGFR1) signal faded in both the injured and the preconditioned animals. The pharmacological blockade of the AT2-R by the drug PD123319 (1.69 mM in the lateral ventricle) diminished the resilience of the microvasculature to HI injury provided by preconditioning and also the Flk-1 increase that occurred in these animals. In conclusion these results suggest an interaction of the AT2-R with VEGFR2 in the neonatal brain microvasculature that produces protective effects which are associated with injury tolerance.

Neuroprotective effects of NEP1-40 and fasudil on Nogo-A expression in neonatal rats with hypoxic-ischemic brain damage.

The hypoxic-ischemic encephalopathy caused by peripartum asphyxia is a serious disease in newborn infants, and effective therapies need to be developed to reduce injury-related disorders. We evaluated the effects of NEP1-40 and fasudil on Nogo-A expression in neonatal hypoxic-ischemic brain damage (HIBD) rats. Seven-day-old Wistar rats were randomly divided into control, HIBD, NEP1-40, and fasudil groups. NEP1-40 and fasudil groups were injected intraperitoneally with these compounds. Rat brains at 6, 24, 72 h, and 7 days after HIBD were collected to determine histopathological damage and the expression levels of Nogo-A. Histopathological damage was reduced in NEP1-40 and fasudil groups compared with the untreated HIBD group. The expression of Nogo-A in the HIBD group was significantly higher than that in control, NEP1-40 and fasudil groups at the same times. Compared with the fasudil group, the expression levels of Nogo-A were significantly reduced in the NEP1-40 group. We conclude that NPE1-40 and fasudil have potential for neuroprotective effects in the neonatal rat HIBD model, mediated by inhibiting Nogo-A/ Rho pathways.

NAP prevents acute cerebral oxidative stress and protects against long-term brain injury and cognitive impairment in a model of neonatal hypoxia-ischemia.

Hypoxia-ischemia (HI) is a common cause of neonatal brain damage with lifelong morbidities in which current therapies are limited. In this study, we investigated the effect of neuropeptide NAP (NAPVSIPQ) on early cerebral oxidative stress, long-term neurological function and brain injury after neonatal HI. Seven-day-old rat pups were subjected to an HI model by applying a unilateral carotid artery occlusion and systemic hypoxia. The animals were randomly assigned to groups receiving an intraperitoneal injection of NAP (3 µg/g) or vehicle immediately (0 h) and 24 h after HI. Brain DNA damage, lipid peroxidation and reduced glutathione (GSH) content were determined 24 h after the last NAP injection. Cognitive impairment was assessed on postnatal day 60 using the spatial version of the Morris water maze learning task. Next, the animals were euthanized to assess the cerebral hemispheric volume using the Cavalieri principle associated with the counting point method. We observed that NAP prevented the acute HI-induced DNA and lipid membrane damage and also recovered the GSH levels in the injured hemisphere of the HI rat pups. Further, NAP was able to prevent impairments in learning and long-term spatial memory and to significantly reduce brain damage up to 7 weeks following the neonatal HI injury. Our findings demonstrate that NAP confers potent neuroprotection from acute brain oxidative stress, long-term cognitive impairment and brain lesions induced by neonatal HI through, at least in part, the modulation of the glutathione-mediated antioxidant system.

Hipotermia en recíen nacidos con asfixia perinatal / Hypothermia in newborns with perinatal asphyxia

Se ha demostrado que la hipotermia controlada puede reducir la muerte o discapacidad grave, la mortalidad y los trastornos del neurodesarrollo en recién nacidos que han sufrido asfixia perinatal. Con el objetivo de implementar la realización de hipotermia se analizó su aplicación en 10 recién nacidos de término que cumplieron con criterios de inclusión en dos centros neonatales de Montevideo en un período de dos años. Se alcanzó la temperatura objetivo (33,5°C) en las primeras 6 horas de vida de los pacientes y se mantuvo en ese rango durante 72 horas en 7/10 pacientes. En 8/10 pacientes se utilizó un gorro con agua fría circulante y en 2/10 placas de gel congelado para el enfriamiento encefálico directo y de todo el cuerpo en forma indirecta. Tres pacientes se retiraron del protocolo luego de 48 horas de hipotermia por alteraciones de la coagulación, bradicardia mantenida y paro cardiorrespiratorio, respectivamente. El recalentamiento se logró en todos los casos en seis horas sin alteraciones. El 60% de los pacientes presentaron convulsiones durante su internación y el 100% recibieron fenobarbital. En el grupo analizado se produjeron dos muertes, uno de ellos próximo a la supresión de la terapia y otro en la evolución alejada. De manera complementaria se presentó la caracterización del impacto de la hipoxia severa y de la inducción de hipotermia sobre las variables más relevantes en un modelo de cerdo recién nacido. Se concluye que el desarrollo de hipotermia controlada es una estrategia terapéutica posible y segura, que brinda una oportunidad a los pacientes que han sufrido asfixia perinatal

Hipotermia en recíen nacidos con asfixia perinatal / Hypothermia in newborns with perinatal asphyxia

