RESUMO
Neonatal hypoxia-ischemia (HI) is a major cause of mortality and morbidity in newborns and, despite recent advances in neonatal intensive care, there is no definitive treatment for this pathology. Once preclinical studies have shown that environmental enrichment (EE) seems to be a promising therapy for children with HI, the present study conducts a systematic review and meta-analysis of articles with EE in HI rodent models focusing on neurodevelopmental reflexes, motor and cognitive function as well as brain damage. The protocol was registered a priori at PROSPERO. The search was conducted in PubMed, Embase and PsycINFO databases, resulting in the inclusion of 22 articles. Interestingly, EE showed a beneficial impact on neurodevelopmental reflexes (SMD= -0.73, CI= [-0.98; -0.47], p< 0.001, I2= 0.0%), motor function (SMD= -0.55, CI= [-0.81; -0.28], p< 0.001, I2= 62.6%), cognitive function (SMD= -0.93, CI= [-1.14; -0.72], p< 0.001, I2= 27.8%) and brain damage (SMD= -0.80, CI= [-1.03; -0.58], p< 0.001, I2= 10.7%). The main factors that potentiate EE positive effects were enhanced study quality, earlier age at injury as well as earlier start and longer duration of EE exposure. Overall, EE was able to counteract the behavioral and histological damage induced by the lesion, being a promising therapeutic strategy for HI.
Assuntos
Hipóxia-Isquemia Encefálica , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Meio Ambiente , Hipóxia-Isquemia Encefálica/patologia , Isquemia , Ratos , Ratos Wistar , RoedoresRESUMO
Intracerebral hemorrhage (ICH) is a severe stroke subtype caused by the rupture of blood vessels within the brain. Increased levels of S100B protein may contribute to neuroinflammation after ICH through activation of astrocytes and resident microglia, with the consequent production of proinflammatory cytokines and reactive oxygen species (ROS). Inhibition of astrocytic synthesis of S100B by arundic acid (AA) has shown beneficial effects in experimental central nervous system disorders. In present study, we administered AA in a collagenase-induced ICH rodent model in order to evaluate its effects on neurological deficits, S100B levels, astrocytic activation, inflammatory, and oxidative parameters. Rats underwent stereotactic surgery for injection of collagenase in the left striatum and AA (2 µg/µl; weight × 0.005) or vehicle in the left lateral ventricle. Neurological deficits were evaluated by the Ladder rung walking and Grip strength tests. Striatal S100B, astrogliosis, and microglial activation were assessed by immunofluorescence analysis. Striatal levels of interleukin 1ß (IL-1ß) and tumor necrosis factor α (TNF-α) were measured by ELISA, and the ROS production was analyzed by dichlorofluorescein (DCF) oxidation. AA treatment prevented motor dysfunction, reduced S100B levels, astrogliosis, and microglial activation in the damaged striatum, thus decreasing the release of proinflammatory cytokines IL-1ß and TNF-α, as well as ROS production. Taken together, present results suggest that AA could be a pharmacological tool to prevent the harmful effects of increased S100B, attenuating neuroinflammation and secondary brain damage after ICH.
