RESUMEN
OBJECTIVE: To determine the effect of intrauterine inflammation on fetal responses to umbilical cord occlusion (UCO). STUDY DESIGN: In pregnant sheep, lipopolysaccharide (LPS) or saline (SAL) was infused intra-amniotically for 4 weeks from 80 days of gestation (d). At 110 d, fetuses were instrumented for UCOs (5 × 2-minutes, 30-minute intervals: LPS + UCO, n = 6; SAL + UCO, n = 8) or no UCO (sham, n = 6) on 117 and 118 d. Tissues were collected at 126 d. RESULTS: Fetal physiological responses to UCO were similar between LPS + UCO and SAL + UCO. Histologic chorioamnionitis and increased amniotic fluid interleukin 8 (IL-8) were observed in LPS + UCO pregnancies (versus SAL + UCO, P < .05). CNPase-positive oligodendrocyte number in the cerebral white matter was lower in LPS + UCO and SAL + UCO than sham (P < .05); there was no effect on astrocytes or activated microglia/macrophages. Two of the SAL + UCO fetuses had white matter lesions; none were observed in LPS + UCO or sham. CONCLUSION: Chronic pre-existing intrauterine inflammation did not exacerbate fetal brain injury induced by intermittent UCO.
Asunto(s)
Encéfalo/embriología , Encéfalo/patología , Desarrollo Fetal/fisiología , Hipoxia Fetal/patología , Cordón Umbilical/patología , Animales , Encéfalo/metabolismo , Enfermedad Crónica , Femenino , Hipoxia Fetal/sangre , Feto , Inflamación/sangre , Inflamación/patología , Embarazo , OvinosRESUMEN
Psychiatric disorders associated with elevated stress levels, such as depression, are present in many epilepsy patients, including those with mesial Temporal Lobe Epilepsy (mTLE). Evidence suggests that these psychiatric disorders can predate the onset of epilepsy, suggesting a causal/contributory role. Prolonged exposure to elevated corticosterone, used as a model of chronic stress/depression, accelerates limbic epileptogenesis in the amygdala kindling model. The current study examined whether exposure to repeated stress could similarly accelerate experimental epileptogenesis. Female adult non-epileptic Wistar rats were implanted with a bipolar electrode into the left amygdala, and were randomly assigned into stressed (n=18) or non-stressed (n=19) groups. Rats underwent conventional amygdala kindling (two electrical stimulations per day) until 5 Class V seizures had been experienced ('the fully kindled state'). Stressed rats were exposed to 30min restraint immediately prior to each kindling stimulation, whereas non-stressed rats received control handling. Restraint stress increased circulating corticosterone levels (pre-stress: 122±17ng/ml; post-stress: 632±33ng/ml), with no habituation observed over the experiment. Stressed rats reached the 'fully kindled state' in significantly fewer stimulations than non-stressed rats (21±1 vs 33±3 stimulations; p=0.022; ANOVA), indicative of a vulnerability to epileptogenesis. Further, seizure durations were significantly longer in stressed rats (p<0.001; ANOVA). These data demonstrate that exposure to repeated experimental stress accelerates the development of limbic epileptogenesis, an effect which may be related to elevated corticosterone levels. This may have implications for understanding the effects of chronic stress and depression in disease onset and progression of mTLE in humans.
Asunto(s)
Amígdala del Cerebelo/fisiología , Epilepsia/fisiopatología , Excitación Neurológica/fisiología , Estrés Psicológico/fisiopatología , Animales , Corticosterona/metabolismo , Modelos Animales de Enfermedad , Estimulación Eléctrica/métodos , Epilepsia/sangre , Epilepsia/complicaciones , Femenino , Habituación Psicofisiológica/fisiología , Ratas , Ratas Wistar , Restricción Física/métodos , Restricción Física/fisiología , Estrés Psicológico/sangre , Estrés Psicológico/complicacionesRESUMEN
PURPOSE: Intrauterine infection is a common antecedent of preterm birth. Infants born very preterm are at increased risk for neurologic dysfunction, including visual deficits. With increasing survival of very preterm infants, there is a need for therapies that prevent adverse neurologic outcomes. Using an ovine model, the authors investigated the neuroprotective potential of recombinant human erythropoietin (rhEPO) on retinal injury induced by intrauterine inflammation. METHODS: At 107 ± 1 days of gestational age (DGA), chronically catheterized fetal sheep received either of the following on 3 consecutive days: intravenous (IV) bolus dose of lipopolysaccharide (LPS; â¼0.9 µg/kg; n = 8); IV bolus dose of LPS, followed at 1 hour by 5000 IU/kg rhEPO (LPS + rhEPO; n = 8); rhEPO alone (n = 5). Untreated fetuses (n = 8) were used for comparison with the three treatment groups. Fetal physiological parameters were monitored. At 116 ± 1 DGA, fetal retinas were assessed quantitatively for morphologic and neurochemical alterations. RESULTS: Exposure to LPS alone, but not to rhEPO alone, resulted in fetal hypoxemia and hypotension (P < 0.05). Exposure to LPS alone caused retinal changes, including reductions in thickness of the inner nuclear layer (INL), somal areas of INL neurons, process growth in the plexiform layers, and numbers of ganglion and tyrosine hydroxylase immunoreactive (TH-IR) dopaminergic amacrine cells. Treatment of LPS-exposed fetuses with rhEPO did not alter the physiological effects of LPS but significantly reduced alterations in retinal layers and ganglion and TH-IR cell numbers. CONCLUSIONS: rhEPO treatment was beneficial in protecting the developing retina after LPS-induced inflammation. Retinal protection could occur by the antiapoptotic or anti-inflammatory actions of EPO.