Se ha demostrado que la hipotermia controlada puede reducir la muerte o discapacidad grave, la mortalidad y los trastornos del neurodesarrollo en recién nacidos que han sufrido asfixia perinatal. Con el objetivo de implementar la realización de hipotermia se analizó su aplicación en 10 recién nacidos de término que cumplieron con criterios de inclusión en dos centros neonatales de Montevideo en un período de dos años. Se alcanzó la temperatura objetivo (33,5°C) en las primeras 6 horas de vida de los pacientes y se mantuvo en ese rango durante 72 horas en 7/10 pacientes. En 8/10 pacientes se utilizó un gorro con agua fría circulante y en 2/10 placas de gel congelado para el enfriamiento encefálico directo y de todo el cuerpo en forma indirecta. Tres pacientes se retiraron del protocolo luego de 48 horas de hipotermia por alteraciones de la coagulación, bradicardia mantenida y paro cardiorrespiratorio, respectivamente. El recalentamiento se logró en todos los casos en seis horas sin alteraciones. El 60% de los pacientes presentaron convulsiones durante su internación y el 100% recibieron fenobarbital. En el grupo analizado se produjeron dos muertes, uno de ellos próximo a la supresión de la terapia y otro en la evolución alejada. De manera complementaria se presentó la caracterización del impacto de la hipoxia severa y de la inducción de hipotermia sobre las variables más relevantes en un modelo de cerdo recién nacido. Se concluye que el desarrollo de hipotermia controlada es una estrategia terapéutica posible y segura, que brinda una oportunidad a los pacientes que han sufrido asfixia perinatal

Apotransferrin-induced recovery after hypoxic/ischaemic injury on myelination.

We have previously demonstrated that aTf (apotransferrin) accelerates maturation of OLs (oligodendrocytes) in vitro as well as in vivo. The purpose of this study is to determine whether aTf plays a functional role in a model of H/I (hypoxia/ischaemia) in the neonatal brain. Twenty-four hours after H/I insult, neonatal rats were intracranially injected with aTf and the effects of this treatment were evaluated in the CC (corpus callosum) as well as the SVZ (subventricular zone) at different time points. Similar to previous studies, the H/I event produced severe demyelination in the CC. Demyelination was accompanied by microglial activation, astrogliosis and iron deposition. Ferritin levels increased together with lipid peroxidation and apoptotic cell death. Histological examination after the H/I event in brain tissue of aTf-treated animals (H/I aTF) revealed a great number of mature OLs repopulating the CC compared with saline-treated animals (H/I S). ApoTf treatment induced a gradual increase in MBP (myelin basic protein) and myelin lipid staining in the CC reaching normal levels after 15 days. Furthermore, significant increase in the number of OPCs (oligodendroglial progenitor cells) was found in the SVZ of aTf-treated brains compared with H/I S. Specifically, there was a rise in cells positive for OPC markers, i.e. PDGFRα and SHH(+) cells, with a decrease in cleaved-caspase-3(+) cells compared with H/I S. Additionally, neurospheres from aTf-treated rats were bigger in size and produced more O4/MBP(+) cells. Our findings indicate a role for aTf as a potential inducer of OLs in neonatal rat brain in acute demyelination caused by H/I and a contribution to the differentiation/maturation of OLs and survival/migration of SVZ progenitors after demyelination in vivo.

Prophylactic phenobarbital and whole-body cooling for neonatal hypoxic-ischemic encephalopathy.

In infants with hypoxic-ischemic encephalopathy, cooling reduces death/neurodevelopmental impairment, whereas prophylactic anticonvulsants may not. This retrospective analysis shows no reduction in neurodevelopmental impairment (23% in prophylactic phenobarbital group vs 45% in controls, P = .3) but fewer clinical seizures in cooled infants who received prophylactic phenobarbital (15% vs 82% P < .0001).

Human cord blood transplantation in a neonatal rat model of hypoxic-ischemic brain damage: functional outcome related to neuroprotection in the striatum.

Human umbilical cord blood mononuclear cells (HUCB) have been shown to have a therapeutic role in different models of central nervous system (CNS) damage, including stroke. We evaluated the possible therapeutic potential of HUCB in P7 rats submitted to the Rice-Vannucci model of neonatal hypoxic-ischemic (HI) brain damage. Our results demonstrated that intraperitoneal transplantation of HUCB, 3 h after the HI insult, resulted in better performance in two developmental sensorimotor reflexes, in the first week after the injury. We also showed a neuroprotective effect in the striatum, and a decrease in the number of activated microglial cells in the cerebral cortex of treated animals. We suggest that HUCB transplantation might rescue striatal neurons from cell death after a neonatal HI injury resulting in better functional recovery.

Effect of treadmill exercise on cell damage in rat hippocampal slices submitted to oxygen and glucose deprivation.

We have recently demonstrated that high intensity training exercise exacerbates brain damage, while a moderate intensity (2 weeks of 20 min/day of treadmill training) reduces the injury caused by in vitro ischemia, oxygen and glucose deprivation (OGD), to hippocampal slices from Wistar rats. In the present paper, the effect of different running programs on severity of ischemic OGD lesion was examined, by the evaluation of three protocols designed to simulate exercise conditions common to humans: one or three 20-min sessions per week, during 12 weeks (moderate intensity), and two 20-min daily sessions for 3 weeks. OGD caused an increase of lactate dehydrogenase (LDH) release into the incubation media, a marker of tissue necrosis, and a decline of cell viability, as assessed by the decrease of mitochondrial dehydrogenase activity (MTT method). Moderate exercise, three times a week during 12-week treadmill training, decreased LDH release after OGD, while one weekly session and 3 weeks of two daily sessions did not affect OGD-induced LDH released. No exercise protocol evaluated altered MTT reduction. Our data support the hypothesis that moderate intensity exercise reduces hippocampal susceptibility to in vitro ischemia.

Exercise intensity influences cell injury in rat hippocampal slices exposed to oxygen and glucose deprivation.

We evaluated the effects of two levels of daily forced exercise intensity (moderate and high) in the treadmill over cell susceptibility to oxygen and glucose deprivation (OGD) in hippocampal slices from Wistar rats. Moderate exercise decreased lactate dehydrogenase (LDH) release after OGD, while a significant increase in LDH release was observed in the high intensity group submitted to OGD. Our data corroborate the hypothesis that higher training intensity exacerbates brain damage, while a moderate intensity reduces the injury caused by in vitro ischemia.