Assuntos
Transtornos Motores , Doenças Neuroinflamatórias , Animais , Caprilatos/farmacologia , Hemorragia Cerebral/complicações , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/metabolismo , Microglia/metabolismo , Transtornos Motores/complicações , RatosRESUMO
In the last decade, increased homocysteine levels have been implicated as a risk factor for neurodegenerative and psychiatric disorders. We have developed an experimental model of chronic mild hyperhomocysteinemia (HHcy) in order to observe metabolic impairments in the brain of adult rodents. Besides its known effects on brain metabolism, the present study sought to investigate whether chronic mild HHcy could induce learning/memory impairments associated with biochemical and histological damage to the hippocampus. Adult male Wistar rats received daily subcutaneous injections of homocysteine (0.03 µmol/g of body weight) twice a day, from the 30th to the 60th day of life or saline solution (Controls). After injections, anxiety-like and memory tests were performed. Following behavioral analyses, brains were sliced and hippocampal volumes assessed and homogenized for redox state assessment, antioxidant activity, mitochondrial functioning (chain respiratory enzymes and ATP levels) and DNA damage analyses. Behavioral analyses showed that chronic mild HHcy may induce anxiety-like behavior and impair long-term aversive memory (24 h) that was evaluated by inhibitory avoidance task. Mild HHcy decreased locomotor and/or exploratory activities in elevated plus maze test and caused hippocampal atrophy. Decrease in cytochrome c oxidase, DNA damage and redox state changes were also observed in hippocampus of adult rats subjected to mild HHcy. Our findings show that chronic mild HHcy alters biochemical and histological parameters in the hippocampus, leading to behavioral impairments. These findings might be considered in future studies aiming to search for alternative strategies for treating the behavioral impairments in patients with mild elevations in homocysteine levels.
Assuntos
Ansiedade/etiologia , Hipocampo/patologia , Hiper-Homocisteinemia/complicações , Transtornos da Memória/etiologia , Trifosfato de Adenosina/metabolismo , Animais , Ansiedade/patologia , Atrofia/etiologia , Atrofia/patologia , Aprendizagem da Esquiva , Doença Crônica , Dano ao DNA/fisiologia , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Hipocampo/fisiopatologia , Homocisteína/sangue , Hiper-Homocisteinemia/induzido quimicamente , Masculino , Transtornos da Memória/fisiopatologia , Teste de Campo Aberto , Estresse Oxidativo/fisiologia , Ratos , Ratos WistarRESUMO
Preterm birth and hypoxia-ischemia (HI) are major causes of neonatal death and neurological disabilities in newborns. The widely used preclinical HI model combines carotid occlusion with hypoxia exposure; however, the relationship between different hypoxia exposure periods with brain tissue loss, astrocyte reactivity and behavioral impairments following HI is lacking. Present study evaluated HI-induced behavioral and morphological consequences in rats exposed to different periods of hypoxia at postnatal day 3. Wistar rats of both sexes were assigned into four groups: control group, HI-120 min, HI-180 min and HI-210 min. Neurodevelopmental reflexes, exploratory abilities and cognitive function were assessed. At adulthood, tissue damage and reactive astrogliosis were measured. Animals exposed to HI-180 and HI-210 min had delayed neurodevelopmental reflexes compared to control group. Histological assessment showed tissue loss that was restricted to the ipsilateral hemisphere in lower periods of hypoxia exposure (120 and 180 min) but affected both hemispheres when 210 min was used. Reactive astrogliosis was increased only after 210 min of hypoxia. Interestingly, cognitive deficits were induced regardless the duration of hypoxia and there were correlations between behavioral parameters and cortex, hippocampus and corpus callosum volumes. These results show the duration of hypoxia has a close relationship with astrocytic response and tissue damage progression. Furthermore, the long-lasting cognitive memory deficit and its association with brain structures beyond the hippocampus suggests that complex anatomical changes should be involved in functional alterations taking place as hypoxia duration is increased, even when the cognitive impairment limit is achieved.