Asunto(s)
Modelos Animales de Enfermedad , Eritropoyetina/farmacología , Hipoxia Fetal/tratamiento farmacológico , Retina/efectos de los fármacos , Enfermedades de la Retina/prevención & control , Células Amacrinas/efectos de los fármacos , Células Amacrinas/patología , Animales , Recuento de Células , Escherichia coli , Femenino , Hipoxia Fetal/inducido químicamente , Técnica del Anticuerpo Fluorescente Indirecta , Edad Gestacional , Técnicas para Inmunoenzimas , Lipopolisacáridos/toxicidad , Macrófagos/efectos de los fármacos , Macrófagos/patología , Microglía/efectos de los fármacos , Microglía/patología , Embarazo , Receptores de Eritropoyetina/metabolismo , Proteínas Recombinantes , Retina/embriología , Enfermedades de la Retina/inducido químicamente , Células Ganglionares de la Retina/efectos de los fármacos , Células Ganglionares de la Retina/patología , Oveja Doméstica , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Ibuprofen is an effective pharmacological intervention for closure of a patent ductus arteriosus (PDA) in preterm infants and is an alternative to surgical ligation; however, it is not certain whether ibuprofen treatment is associated with adverse effects on the brain. Therefore, this study examined neuropathological outcomes of ibuprofen therapy for a PDA. Fetal baboons were delivered at 125 d of gestation (dg; term â¼185 dg) by caesarean section, given surfactant, and ventilated for 14 d with positive pressure ventilation (PPV). Baboons were randomly allocated to receive either ibuprofen (PPV+ ibuprofen, n = 8) or no therapy (PPV, n = 5). Animals were killed on day 14 and brains assessed for cerebral growth, development, and neuropathology. Body and brain weights, the total volume of the brain, and the surface folding index (measure of brain growth) were not different (p > 0.05) between PPV+ ibuprofen-treated and PPV animals. There was no difference (p > 0.05) in the number of myelin basic protein-immunoreactive (IR) oligodendrocytes, glial fibrillary acid protein-IR astrocytes, or Iba1-IR macrophages/microglia in the forebrain. No overt cerebellar alterations were observed in either group. Ibuprofen treatment for PDA closure in the preterm baboon neonate is not associated with any increased risk of neuropathology or alterations to brain growth and development.
Asunto(s)
Encéfalo/efectos de los fármacos , Inhibidores de la Ciclooxigenasa/farmacología , Conducto Arterioso Permeable/tratamiento farmacológico , Ibuprofeno/farmacología , Animales , Animales Recién Nacidos , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Encéfalo/patología , Inhibidores de la Ciclooxigenasa/efectos adversos , Modelos Animales de Enfermedad , Edad Gestacional , Proteína Ácida Fibrilar de la Glía/metabolismo , Ibuprofeno/efectos adversos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Microglía/efectos de los fármacos , Microglía/metabolismo , Papio , Respiración con Presión Positiva , Nacimiento Prematuro , Surfactantes Pulmonares/farmacología , Factores de TiempoRESUMEN
BACKGROUND: Lipopolysaccharide (LPS) delivered acutely to the ovine fetus induces cerebral white matter injury and brain inflammation. N-acetyl cysteine (NAC) is potentially neuroprotective as it blocks the production of inflammatory cytokines and increases glutathione levels; however, it is unknown whether NAC affects the physiological status of the fetus already exposed to an inflammatory environment. OBJECTIVES: Our objective was to determine whether NAC influences the physiological effects of LPS exposure in the ovine fetus. METHODS: Catheterized fetal sheep underwent one of four treatments (saline, n = 6; LPS, n = 6; LPS + NAC, n = 6; NAC, n = 3) on 5 consecutive days from 95 days of gestation (term approximately 147 days). Fetal arterial pressure and heart rate were recorded and blood samples collected. RESULTS: LPS administration resulted in fetal hypoxemia and hypotension; simultaneous treatment with NAC exacerbated these effects and induced polycythemia. NAC treatment alone had no effect on the fetus. CONCLUSION: In the presence of LPS, NAC compromises fetal physiological status, suggesting that it may not be a suitable antenatal treatment for a fetus with evidence of inflammation.
