| 1. |
- Bentzer, Peter, et al.
(author)
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Infusion of prostacyclin following experimental brain injury in the rat reduces cortical lesion volume
- 2001
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In: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 1557-9042 .- 0897-7151. ; 18:3, s. 275-285
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Journal article (peer-reviewed)abstract
- Endothelial-derived prostacyclin is an important regulator of microvascular function, and its main actions are inhibition of platelet/leukocyte aggregation and adhesion, and vasodilation. Disturbances in endothelial integrity following traumatic brain injury (TBI) may result in insufficient prostacyclin production and participate in the pathophysiological sequelae of brain injury. The objective of this study was to evaluate the potential therapeutic effects of a low-dose prostacyclin infusion on cortical lesion volume, CA3 neuron survival and functional outcome following TBI in the rat. Anesthetized animals (sodium pentobarbital, 60 mg/kg, i.p.) were subjected to a lateral fluid percussion brain injury (2.5 atm) or sham injury. Following TBI, animals were randomized to receive a constant infusion of either prostacyclin (1 ng/kg x min(-1) i.v.) or vehicle over 48 h. All sham animals received vehicle (n = 6). Evaluation of neuromotor function, lesion volume, and CA3 neuronal loss was performed blindly. By 7 days postinjury, cortical lesion volume was significantly reduced by 43% in the prostacyclin-treated group as compared to the vehicle treated group (p < 0.01; n = 12 prostacyclin, n = 12 vehicle). No differences were observed in neuromotor function (48 h and 7 days following TBI), or in hippocampal cell loss (7 days following TBI) between the prostacyclin- and vehicle-treated groups. We conclude that prostacyclin in a low dose reduces loss of neocortical neurons following TBI and may be a potential clinical therapeutic agent to reduce neuronal cell death associated with brain trauma.
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| 2. |
- Deierborg Olsson, Tomas, et al.
(author)
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Overexpression of UCP2 protects thalamic neurons following global ischemia in the mouse.
- 2008
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In: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016 .- 0271-678X. ; 28, s. 1186-1195
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Journal article (peer-reviewed)abstract
- Uncoupling protein 2 (UCP2) is upregulated in the brain after sublethal ischemia, and overexpression of UCP2 is neuroprotective in several models of neurodegenerative disease. We investigated if increased levels of UCP2 diminished neuronal damage after global brain ischemia by subjecting mice overexpressing UCP2 (UCP2/3tg) and wild-type littermates (wt) to a 12-min global ischemia. The histopathological outcome in the cortex, hippocampus, striatum, and thalamus was evaluated at 4 days of recovery, allowing maturation of the selective neuronal death. Global ischemia led to extensive cell death in the striatum, thalamus, and in the CA1 and CA2, and less-pronounced cell death in the CA3 and dentate gyrus (DG) hippocampal subfields. Histologic damage was significantly lower in the ventral posterolateral VPL and medial VPM thalamic nuclei in UCP2/3tg animals compared with wt. These thalamic regions showed a larger increase in UCP2 expression in UCP2/3tg compared with wt animals relative to the nonprotected DG. In the other regions studied, the histologic damage was lower or equal in UCP2/3tg animals compared with wt. Consequently, neuroprotection in the thalamus correlated with a high expression of UCP2, which is neuroprotective in a number of models of neurodegenerative diseases.Journal of Cerebral Blood Flow & Metabolism advance online publication, 27 February 2008; doi:10.1038/jcbfm.2008.8.
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| 3. |
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| 4. |
- Hansson, Magnus, et al.
(author)
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Increased potassium conductance of brain mitochondria induces resistance to permeability transition by enhancing matrix volume.
- 2010
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In: Journal of Biological Chemistry. - 1083-351X. ; 285, s. 741-750
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Journal article (peer-reviewed)abstract
- Modulation of K+ conductance of the inner mitochondrial membrane has been proposed to mediate preconditioning in ischemia-reperfusion injury. The mechanism is not entirely understood but it has been linked to a decreased activation of mitochondrial permeability transition (mPT). In the present study, K+ channel activity was mimicked by picomolar concentrations of valinomycin. Isolated brain mitochondria were exposed to continuous infusions of calcium. Monitoring of extramitochondrial Ca2+ and mitochondrial respiration provided a quantitative assay for mPT-sensitivity by determining calcium retention capacity (CRC). Valinomycin and cyclophilin D-inhibition separately and additively increased CRC. Comparable degrees of respiratory uncoupling induced by increased K+ or H+ conductance had opposite effects on mPT sensitivity. Protonophores dose-dependently decreased CRC, demonstrating that so-called mild uncoupling was not beneficial per se. The putative mitoKATP channel opener diazoxide did not mimic the effect of valinomycin. An alkaline matrix pH was required in order for mitochondria to retain calcium, but increased K+ conductance did not result in augmented DeltapH. The beneficial effect of valinomycin on CRC was not mediated by H2O2-induced PKCepsilon activation. In contrast, increased K+ conductance reduced H2O2 generation during calcium infusion. Lowering the osmolarity of the buffer induced an increase in mitochondrial volume and improved CRC similar to valinomycin without inducing uncoupling or otherwise affecting respiration. We propose that increased potassium conductance in brain mitochondria may cause a direct physiological effect on matrix volume inducing resistance to pathological calcium challenges.
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| 5. |
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| 6. |
- Jungner, Mårten, et al.
(author)
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Effects on brain edema of crystalloid and albumin fluid resuscitation after brain trauma and hemorrhage in the rat.