Assuntos
Astrócitos/fisiologia , Hipóxia-Isquemia Encefálica/fisiopatologia , Animais , Animais Recém-Nascidos , Encéfalo/patologia , Disfunção Cognitiva/fisiopatologia , Feminino , Gliose/fisiopatologia , Hipóxia-Isquemia Encefálica/patologia , Masculino , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/fisiopatologia , Ratos Wistar , Análise de Regressão , Fatores de TempoRESUMO
INTRODUCTION: Perinatal hypoxia-ischemia (HI) is one of the main causes of mortality and chronic neurological morbidity in infants and children. Astrocytes play a key role in HI progression, becoming reactive in response to the injury, releasing S100 calcium binding protein B (S100B). Since S100B inhibition seems to have neuroprotective effects on central nervous system injury models, here we evaluated the neuroprotective effects of an S100B inhibitor, arundic acid (AA) in a HI model. METHODS: On the 7th postnatal day, animals were submitted to the combination of common carotid artery occlusion and hypoxic atmosphere (8% O2) for 60â¯min. Three experiments were performed in order to: (1) define AA dose (0.1, 1 or 10â¯mg/kg, pre-hypoxia i.p. injection), (2) test if repeated AA administrations (10â¯mg/kg at 3 time points: Pre-hypoxia, 24â¯h and 48â¯h after HI) would improve the response and (3) investigate biochemical mechanisms involved in AA protection two days after HI. RESULTS: AA at a dose of 10â¯mg/kg applied before and after hypoxia, was the only treatment protocol that was able to improve HI-induced memory deficits, to reduce tissue damage, to promote astrocytic survival in the hippocampus and to reduced extracellular release of S100B in the cerebrospinal fluid. CONCLUSION: Overall, AA treatment showed beneficial effects on memory deficits, tissue damage, promoting astrocyte survival likely by reducing S100B release. Protection aided to astrocytes by AA treatment against HI lesion may lead to development of new therapeutic strategies that target these particular cells.
Assuntos
Astrócitos/efeitos dos fármacos , Caprilatos/farmacologia , Hipóxia-Isquemia Encefálica/complicações , Transtornos da Memória/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Animais , Animais Recém-Nascidos , Astrócitos/patologia , Encéfalo/patologia , Sobrevivência Celular/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Glutamato-Amônia Ligase/metabolismo , Hipóxia-Isquemia Encefálica/patologia , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/etiologia , Ratos , Subunidade beta da Proteína Ligante de Cálcio S100/antagonistas & inibidores , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismoRESUMO
Environmental enrichment (EE) is an experimental strategy to attenuate the negative effects of different neurological conditions including neonatal hypoxia ischemia encephalopathy (HIE). The aim of the present study was to investigate the influence of prenatal and early postnatal EE in animals submitted to neonatal HIE model at postnatal day (PND) 3. Wistar rats were housed in EE or standard conditions (SC) during pregnancy and lactation periods. Pups of both sexes were assigned to one of four experimental groups, considering the early environmental conditions and the injury: SC-Sham, SC-HIE, EE-sham, and EE-HIE. The offspring were euthanized at two different time points: 48 h after HIE for biochemical analyses or at PND 67 for histological analyses. Behavioral tests were performed at PND 7, 14, 21, and 60. Offspring from EE mothers had better performance in neurodevelopmental and spatial memory tests when compared to the SC groups. HIE animals showed a reduction of IGF-1 and VEGF in the parietal cortex, but no differences in BDNF and TrkB levels were found. EE-HIE animals showed reduction in cell death, lower astrocyte reactivity, and an increase in AKTp levels in the hippocampus and parietal cortex. In addition, the EE was also able to prevent the hippocampus tissue loss. Altogether, present findings point to the protective potential of the prenatal and early postnatal EE in attenuating molecular and histological damage, as well as the neurodevelopmental impairments and the cognitive deficit, caused by HIE insult at PND 3.
Assuntos
Morte Celular/fisiologia , Hipocampo/metabolismo , Hipóxia-Isquemia Encefálica/complicações , Transtornos da Memória/prevenção & controle , Lobo Parietal/metabolismo , Animais , Animais Recém-Nascidos , Comportamento Animal , Meio Ambiente , Feminino , Abrigo para Animais , Hipóxia-Isquemia Encefálica/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Ratos , Ratos Wistar , Receptor trkB/metabolismo , Memória Espacial/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
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.