Asunto(s)
Acetilcisteína/farmacología , Antiinflamatorios no Esteroideos/farmacología , Feto/efectos de los fármacos , Hipotensión/inducido químicamente , Hipoxia/inducido químicamente , Lipopolisacáridos/toxicidad , Policitemia/inducido químicamente , Animales , Dióxido de Carbono/metabolismo , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Feto/metabolismo , Feto/fisiopatología , Edad Gestacional , Hemodinámica/efectos de los fármacos , Hipotensión/metabolismo , Hipotensión/fisiopatología , Hipoxia/metabolismo , Hipoxia/fisiopatología , Oximetría , Oxígeno/metabolismo , Policitemia/metabolismo , OvinosRESUMEN
High-frequency oscillatory ventilation (HFOV) may improve pulmonary outcome in very preterm infants, but the effects on the brain are largely unknown. We hypothesized that early prolonged HFOV compared with low volume positive pressure ventilation (LV-PPV) would not increase the risk of delayed brain growth or injury in a primate model of neonatal chronic lung disease. Baboons were delivered at 127 +/- 1 d gestation (dg; term approximately 185 dg), ventilated for 22-29 d with either LV-PPV (n = 6) or HFOV (n = 5). Gestational controls were delivered at 153 dg (n = 4). Brains were assessed using quantitative histology. Body, brain, and cerebellar weights were lower in both groups of prematurely delivered animals compared with controls; the brain to body weight ratio was higher in HFOV compared with LV-PPV, and the surface folding index was lower in the LV-PPV compared with controls. In both ventilated groups compared with controls, there was an increase in astrocytes and microglia and a decrease in oligodendrocytes (p < 0.05) in the forebrain and a decrease in cerebellar granule cell proliferation (p < 0.01); there was no difference between ventilated groups. LV-PPV and HFOV ventilation in prematurely delivered animals is associated with decreased brain growth and an increase in subtle neuropathologies; HFOV may minimize adverse effects on brain growth.
Asunto(s)
Encefalopatías/patología , Ventilación de Alta Frecuencia/métodos , Enfermedades Pulmonares/patología , Animales , Astrocitos/patología , Peso Corporal , Encéfalo/crecimiento & desarrollo , Encéfalo/patología , Encefalopatías/etiología , Proliferación Celular , Modelos Animales de Enfermedad , Femenino , Masculino , Necrosis , Oligodendroglía/metabolismo , Papio , Primates , RiesgoRESUMEN
Premature infants now have an improved chance of survival, but the impact of respiratory therapies on the brain, particularly the cerebellum, remains unclear. We examined the effects of early nasal continuous positive airway pressure (EnCPAP) ventilation and delayed (Dn) CPAP on the development of the cerebellum in prematurely delivered baboons. The baboons were delivered at 125 +/- 2days of gestation and ventilated for 28 days with either EnCPAP commencing at 24 hours (n = 5) or DnCPAP commencing at 5 days (n = 5). Gestational controls (n = 4) were delivered at 153 days. Cerebella were assessed histologically, and an ontogeny study (90 days to term) was performed to establish values for key cerebellar developmental indicators. Cerebellar weight was reduced in DnCPAP but not EnCPAP animals versus controls; cerebellar/total brain weight ratio was increased in EnCPAP (p < 0.05) versus control and DnCPAP animals. There was no overt damage in the cerebella of any animals, but a microstructural alteration index based on morphological developmental parameters and microglial immunoreactivity was increased in both prematurely delivered cohorts versus controls (p < 0.001) and was higher in DnCPAP than EnCPAP animals (p < 0.05). These results indicate that respiratory regimens can influence cerebellar development and that early compared with delayed extubation to nCPAP seems to be beneficial.
Asunto(s)
Cerebelo/anomalías , Cerebelo/fisiopatología , Nacimiento Prematuro/patología , Nacimiento Prematuro/terapia , Respiración Artificial/métodos , Animales , Presión Sanguínea/fisiología , Peso Corporal , Proteínas de Unión al Calcio/metabolismo , Proliferación Celular , Cerebelo/patología , Modelos Animales de Enfermedad , Femenino , Etiquetado Corte-Fin in Situ/métodos , Antígeno Ki-67/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Oligodendroglía/metabolismo , Oligodendroglía/patología , Tamaño de los Órganos , Papio , Embarazo , Nacimiento Prematuro/fisiopatología , Células de Purkinje/metabolismo , Células de Purkinje/patología , Respiración , Factores de TiempoRESUMEN
The aim of this study was to determine whether inner retinal dysfunction in diabetic rats is correlated with structural and/or biochemical changes in the retina and optic nerve. Using the electroretinogram (ERG; -5.83 to 1.28 log cd.s.m(-2)) retinal function (photoreceptor, bipolar, amacrine and ganglion cell components) was measured in control (n=13; citrate buffer) and diabetic (n=13; streptozotocin, STZ, 50 mg kg(-1)) rats, 12 weeks following treatment. Retinae and optic nerves were analyzed for structural changes and retinae were assessed for alterations in growth factor/cytokine expression using quantitative real-time PCR. We found that phototransduction efficiency was reduced 12 weeks after STZ-induced diabetes (-30%), leading to reduced amplitude of ON-bipolar (-18%) and amacrine cell (-29%) dominated responses; ganglion cell dysfunction (-84%) was more profound. In the optic nerve, nerve fascicle area and myelin sheath thickness were reduced (p<0.05), whereas the ratio of blood vessels and connective tissue to total nerve cross-sectional area was increased (p<0.05) in diabetic compared to control rats. In the retina, connective tissue growth factor (CTGF), transforming growth factor beta, type 2 receptor (TGFbeta-r2) mRNA and platelet-derived growth factor B (PDGF-B) mRNA were increased (p<0.035). Reduced ganglion cell function was correlated with increased CTGF and TGFbeta-r2, but not PDGF-B mRNA. In summary, the ganglion cell component exhibited the greatest level of dysfunction within the ERG components examined after 12 weeks of STZ-induced diabetes; the level correlated with increased CTGF and TGFbeta-r2 mRNA, but not with gross morphological changes in the retina or optic nerve.
