0000000000074580
AUTHOR
Henrike Bauer
FTY720 reduces post-ischemic brain lymphocyte influx but does not improve outcome in permanent murine cerebral ischemia.
Background The contribution of neuroinflammation and specifically brain lymphocyte invasion is increasingly recognised as a substantial pathophysiological mechanism after stroke. FTY720 is a potent treatment for primary neuroinflammatory diseases by inhibiting lymphocyte circulation and brain immigration. Previous studies using transient focal ischemia models showed a protective effect of FTY720 but did only partially characterize the involved pathways. We tested the neuroprotective properties of FTY720 in permanent and transient cortical ischemia and analyzed the underlying neuroimmunological mechanisms. Methodology/Principal Findings FTY720 treatment resulted in substantial reduction of c…
Functional Improvement after Photothrombotic Stroke in Rats Is Associated with Different Patterns of Dendritic Plasticity after G-CSF Treatment and G-CSF Treatment Combined with Concomitant or Sequential Constraint-Induced Movement Therapy
We have previously shown that granulocyte-colony stimulating factor (G-CSF) treatment alone, or in combination with constraint movement therapy (CIMT) either sequentially or concomitantly, results in significantly improved sensorimotor recovery after photothrombotic stroke in rats in comparison to untreated control animals. CIMT alone did not result in any significant differences compared to the control group (Diederich et al., Stroke, 2012;43:185-192). Using a subset of rat brains from this former experiment the present study was designed to evaluate whether dendritic plasticity would parallel improved functional outcomes. Five treatment groups were analyzed (n = 6 each) (i) ischemic contr…
Prevention of an increase in cortical ligand binding to AMPA receptors may represent a novel mechanism of endogenous brain protection by G-CSF after ischemic stroke
PURPOSE Using G-CSF deficient mice we recently demonstrated neuroprotective properties of endogenous G-CSF after ischemic stroke. The present follow-up study was designed to check, whether specific alterations in ligand binding densities of excitatory glutamate or inhibitory GABAA receptors may participate in this effect. METHODS Three groups of female mice were subjected to 45 minutes of MCAO: wildtype, G-CSF deficient and G-CSF deficient mice substituted with G-CSF. Infarct volumes were determined after 24 hours and quantitative in vitro receptor autoradiography was performed using [3H]MK-801, [3H]AMPA and [3H]muscimol for labeling of NMDA, AMPA and GABAA receptors, respectively. Ligand b…
Neuroprotective effect of Fn14 deficiency is associated with induction of the granulocyte-colony stimulating factor (G-CSF) pathway in experimental stroke and enhanced by a pathogenic human antiphospholipid antibody
Using a transgenic mouse model of ischemic stroke we checked for a possible interaction of antiphospholipid antibodies (aPL) which often cause thromboses as well as central nervous system (CNS) involvement under non-thrombotic conditions and the TWEAK/Fn14 pathway known to be adversely involved in inflammatory and ischemic brain disease. After 7 days, infarct volumes were reduced in Fn14 deficient mice and were further decreased by aPL treatment. This was associated with strongest increase of the endogenous neuroprotective G-CSF/G-CSF receptor system. This unexpected beneficial action of aPL is an example for a non-thrombogenic action and the double-edged nature of aPL.
Distribution of the hematopoietic growth factor G-CSF and its receptor in the adult human brain with specific reference to Alzheimer's disease
The granulocyte colony-stimulating factor (G-CSF), being a member of the hematopoietic growth factor family, is also critically involved in controlling proliferation and differentiation of neural stem cells. Treatment with G-CSF has been shown to result in substantial neuroprotective and neuroregenerative effects in various experimental models of acute and chronic diseases of the central nervous system. Although G-CSF has been tested in a clinical study for treatment of acute ischemic stroke, there is only fragmentary data on the distribution of this cytokine and its receptor in the human brain. Therefore, the present study was focused on the immunohistochemical analysis of the protein expr…
Inhibition of lymphocyte trafficking shields the brain against deleterious neuroinflammation after stroke
T lymphocytes are increasingly recognized as key modulators of detrimental inflammatory cascades in acute ischaemic stroke, but the potential of T cell-targeted therapy in brain ischaemia is largely unexplored. Here, we characterize the effect of inhibiting leukocyte very late antigen-4 and endothelial vascular cell adhesion molecule-1-mediated brain invasion-currently the most effective strategy in primary neuroinflammatory brain disease in murine ischaemic stroke models. