50 research outputs found
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HIGH GLUCOSE CONCENTRATIONS INCREASE LEUKOCYTE ADHESION TO ASTROCYTES IN A POST-TRAUMATIC NEUROINFLAMMATION MODEL 144
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Traumatic Injury Activates MAP Kinases in Astrocytes: Mechanisms of Hypothermia and Hyperthermia
Hyperthermia is common following traumatic brain injury (TBI) and has been associated with poor neurologic outcome, and hypothermia has emerged as a potentially effective therapy for TBI, although its mechanism is still unclear. In this study we investigated the effects of temperature modulations on astrocyte survival following traumatic injury and the involved MAPK pathways. Trauma was produced by scratch injury of a monolayer of confluent astrocytes in culture, followed by incubation at hypothermia (30°C), normothermia (37°C), or hyperthermia (39°C). The activation of MAPK pathways including extracellular signal-regulated protein kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and p38 MAPK were measured at 0, 15, 30, 60, and 120 min after traumatic injury followed by temperature modulation. Apoptosis of astrocytes was assessed by quantitation of cleaved caspase-3 expression 24 h after injury. Our findings showed that only JNK activation at 15 min after trauma was reduced by hypothermia, and this was associated with a marked reduction in apoptosis. Hyperthermia activated both ERK and JNK and increased apoptosis. The specific JNK inhibitor, SP60025, markedly reduced JNK-induced apoptosis at normothermia and hyperthermia, and showed a dose-dependent effect. In conclusion, the JNK pathway appears to mediate traumatic injury–induced apoptosis in astrocytes. Prolonged hyperthermia as a secondary insult worsens apoptosis by increasing JNK activation. Hypothermia protects against traumatic injury via early suppression on JNK activation and subsequent prevention of apoptosis. Manipulation of the JNK pathway in astrocytes may represent a therapeutic target for ameliorating the devastating progression of tissue injury and cell death after TBI
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New pediatric model of ischemic stroke in infant piglets by photothrombosis: acute changes in cerebral blood flow, microvasculature, and early histopathology
The etiology and pathophysiology of acute ischemic stroke in children differ greatly from those in adults. The purpose of this study was to establish a new pediatric model of ischemic stroke in infant piglets for use in future studies of the response of the developing brain to focal ischemic injury.
Ischemic stroke was produced in male infant piglets (2 to 4 weeks old) by photothrombotic occlusion of the middle cerebral artery. Regional cerebral blood flow was measured with radiolabeled microspheres up to 4 hours after occlusion. Early histopathology, including caspase-3 immunohistochemistry for apoptosis, was examined 4 hours after ischemia. The nature of the thrombus and its interaction with vascular endothelium were assessed by electron microscopy.
Severe ischemia (0 to 15 mL/100 g per min) occurred rapidly in 1.4+/-0.2 g of tissue at 15 minutes and increased to 2.4+/-0.7 g at 4 hours. Similarly, moderate ischemia (16 to 30 mL/100 g per min) was measured in 1.2+/-0.3 g of tissue at 15 minutes and increased to 2.0+/-0.6 g at 4 hours. These regional cerebral blood flow values represent ischemic levels of blood flow in 20% to 25% of the volume of the ischemic hemisphere at 4 hours after ischemia. Ischemic infarction occurred in both gray and white matter, and cerebral microvessels in the ischemic hemisphere contained large numbers of inflammatory leukocytes. Caspase-3-positive cells were few in number and were found in the periphery of the infarct; cell death appeared to occur primarily by necrosis rather than apoptosis at 4 hours. Electron microscopy revealed a pure platelet thrombus firmly attached to the vascular endothelium, which in some areas appeared to be detached from the basement membrane.