Asunto(s)
Diabetes Mellitus Experimental/patología , Células Ganglionares de la Retina/fisiología , Animales , Factor de Crecimiento del Tejido Conjuntivo/biosíntesis , Factor de Crecimiento del Tejido Conjuntivo/genética , Diabetes Mellitus Experimental/metabolismo , Electrorretinografía/métodos , Masculino , Nervio Óptico/patología , Proteínas Proto-Oncogénicas c-sis/biosíntesis , Proteínas Proto-Oncogénicas c-sis/genética , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Retina/metabolismo , Retina/fisiopatología , Células Ganglionares de la Retina/metabolismo , Factor de Crecimiento Transformador beta2/biosíntesis , Factor de Crecimiento Transformador beta2/genéticaRESUMEN
The incidence of psychiatric disturbances is elevated in temporal lobe epilepsy (TLE) patients. Early life stressful events are believed to have a major impact on mental health later in life, and increasing evidence suggests that such stresses may also promote a vulnerability to TLE. This study investigated whether subjecting rats to early life stress exacerbated mood and cognitive disturbances associated with the development of epilepsy. On postnatal days 2-14, rat pups were separated from their dams for either 180 min/day (handling and maternal separation--HMS180, modelling early life stress) or 15 min/day (control handling and maternal separation--HMS15). At 7 weeks, rats were implanted with a bipolar electrode into the left amygdala. Following recovery, one group of rats from each litter underwent rapid amygdala kindling (RAK) epileptogenesis, while another underwent sham kindling. One week following this, rats were subjected to behavioural tests assessing anxiety and cognition. HMS180-exposed rats kindled faster than HMS15 rats (p<0.0001). RAK induced a potent anxiolytic effect as evidenced by increased % time spent in the open arms of the elevated plus maze, compared with sham kindled rats (p<0.0001). This anxiolytic effect was also observed in the open field task, as evidenced by increased time spent in the inner area (p=0.010). Neither RAK nor maternal separation had any effect on cognitive function in the Morris water maze. We conclude that maternal separation stress accelerates limbic epileptogenesis in adult rats, and that RAK induces potent anxiolytic effects that are not influenced by such early life stressful events.
Asunto(s)
Amígdala del Cerebelo/crecimiento & desarrollo , Amígdala del Cerebelo/fisiopatología , Ansiedad/fisiopatología , Epilepsia del Lóbulo Temporal/etiología , Estrés Psicológico/complicaciones , Animales , Animales Recién Nacidos , Cognición/fisiología , Estimulación Eléctrica , Electrodos Implantados , Epilepsia del Lóbulo Temporal/fisiopatología , Conducta Exploratoria/fisiología , Privación Materna , Aprendizaje por Laberinto/fisiología , Distribución Aleatoria , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
A patent ductus arteriosus (PDA) alters pulmonary mechanics and regional blood flow in the preterm infant. Its significance with respect to brain injury and brain development are unclear. We evaluated the effects of surgical ductal ligation on the preterm baboon brain. Baboons were delivered at 125 d of gestation (dg, term approximately 185 dg) and ventilated for 14 d (n = 12). The PDA was ligated 6 d after delivery (n = 7) or left untreated (n = 5). Animals were euthanized at 139 dg and brains compared histologically with gestational control fetuses (n = 7) at 140 dg. Brain and body weights were reduced (p < 0.05) in both groups of ventilated preterm animals; however, the brain to body weight ratio was increased (p < 0.01) in ligated, but not unligated newborns compared with gestational controls. No overt lesions were observed in either premature newborn group. Astrocyte density in the neocortex and hippocampus were greatest in the unligated newborns (p < 0.01). Myelination and oligodendrocytes were reduced (p < 0.05) in both premature newborn groups. The brain growth and development index was reduced, and the damage index was increased in prematurely delivered baboons. Surgical ligation of the PDA does not increase the incidence of brain injury and may be beneficial if the PDA is contributing to persistent pulmonary and hemodynamic instability.