- 2010
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In: Anesthesiology. - 1528-1175. ; 112:5, s. 1194-1203
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Journal article (peer-reviewed)abstract
- BACKGROUND: It has been hypothesized that resuscitation with crystalloids after brain trauma increases brain edema compared with colloids, but previous studies on the subject have been inconclusive. To test this hypothesis, the authors compared groups resuscitated with either colloid or crystalloid. METHODS: After fluid percussion injury, rats were subjected to a controlled hemorrhage of 20 ml/kg and were randomized to 5% albumin at 20 ml/kg (A20), isotonic Ringer's acetate at 50 ml/kg (C50), or 90 ml/kg (C90). After 3 or 24 h, water content in the injured cortex was determined using a wet/dry weight method. Blood volume was calculated from plasma volume, measured by 125I-albumin dilution, and hematocrit. Oncotic pressure and osmolality were measured with osmometers. RESULTS: At 3 h, blood volume was equal in the A20 and C90 groups and lower in the C50 group. Oncotic pressure was reduced by 35-40% in the crystalloid groups and unchanged in the albumin group. Cortical water content in the A20 group was lower than in the C90 group (81.3 +/- 0.5% vs. 82.1 +/- 1.1%, P < 0.05), but it was not different from the C50 group (81.8 +/- 1.1%). At 24 h, oncotic pressure and blood volume were normalized in all groups, and cortical water content was significantly lower in the albumin group than in the crystalloid groups. Osmolality and arterial pressure were equal in all groups throughout the experiment. CONCLUSIONS: When given to the same intravascular volume expansion, isotonic crystalloids caused greater posttraumatic brain edema than 5% albumin at 3 and 24 h after trauma.
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| 7. |
- Lybeck, Anna, et al.
(author)
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Bedside interpretation of simplified continuous EEG after cardiac arrest
- 2020
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In: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172 .- 1399-6576. ; 64:1, s. 85-92
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Journal article (peer-reviewed)abstract
- Background: Continuous EEG-monitoring (cEEG) in the ICU is recommended to assess prognosis and detect seizures after cardiac arrest but implementation is often limited by the lack of EEG-technicians and experts. The aim of the study was to assess ICU physicians ability to perform preliminary interpretations of a simplified cEEG in the post cardiac arrest setting. Methods: Five ICU physicians received training in interpretation of simplified cEEG - total training duration 1 day. The ICU physicians then interpreted 71 simplified cEEG recordings from 37 comatose survivors of cardiac arrest. The cEEG included amplitude-integrated EEG trends and two channels with original EEG-signals. Basic EEG background patterns and presence of epileptiform discharges or seizure activity were assessed on 5-grade rank-ordered scales based on standardized EEG terminology. An EEG-expert was used as reference. Results: There was substantial agreement (κ 0.69) for EEG background patterns and moderate agreement (κ 0.43) for epileptiform discharges between ICU physicians and the EEG-expert. Sensitivity for detecting seizure activity by ICU physicians was limited (50%), but with high specificity (87%). Conclusions: After cardiac arrest, preliminary bedside interpretations of simplified cEEGs by trained ICU physicians may allow earlier detection of clinically relevant cEEG changes, prompting changes in patient management as well as additional evaluation by an EEG-expert. This strategy requires awareness of limitations of both the simplified electrode montage and the cEEG interpretations performed by ICU physicians. cEEG evaluation by an expert should not be delayed.
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| 8. |
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| 9. |
- Mattiasson, Gustav
(author)
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Experimental Traumatic Brain Injury and Cell Death - in vivo and in vitro aspects
- 2003
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Doctoral thesis (other academic/artistic)abstract
- Traumatic and ischemic brain damage are major causes of disability and death. While much effort has been spent on developing pharmacological treatments for these conditions, no neuroprotective drugs are in clinical use. Neuronal death following trauma and ischemia occurs in selected cell populations of the brain at various time points after the injury, and causes cognitive and behavioral dysfunction. The injury mechanisms are similar in both types of injury. Brain trauma causes ischemia, and mitochondrial dysfunction is an important initiator of both types of cell death. In the first part of the study, a clinically relevant model of traumatic brain injury (TBI) in the rat was used to evaluate the rotating pole test as a test of neuromotor function, as well as the neuroprotective effect of administration of a low dose of prostacyclin following TBI. The rotating pole test was useful to assess outcome and functional improvement following injury, and administration of prostacyclin led to a significantly reduced cortical lesion volume, presumably through an improved microcirculation. Here we show that a low dose of prostacyclin without side effects such as systemic hypotension reduces cell death following experimental TBI. In the second part of the study, the role of mitochondria in cell death following acute brain injury was studied. A flow cytometric method for the analysis of minute samples of isolated brain mitochondria was developed, and applied to compare mitochondria from hippocampal subregions. Cell vulnerability correlated with an increased mitochondrial production of reactive oxygen species and increased sensitivity to calcium-induced mitochondrial permeability transition (mPT). In the final study, we used a functional genomics approach to identify potentially neuroprotective genes that were upregulated following ischemic preconditioning. Increased expression of the mitochondrial protein UCP-2 correlated with cell survival, and overexpression of UCP-2 was neuroprotective both in vivo and in vitro. The results suggest that under basal conditions, UCP-2 may signal through cellular redox systems to upregulate neuroprotective genes. Following injury, UCP-2 inhibits mPT, activation of caspases and cell death. Mitochondrial involvement in ischemic and traumatic brain injury is supported by the strong neuroprotective effect of inhibitors of mPT (e.g. cyclosporin A). The uncoupling proteins have attracted much interest as potential targets for the treatment of obesity, which have led to devlopment of pharmacological inducers of these proteins. The results of this study suggest that such compounds may also be used to induce neuroprotection.
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