Ischemic stroke can be produced in infant piglets by middle cerebral artery photothrombosis. The stroke involved both gray and white matter and exhibited a robust inflammatory component. The mean infarct volume determined histopathologically amounted to 9.6+/-2.4% of the affected (ipsilateral) hemisphere, which was correlated well with the mass equivalent of tissue (12.0+/-3.5%), in which severe declines in regional cerebral blood flow were observed at 4 hours
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NEURONAL INJURY AND LEUKOCYTE ACCUMULATION IN PIGLET BRAIN AFTER PHOTOTHROMBOSIS OF THE COMMON CAROTID ARTERY
Role of nitric oxide in the cerebrovascular and thermoregulatory response to interleukin-1β
Central administration of interleukin-1β (IL-1β) increases cerebral blood flow (CBF) and body temperature, in part, through the production of prostaglandins. In previous studies, the temporal relationship between these effects of IL-1β have not been measured. In this study, we hypothesized that the increase in CBF occurs before any change in brain or body temperature and that the cerebrovascular and thermoregulatory effects of IL-1β would be attenuated by inhibiting the production of nitric oxide (NO). Adult male rats received 100 ng intracerebroventricular (icv) injection of IL-1β, and cortical CBF (cCBF) was measured by laser-Doppler in the contralateral cerebral cortex. A central injection of IL-1β caused a rapid increase in cCBF to 133 ± 12% of baseline within 15 min and to an average of 137 ± 12% for the remainder of the 3-h experiment. Brain and rectal temperature increased by 0.4 ± 0.2 and 0.5 ± 0.2°C, but not until 45 min after IL-1β administration. Pretreatment with N ω-nitro-l-arginine methyl ester (l-NAME; 5 mg/kg iv) completely prevented the changes in cCBF and brain and rectal temperature induced by IL-1β.l-Arginine (150 mg/kg iv) partially reversed the effects ofl-NAME and resulted in increases in both cCBF and temperature. These findings suggest that the vasodilatory effects of IL-1β in the cerebral vasculature are independent of temperature and that NO plays a major role in both the cerebrovascular and thermoregulatory effects of centrally administered IL-1β
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Cognitive Deficits in the R6/2 model of Huntington’s Disease and Amelioration with Donepezil
The neurodegenerative disorder Huntington’s disease (HD) is characterized by motor dysfunction, cognitive impairment and psychiatric symptoms. The R6/2 (120 CAG repeats) mouse model of HD recapitulates many of the symptoms of the disease, including marked impairments in cognition and severe motor deficits. As cholinergic function has been reported to be affected in both HD patients and this mouse model, we tested whether treatment with the cholinesterase inhibitor donepezil could improve the R6/2 mice performance in the two-choice swim tank visual discrimination and reversal task. In this test mice are trained to swim towards a light cued platform located on one side of a water-filled tank. Once mice reach an acquisition criterion a reversal ensues. Wild-type and R6/2 mice were dosed with donepezil (0.6 mg/kg/day) or vehicle starting at 8 weeks of age and tested starting at 9 weeks of age. In experiment 1, vehicle-treated R6/2 mice showed a significant deficit during acquisition and reversal as compared to vehicle-treated WT mice. Donepezil improved reversal in the R6/2 group. In experiment 2, we confirmed the beneficial effect of donepezil on reversal in similar conditions. Donepezil had no effect on activity as measured in the open field test or through the latency to reach the platform during the swim test. We suggest that the donepezil-induced improvements in cognitive function observed in the R6/2 transgenic model of HD may reflect amelioration of deficits in cholinergic function that have been reported previously in this model. Further work is required to confirm the findings of these interesting although preliminary studies
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Cognitive Deficits in the R6/2 model of Huntington’s Disease and Amelioration with Donepezil
The neurodegenerative disorder Huntington’s disease (HD) is characterized by motor dysfunction, cognitive impairment and psychiatric symptoms. The R6/2 (120 CAG repeats) mouse model of HD recapitulates many of the symptoms of the disease, including marked impairments in cognition and severe motor deficits. As cholinergic function has been reported to be affected in both HD patients and this mouse model, we tested whether treatment with the cholinesterase inhibitor donepezil could improve the R6/2 mice performance in the two-choice swim tank visual discrimination and reversal task. In this test mice are trained to swim towards a light cued platform located on one side of a water-filled tank. Once mice reach an acquisition criterion a reversal ensues. Wild-type and R6/2 mice were dosed with donepezil (0.6 mg/kg/day) or vehicle starting at 8 weeks of age and tested starting at 9 weeks of age. In experiment 1, vehicle-treated R6/2 mice showed a significant deficit during acquisition and reversal as compared to vehicle-treated WT mice. Donepezil improved reversal in the R6/2 group. In experiment 2, we confirmed the beneficial effect of donepezil on reversal in similar conditions. Donepezil had no effect on activity as measured in the open field test or through the latency to reach the platform during the swim test. We suggest that the donepezil-induced improvements in cognitive function observed in the R6/2 transgenic model of HD may reflect amelioration of deficits in cholinergic function that have been reported previously in this model. Further work is required to confirm the findings of these interesting although preliminary studies
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Acute Changes in Systemic Hemodynamics and Serum Vasopressin After Complete Cervical Spinal Cord Injury in Piglets
Spinal cord injury (SCI) produces acute hemodynamic alterations through disruption of sympathetic output of the autonomic nervous system and places individuals with SCI at high risk of secondary ischemic insult to the spinal cord as well as to other organs. The purpose of this study was to examine hemodynamics and serum vasopressin concentration in the acute period following complete cervical SCI in piglets.We developed a new model of traumatic complete cervical SCI in piglets and measured acute hemodynamic variables and serum arginine vasopressin (AVP) concentrations at baseline and for 4 h after SCI under fentanyl anesthesia.Complete cervical SCI caused an immediate tachycardia which lasted for approximately 1 h, immediate hypotension which was sustained for the 4-h duration of the study, decreases in both systemic and pulmonary vascular resistance, and a compensatory increase in cardiac output, which resulted initially from an increase in heart rate (HR) but was later sustained after resolution of tachycardia by an increase in cardiac stroke volume. Serum AVP concentration increased significantly after SCI and did not change in the control group. Neurogenic shock did not occur due to the robust increase in cardiac output and cardiac stroke volume.Complete cervical SCI produces hemodynamic alterations consistent with the withdrawal of sympathetic tone. Although mean arterial pressure (MAP) decreased significantly after SCI, the increase in serum vasopressin may have played a role in maintaining blood pressure and preventing circulatory collapse, a complication which is encountered frequently in patients with cervical and upper thoracic SCI