Asunto(s)
Encéfalo/patología , Procedimientos Quirúrgicos Cardíacos , Conducto Arterioso Permeable/cirugía , Nacimiento Prematuro , Animales , Animales Recién Nacidos , Apoptosis , Astrocitos/patología , Peso Corporal , Encéfalo/irrigación sanguínea , Encéfalo/crecimiento & desarrollo , Proliferación Celular , Conducto Arterioso Permeable/patología , Conducto Arterioso Permeable/fisiopatología , Femenino , Edad Gestacional , Hemodinámica , Hipocampo/patología , Ligadura , Neocórtex/patología , Oligodendroglía/patología , Tamaño de los Órganos , Papio papio , Embarazo , Respiración , Respiración Artificial , Factores de TiempoRESUMEN
PURPOSE: Chronic placental insufficiency (CPI) severe enough to cause growth restriction (GR) results in alterations to the retina, including a reduction in tyrosine hydroxylase immunoreactive (TH-IR)-dopaminergic amacrine cells. Brain-derived neurotrophic factor (BDNF) plays a role in the development of the retinal dopaminergic network and may therefore be an appropriate therapy for restoring dopaminergic cells after prenatal compromise. This study was conducted (1) to establish whether BDNF and its receptor NTRK2 (Trk B) are altered in the retina after CPI and (2) to explore the potential of BDNF to enhance dopaminergic cell survival in organotypic retinal cultures from prenatally compromised animals. METHODS: CPI was induced in pregnant guinea pigs at 30 days' gestation (dg; term, approximately 67 dg) via unilateral ligation of the uterine artery. Fetuses were euthanatized at 60 dg and the retinas prepared for enzyme-linked immunosorbent assay (ELISA) analysis of BDNF protein levels and for immunohistochemistry to localize BDNF and NTRK2. Organotypic cultures of retinas from GR and control fetuses at 50 to 52 dg were treated with BDNF, and dopaminergic amacrine cells counts were assessed. RESULTS: Retinal BDNF protein levels and the intensity of BDNF-immunoreactivity (IR) in the ganglion cell layer were reduced (P < 0.05) in GR fetuses compared with control fetuses. Addition of BDNF to organotypic cultures increased (P < 0.05) the survival and neurite growth of dopaminergic neurons from both control and GR fetuses. CONCLUSIONS: Alterations to BDNF levels may underlie reductions in dopaminergic amacrine cells observed after CPI. The addition of BDNF has the potential to increase survival and neurite growth of dopaminergic amacrine cells.
Asunto(s)
Células Amacrinas/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Retardo del Crecimiento Fetal/metabolismo , Insuficiencia Placentaria/metabolismo , Receptor trkB/metabolismo , Retina/metabolismo , Tirosina 3-Monooxigenasa/metabolismo , Células Amacrinas/citología , Animales , Factor Neurotrófico Derivado del Encéfalo/farmacología , Recuento de Células , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Ensayo de Inmunoadsorción Enzimática , Femenino , Cobayas , Técnicas para Inmunoenzimas , Técnicas de Cultivo de Órganos , Embarazo , Retina/efectos de los fármacos , Células Ganglionares de la Retina/metabolismoRESUMEN
We have previously demonstrated that low-dose corticosterone (CS) administration, used as a model of the effect of chronic stress, accelerates epileptogenesis in the electrical amygdala kindling rat model of temporal lobe epilepsy (TLE). This current study examined the relative contributions to this effect of mineralocorticoid (MR) and glucocorticoid (GR) subtypes of glucocorticoid receptors. Female non-epileptic wistar rats 10-13 weeks of age were implanted with a bipolar electrode into the left amygdala. Five treatment groups were subjected to rapid amygdala kindling: water-control (n=9), CS treated (6 mg/100 ml added to drinking water; n=9), CS+spironolactone (MR antagonist, 50 mg/kg sc; n=9), CS+mifepristone (GR antagonist, 25 mg/kg sc; n=9), and CS+both antagonists (n=7). Rats were injected with vehicle or the relevant antagonist twice daily for the entire kindling period. Experimental groups differed significantly in the number of stimulations required to reach the 'fully kindled state' (Racine, 1972) ANOVA, F(4,38)=2.73, p=0.04). Amygdala kindling was accelerated in the CS-treated group compared with water controls (mean stimulations for full kindling: 45.2 vs. 86.5, p<0.01). This acceleration was inhibited by both the MR and GR antagonist treatments (mean stimulations: 69.6 and 70.4, p=0.04 and 0.04 vs. CS group, respectively), with the kindling rates in these groups not significantly different from water-treated subjects (p=0.26 and 0.29, respectively). The kindling rates in the MR and GR antagonist treatment groups did not significantly differ from each other (p=0.93), nor from the combined treatment group (mean stimulations: 62.8, p=0.59 and 0.54, respectively). This study demonstrates that activation of both high-affinity (MR) and low-affinity (GR) glucocorticoid receptors are involved in mediating CS-induced acceleration of amygdala kindling epileptogenesis.