Assuntos
Alcaloides/uso terapêutico , Inibidores da Colinesterase/uso terapêutico , Huperzia , Hipóxia-Isquemia Encefálica/enzimologia , Fármacos Neuroprotetores/uso terapêutico , Extratos Vegetais/uso terapêutico , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Animais , Animais Recém-Nascidos , Inibidores da Colinesterase/isolamento & purificação , Inibidores da Colinesterase/farmacologia , Modelos Animais de Doenças , Feminino , Hipóxia-Isquemia Encefálica/prevenção & controle , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Componentes Aéreos da Planta , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Ratos , Ratos Wistar , Resultado do TratamentoRESUMO
Spinal cord injury (SCI) is a disabling condition resulting in deficits of sensory and motor functions, and has no effective treatment. Considering that protocols with stem cell transplantation and treadmill training have shown promising results, the present study evaluated the effectiveness of stem cells from human exfoliated deciduous teeth (SHEDs) transplantation combined with treadmill training in rats with experimental spinal cord injury. Fifty-four Wistar rats were spinalized using NYU impactor. The rats were randomly distributed into 5 groups: Sham (laminectomy with no SCI, n=10); SCI (laminectomy followed by SCI, n=12); SHEDs (SCI treated with SHEDs, n=11); TT (SCI treated with treadmill training, n=11); SHEDs+TT (SCI treated with SHEDs and treadmill training; n=10). Treatment with SHEDs alone or in combination with treadmill training promoted functional recovery, reaching scores of 15 and 14, respectively, in the BBB scale, being different from the SCI group, which reached 11. SHEDs treatment was able to reduce the cystic cavity area and glial scar, increase neurofilament. Treadmill training alone had no functional effectiveness or tissue effects. In a second experiment, the SHEDs transplantation reduced the TNF-α levels in the cord tissue measured 6 h after the injury. Contrary to our hypothesis, treadmill training either alone or in combination, caused no functional improvement. However, SHEDs showed to be neuroprotective, by the reduction of TNF-α levels, the cystic cavity and the glial scar associated with the improvement of motor function after SCI. These results provide evidence that grafted SHEDs might be an effective therapy to spinal cord lesions, with possible anti-inflammatory action.
Assuntos
Polpa Dentária/citologia , Terapia por Exercício/métodos , Condicionamento Físico Animal/métodos , Traumatismos da Medula Espinal/terapia , Transplante de Células-Tronco/métodos , Animais , Terapia Combinada , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Locomoção , Masculino , Distribuição Aleatória , Ratos Wistar , Recuperação de Função Fisiológica , Fatores de Tempo , Esfoliação de Dente , Resultado do Tratamento , Fator de Necrose Tumoral alfa/análiseRESUMO
Spinal cord injury (SCI) is a disabling condition resulting in deficits of sensory and motor functions, and has no effective treatment. Considering that protocols with stem cell transplantation and treadmill training have shown promising results, the present study evaluated the effectiveness of stem cells from human exfoliated deciduous teeth (SHEDs) transplantation combined with treadmill training in rats with experimental spinal cord injury. Fifty-four Wistar rats were spinalized using NYU impactor. The rats were randomly distributed into 5 groups: Sham (laminectomy with no SCI, n=10); SCI (laminectomy followed by SCI, n=12); SHEDs (SCI treated with SHEDs, n=11); TT (SCI treated with treadmill training, n=11); SHEDs+TT (SCI treated with SHEDs and treadmill training; n=10). Treatment with SHEDs alone or in combination with treadmill training promoted functional recovery, reaching scores of 15 and 14, respectively, in the BBB scale, being different from the SCI group, which reached 11. SHEDs treatment was able to reduce the cystic cavity area and glial scar, increase neurofilament. Treadmill training alone had no functional effectiveness or tissue effects. In a second experiment, the SHEDs transplantation reduced the TNF-α levels in the cord tissue measured 6 h after the injury. Contrary to our hypothesis, treadmill training either alone or in combination, caused no functional improvement. However, SHEDs showed to be neuroprotective, by the reduction of TNF-α levels, the cystic cavity and the glial scar associated with the improvement of motor function after SCI. These results provide evidence that grafted SHEDs might be an effective therapy to spinal cord lesions, with possible anti-inflammatory action.
