| 1. |
- Christensen, Jakob Hakon, et al.
(författare)
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Preservation of the blood brain barrier and cortical neuronal tissue by liraglutide, a long acting glucagon-like-1 analogue, after experimental traumatic brain injury.
- 2015
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:3
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral edema is a common complication following moderate and severe traumatic brain injury (TBI), and a significant risk factor for development of neuronal death and deterioration of neurological outcome. To this date, medical approaches that effectively alleviate cerebral edema and neuronal death after TBI are not available. Glucagon-like peptide-1 (GLP-1) has anti-inflammatory properties on cerebral endothelium and exerts neuroprotective effects. Here, we investigated the effects of GLP-1 on secondary injury after moderate and severe TBI. Male Sprague Dawley rats were subjected either to TBI by Controlled Cortical Impact (CCI) or sham surgery. After surgery, vehicle or a GLP-1 analogue, Liraglutide, were administered subcutaneously twice daily for two days. Treatment with Liraglutide (200 μg/kg) significantly reduced cerebral edema in pericontusional regions and improved sensorimotor function 48 hours after CCI. The integrity of the blood-brain barrier was markedly preserved in Liraglutide treated animals, as determined by cerebral extravasation of Evans blue conjugated albumin. Furthermore, Liraglutide reduced cortical tissue loss, but did not affect tissue loss and delayed neuronal death in the thalamus on day 7 post injury. Together, our data suggest that the GLP-1 pathway might be a promising target in the therapy of cerebral edema and cortical neuronal injury after moderate and severe TBI.
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| 2. |
- Christensen, Jakob Hakon
(författare)
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Removing the barriers of plasticity after experimental brain injury
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ischemic stroke and traumatic brain injuries (TBI) are leading causes of disability and death worldwide. Both injuries result in regional cell death and disruption of local and remote functional neuronal networks, leading to loss of neurological function. Despite much effort spent on developing pharmacological therapies to reduce neuronal damage following these conditions, no neuroprotective strategies have reached clinical use. Spontaneous recovery of lost function after stroke and TBI is limited but can be enhanced by rehabilitative strategies that stimulate experience-driven brain plasticity.In the experimental setting, exposure to multimodal stimulation by enriched environments (EE) stimulates brain plasticity and recovery following brain injuries. At the system level, we demonstrated that improvement of tactile- proprioceptive function following rehabilitation in EE was associated with enhanced functional-connectivity among distinct brain regions involved in integration of multisensory input and control of movement. Inhibition of the metabotropic glutamate receptor 5 (mGluR5) and genetic disruption of peri- neuronal nets facilitated remodeling of resting-state networks within contralesional cortical sensorimotor areas during stroke recovery. Using the EE regime, we identified several molecular barriers, which appear to impair functional recovery and plasticity in the first weeks following stroke and TBI. These included peri- lesional inflammation, parvalbumin expressing GABAergic inhibitory interneurons and aberrant mGluR5 activation.Overall this thesis presents novel data regarding molecular and network level mechanisms of plasticity, and provide potential targets for future therapies, which may support rehabilitation of patients following matured brain injury.
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| 3. |
- Quattromani, Miriana Jlenia, et al.
(författare)
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Extracellular Matrix Modulation Is Driven by Experience-Dependent Plasticity During Stroke Recovery
- 2018
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Ingår i: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 55:3, s. 2196-2213
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Tidskriftsartikel (refereegranskat)abstract
- Following stroke, complete cellular death in the ischemic brain area may ensue, with remaining brain areas undergoing tissue remodelling to various degrees. Experience-dependent brain plasticity exerted through an enriched environment (EE) promotes remodelling after central nervous system injury, such as stroke. Post-stroke tissue reorganization is modulated by growth inhibitory molecules differentially expressed within the ischemic hemisphere, like chondroitin sulfate proteoglycans found in perineuronal nets (PNNs). PNNs in the neocortex predominantly enwrap parvalbumin-containing GABAergic (PV/GABA) neurons, important in sensori-information processing. Here, we investigate how extracellular matrix (ECM) proteases and their inhibitors may participate in the regulation of PNN integrity during stroke recovery. Rats were subjected to photothrombotic stroke in the motor cortex, and functional deficits were assessed at 7 days of recovery. Sham and stroked rats were housed in either standard or EE conditions for 5 days, and infarct volumes were calculated. PNNs were visualized by immunohistochemistry and counted in the somatosensory cortex of both hemispheres. mRNA expression levels of ECM proteases and protease inhibitors were assessed by RT-qPCR and their activity analyzed by gel zymography. PNNs and protease activity were also studied in brains from stroke patients where similar results were observed. EE starting 2 days after stroke and continuing for 5 days stimulated behavioral recovery of limb-placement ability without affecting infarct size. EE promoted a decrease of PNNs around PV/GABA neurons and a concomitant modulation of the proteolytic activity and mRNA expression of ECM proteases and protease inhibitors in the somatosensory cortex. This study provides molecular targets for novel therapies that could support rehabilitation of stroke patients.
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