Asunto(s)
Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/fisiología , Corticosterona/farmacología , Epilepsia/fisiopatología , Excitación Neurológica/efectos de los fármacos , Excitación Neurológica/fisiología , Receptores de Glucocorticoides/efectos de los fármacos , Receptores de Mineralocorticoides/efectos de los fármacos , Glándulas Suprarrenales/efectos de los fármacos , Glándulas Suprarrenales/crecimiento & desarrollo , Animales , Encéfalo/patología , Corticosterona/administración & dosificación , Interpretación Estadística de Datos , Relación Dosis-Respuesta a Droga , Femenino , Excitación Neurológica/patología , Antagonistas de Receptores de Mineralocorticoides , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Wistar , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/antagonistas & inhibidores , Receptores de Mineralocorticoides/agonistasRESUMEN
Inhaled nitric oxide (iNO) enhances ventilation in very preterm infants, but the effects on the brain remain uncertain. We evaluated the impact of iNO on brain growth and cerebral injury in a premature baboon model. Baboons were delivered at 125 d of gestation (term 185 d of gestation) and ventilated for 14 d with either positive pressure ventilation (PPV) (n = 7) or PPV + iNO (n = 8). Brains were assessed histologically for parameters of development and injury. Compared with gestational controls (n = 7), brain and body weights were reduced but brain-to-body weight ratios were increased in all prematurely delivered (PD) animals; the surface folding index (SFI), was reduced in PPV but not PPV + iNO animals. Compared with controls, the brain damage index was increased (p < 0.05) in both cohorts of PD animals. There was no difference between ventilatory regimens, however, in 25% of animals with iNO therapy, there were organized hematomas in the subarachnoid space. Overall, iNO did not alter the extent of brain damage but did result in the presence of hematomas. These results do not confirm any protective or major injurious effect of nitric oxide therapy on the developing brain.
Asunto(s)
Lesiones Encefálicas , Encéfalo/crecimiento & desarrollo , Encéfalo/patología , Óxido Nítrico , Nacimiento Prematuro , Administración por Inhalación , Animales , Animales Recién Nacidos , Peso Corporal , Encéfalo/anatomía & histología , Encéfalo/fisiología , Lesiones Encefálicas/patología , Lesiones Encefálicas/fisiopatología , Lesiones Encefálicas/terapia , Femenino , Edad Gestacional , Óxido Nítrico/administración & dosificación , Óxido Nítrico/uso terapéutico , Tamaño de los Órganos , Papio , EmbarazoRESUMEN
BACKGROUND: The survival of prematurely born infants has greatly increased in recent decades because of advances in neonatal intensive care, which have included the advent of ventilatory therapies. However, there is limited knowledge as to the impact of these therapies on the developing brain. The purpose of this work was to evaluate the influence of randomized respiratory therapy with either early continuous positive airway pressure or delayed continuous positive airway pressure preceded by positive pressure ventilation on the extent of brain injury and altered development in a prematurely delivered primate model. METHODS: Fetal baboons were delivered at 125 days of gestation (term: approximately 185 days of gestation) by cesarean section. Animals were maintained for 28 days postdelivery with either: early continuous positive airway pressure (commencing at 24 hours; n = 6) or delayed continuous positive airway pressure (positive pressure ventilation for 5 days followed by nCPAP; n = 5). Gestational controls (n = 4) were delivered at 153 days of gestation. At the completion of the study, animals were killed, the brains were assessed histologically for growth and development, and evidence of cerebral injury and indices for both parameters were formulated. RESULTS: Brain and body weights were reduced in all of the nasal continuous positive airway pressure animals compared with controls; however, the brain/body weight ratio was increased in early continuous positive airway pressure animals. Within both nasal continuous positive airway pressure groups compared with controls, there was increased gliosis in the subcortical and deep white matter and cortex and a persistence of radial glia. Early continuous positive airway pressure was associated with less cerebral injury than delayed continuous positive airway pressure therapy. Neuropathologies were not observed in controls. CONCLUSIONS: Premature delivery, in the absence of potentiating factors, such as hypoxia or infection, is associated with a decrease in brain growth and the presence of subtle brain injury, which seems to be modified by respiratory therapies with early continuous positive airway pressure being associated with less overall cerebral injury.
Asunto(s)
Lesiones Encefálicas/prevención & control , Encéfalo/crecimiento & desarrollo , Animales , Peso Corporal , Encéfalo/patología , Lesiones Encefálicas/etiología , Presión de las Vías Aéreas Positiva Contínua , Modelos Animales de Enfermedad , Femenino , Gliosis/etiología , Humanos , Recién Nacido , Recien Nacido Prematuro , Masculino , Papio , Respiración con Presión Positiva , Distribución Aleatoria , Factores de TiempoRESUMEN
Prenatal hypoxia affects neuronal survival and process outgrowth. Brain-derived neurotrophic factor, which influences neural growth, is decreased in these conditions. We tested whether addition of brain-derived neurotrophic factor enhances growth of neurons cultured from guinea pig fetuses (n=7) compromised by chronic placental insufficiency from 30-52 days gestation (term approximately 67 days). Cultures were prepared from the olfactory bulb, hippocampus and cerebellum. Compared with controls (n=7), chronic placental insufficiency resulted in reduced total neurite length in olfactory bulb cultures. Brain-derived neurotrophic factor treatment for 5 days increased the total olfactory neurite length and somal size and number of primary neurites in all cultures from both control and compromised animals. Thus, brain-derived neurotrophic factor can influence the growth of compromised fetal neurons supporting its therapeutic use following chronic placental insufficiency.