Assuntos
Humanos , Animais , Masculino , Condicionamento Físico Animal/métodos , Traumatismos da Medula Espinal/terapia , Transplante de Células-Tronco/métodos , Polpa Dentária/citologia , Terapia por Exercício/métodos , Fatores de Tempo , Esfoliação de Dente , Ensaio de Imunoadsorção Enzimática , Distribuição Aleatória , Resultado do Tratamento , Ratos Wistar , Terapia Combinada , Recuperação de Função Fisiológica , Citometria de Fluxo , LocomoçãoRESUMO
Hypoxia-ischemia on 3-day-old rats (HIP3) allows the investigation of HI damage in the immature brain. HIP3 is characterized for neurological disabilities caused by white matter injury. This study investigates the relationship between animals' sex and injured hemisphere on HIP3 consequences. Male and female Wistar rats had their right or left common carotid artery occluded under halotane anesthesia and exposed to 8% O2 for 1.5 h. Control rats received sham surgery and exposure to 1.5 h of room air in isolation of their mothers. Sex and injured hemisphere influence in Na+/K+ -ATPase activity 24h after lesion: females and the right brain hemispheres showed decreased enzymatic activity after HIP3. Cognitive impairment was observed in step-down inhibitory avoidance, in which females HIP3 left injured were the most damaged. Histological analysis showed a trend to white matter damage in females left injured without hemispherical nor hippocampal volume decrease in HIP3 rats at postnatal day 21. However, at PND90, hemisphere and sex effects were noted in hemispherical volume and myelination: left brain hemisphere and the females evidenced higher histological damage. Our results points to an increased resistance of male rats and right brain hemisphere to support the impairment caused in Na+/K+ -ATPase activity early after HIP3, and evidencing more discrete behavioral impairments and histological damage at adulthood. Present data adds new evidence of distinct effects of brain lateralization and sex vulnerability on biochemical, behavioral and histological parameters after hypoxia-ischemia.
Assuntos
Encéfalo/patologia , Hipóxia-Isquemia Encefálica/patologia , Hipóxia-Isquemia Encefálica/psicologia , Animais , Animais Recém-Nascidos , Aprendizagem da Esquiva/fisiologia , Encéfalo/enzimologia , Lesões das Artérias Carótidas/enzimologia , Lesões das Artérias Carótidas/patologia , Lesões das Artérias Carótidas/psicologia , Feminino , Lateralidade Funcional/fisiologia , Hipóxia-Isquemia Encefálica/enzimologia , Masculino , Atividade Motora/fisiologia , Fibras Nervosas Mielinizadas/patologia , Ratos , Ratos Wistar , Fatores Sexuais , ATPase Trocadora de Sódio-Potássio/análiseRESUMO
Neonatal cerebral hypoxia-ischemia (HI) is an important cause of neurological disorders. In the preterm children, HI causes preferentially white matter damage and late cognitive impairments. Rodent HI performed at postnatal day 3 (HIP3) provides valuable information on the brain response to injury in immature animals as related to sensory, motor and cognitive impairments observed in humans born prematurely. The present study aimed to observe the effects of brain lateralization and sexual dimorphism following HIP3 on behavior and histological damage assessed in adulthood. Male and female Wistar rats had their right or left common carotid artery occluded and exposed to 8% oxygen for 1.5h; control rats received sham surgery and exposure to 1.5h of room air in isolation of their dams. Sensory and cognitive parameters were assessed by the use of elevated plus maze, cylinder test and Morris water maze. After behavioral testing, hemisphere and hippocampus volumes were used to define brain damage extension; white matter damage was estimated through corpus callosum area ratio. No motor impairments were shown in HIP3 rats and anxiety-related changes were observed only in right injured animals. Females having left occlusion were more vulnerable to HIP3 injury since they presented spatial memory impairment and greater histological damage. These results show the modulation exerted by sex and brain lateralization following early HI at postnatal day 3.