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Factor Neurotrófico Derivado del Encéfalo/farmacología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Animales , Encéfalo/patología , Células Cultivadas , Embrión de Mamíferos , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Cobayas , Inmunohistoquímica/métodos , Proteínas Asociadas a Microtúbulos/metabolismo , Neuritas/efectos de los fármacos , Neuritas/fisiología , Neuronas/citología , Insuficiencia Placentaria/tratamiento farmacológico , Insuficiencia Placentaria/patología , Embarazo , Ácido gamma-Aminobutírico/metabolismoRESUMEN
OBJECTIVE: Fetal brain injury is associated with chorioamnionitis, which is often present without signs of overt infection or fetal compromise. We aimed to determine if prolonged exposure to intrauterine inflammation caused by intra-amniotic infusion of lipopolysaccharide (LPS) would affect the fetal brain. METHODS: At 80 days of pregnancy ewes bearing singletons had osmotic pumps implanted intra-amniotically to infuse Escherichia coli LPS (055:B5; n = 8) or saline (n = 7) for 28 days. At delivery (110 days), umbilical arterial blood and chorioamnion were assessed for inflammation; cytokine concentrations (interleukin [IL]-6 and IL-8) in amniotic fluid and fetal and maternal plasma were measured. The fetal cerebral hemispheres were examined for gross anatomical changes and the number of activated microglia/macrophages, astrocytes, and oligodendrocytes estimated after immunohistochemical staining. RESULTS: Intra-amniotic administration of LPS caused chorioamnionitis, fetal leucocytosis, and a moderate to extensive infiltration of activated microglia/macrophages in the subcortical white matter in six of eight fetuses; the remaining two fetuses were less affected. Within these focal regions of damage there was an attenuation of astrocytic processes, axonal injury, and a reduction in the number of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) immunoreactive oligodendrocytes in areas of extensive focal damage. In control fetuses there was mild (3/7) or no infiltration of activated microglia/macrophages in the subcortical white matter. Overall the infiltration of activated microglia/macrophages in the white matter was significantly greater in LPS-exposed fetuses compared to controls. In regions devoid of injury, the number of oligodendrocytes and astrocytes was not different between groups, nor was there a difference in the volume of cerebral white matter or density of blood vessels within the white matter. Amniotic fluid IL-6 and IL-8, and maternal plasma IL-8 concentrations were significantly increased by LPS infusion. CONCLUSIONS: An increase in inflammatory cells and axonal disruption in the subcortical white matter of the fetal brain can accompany chorioamnionitis induced by intra-amniotic administration of LPS, but cystic lesions do not occur. Thus, the effect on the fetal brain is milder than that reported from animal models of acute fetal/intrauterine infection.
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Encéfalo/efectos de los fármacos , Encéfalo/embriología , Inflamación , Lipopolisacáridos/toxicidad , Líquido Amniótico/química , Animales , Astrocitos , Recuento de Células Sanguíneas , Encéfalo/citología , Citocinas/análisis , Modelos Animales de Enfermedad , Femenino , Inmunohistoquímica , Lectinas/análisis , Oligodendroglía , Embarazo , OvinosRESUMEN
OBJECTIVE: Intrauterine infection has been linked to brain injury in human infants, although the mechanisms are not fully understood. We recently showed that repeated acute exposure of preterm fetal sheep to bacterial endotoxin (lipopolysaccharide [LPS]) results in fetal hypoxemia, hypotension, increased systemic proinflammatory cytokines, and brain damage, including white matter injury. However, it is not clear whether this injury is caused by reduced cerebral oxygen delivery or inflammatory pathways independent of hypoxia. The aim of the present study was to determine the effects on the fetal brain and placenta of a chronic intrauterine inflammatory state, induced by LPS infusion into the fetal circulation, a model that did not cause hypoxia. METHODS: At 0.65 of term, eight catheterized fetal sheep received intravenous infusions of LPS (5 to 15 mug) over 5 days; control fetuses received saline. Fetal physiologic responses were monitored throughout the infusion. Fetal brain and placental tissues were examined histologically 6 days after the conclusion of the infusion. RESULTS: LPS infusions did not result in physiologically significant alterations to fetal blood gases or mean arterial pressure; however, plasma proinflammatory cytokine levels were elevated. Following LPS exposure there was no difference in fetal body or brain weights (P >.05); placental weight was reduced (P <.05), consistent with reduced placentome cross-sectional area (P <.05). In the cerebral hemispheres subcortical white matter injury was present in six LPS-exposed fetuses and included axonal damage, microgliosis, oligodendrocyte injury, and increased beta amyloid precursor protein (beta-APP) expression. CONCLUSIONS: Chronic, systemic exposure of the fetus to LPS resulted in fetal brain damage in the absence of hypoxemia or hypotension, although the resulting injury was less severe than following repeated acute exposure.
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Encefalopatías/veterinaria , Encéfalo/embriología , Lipopolisacáridos/administración & dosificación , Enfermedades de las Ovejas/inducido químicamente , Ovinos/embriología , Precursor de Proteína beta-Amiloide/análisis , Animales , Axones/patología , Encefalopatías/metabolismo , Encefalopatías/patología , Citocinas/sangre , Femenino , Sangre Fetal , Hipoxia/inducido químicamente , Hipoxia/veterinaria , Oligodendroglía/patología , Placenta/efectos de los fármacos , EmbarazoRESUMEN
1. An optimal intra-uterine environment is critical for normal development of the brain. It is now thought that abnormal development in a compromised prenatal and/or early postnatal environment may be a risk factor for several neurological disorders that manifest postnatally, such as cerebral palsy, schizophrenia and epilepsy. 2. The present review examines some of the effects of abnormal prenatal brain development and focuses on one disorder that has been hypothesized to have, at least in part, an early neurodevelopmental aetiology: schizophrenia. 3. The key neuropathological alterations and changes in some of the neurotransmitter systems observed in patients with schizophrenia are reviewed. Evidence in support of a neurodevelopmental hypothesis for schizophrenia is examined. 4. A summary of the animal models that have been used by researchers in an attempt to elucidate the origins of this disorder is presented. Although no animal model of a complex human disorder is ever likely to emulate deficits in all aspects of structure and function observed in patients with a neuropsychiatric illness, our findings and those of others give support to the early neurodevelopmental hypothesis. 5. Thus, it is possible that an adverse event in utero disrupts normal brain development and creates a vulnerability of the brain that predisposes an already at-risk individual (e.g. genetic inheritance) to develop the disorder later in life.
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Encéfalo/anomalías , Esquizofrenia/fisiopatología , Animales , Encéfalo/embriología , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Humanos , Neurotransmisores/metabolismo , Factores de RiesgoRESUMEN
We showed previously that hypoxia in ovo impairs memory consolidation in the chick tested 2 days after hatching. Our present aim was to investigate whether we could detect any morphological effects of the same prenatal hypoxia. Hypoxia was induced by half-wrapping the egg with an impermeable membrane from either days 10-18 (W10-18 chicks) or days 14-18 (W14-18 chicks) of incubation (hatching approximately 21 days). Measurement of blood gases showed that reducing the surface area of the egg for gas exchange resulted in reduced pO2 and increased pCO2 2 days after wrapping. Although this hypoxia was sufficient to impair cognitive processing in the postnatal chick, our data suggest that it did not produce overt structural alterations or changes in the number of neurons, glutamine synthetase-immunoreactive cells or immunoreactivity to synaptophysin in the presynaptic vesicles in the multimodal integration (cortical) area compared to controls. Hence, we found no differences in the astrocyte to neuron ratio, synaptic density and/or vesicle number. Analysis of the ontogeny of astrocytes during the prenatal period of hypoxia showed them to be present at embryonic day 12, but not at the earlier ages examined. Although we found cognitive deficits in chicks from embryos made hypoxic during incubation, our regimen of prenatal hypoxia did not alter any of the parameters measured in the brains. This does not preclude the possibility that changes have occurred at the cellular or molecular levels or in specific neurotransmitter systems.
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Infarto Encefálico/fisiopatología , Hipoxia Fetal/fisiopatología , Hipoxia Encefálica/fisiopatología , Trastornos de la Memoria/fisiopatología , Animales , Infarto Encefálico/etiología , Infarto Encefálico/patología , Embrión de Pollo , Pollos , Modelos Animales de Enfermedad , Hipoxia Fetal/patología , Glutamato-Amoníaco Ligasa/metabolismo , Ácido Glutámico/metabolismo , Hipoxia Encefálica/patología , Inmunohistoquímica , Trastornos de la Memoria/etiología , Trastornos de la Memoria/patología , Microscopía Electrónica de Transmisión , Terminales Presinápticos/metabolismo , Terminales Presinápticos/ultraestructura , Vesículas Sinápticas/metabolismo , Vesículas Sinápticas/ultraestructura , Sinaptofisina/metabolismoRESUMEN
Chronic placental insufficiency (CPI) has the potential to affect fetal brain development and to cause brain injury. Our aim was to determine the effects of exposure to CPI during late gestation on brain and retinal structure and brain neurotrophin expression 8 weeks after birth. Six fetal sheep were exposed to CPI, induced by umbilico-placental embolization, from 120 days of gestation until term (approximately 147 days) such that fetal arterial oxygen saturation (SaO2) was reduced by approximately 50%. Nine untreated animals served as controls. During CPI, fetal arterial PO2, SaO2, pH, and growth were reduced (p < 0.05); these animals remained small at 8 weeks after birth. Structural abnormalities were present in the brains and retinae of all CPI-exposed lambs. There was a reduction in retinal width and in the number of retinal tyrosine hydroxylase-immunoreactive dopaminergic amacrine cells (p < 0.05). In the dorsal hippocampus the combined width of strata oriens and pyramidale was significantly reduced (p < 0.05). In the cerebellum there was a significant reduction (p = 0.05) in cerebellar cross-sectional area, most notably in the inner granule cell layer, and a reduction (p < 0.05) in immunoreactivity for the cytoskeletal protein neurofilament-200 in the white matter. Gliosis was present in either the cerebral white matter or cerebellum in all animals and degeneration was seen around blood vessels in 4/6 umbilico-placental embolization animals. There were reductions in brain-derived neurotrophic factor immunoreactivity in the hippocampus (p < 0.05) and tyrosine kinase B immunoreactivity in the cerebellum (p < 0.05). This study shows that late gestational CPI affects morphology and neurotrophin expression of the postnatal brain. These alterations in the brain can apparently persist from fetal life or become established after birth; some changes that were present in the fetus at term did not persist into postnatal life.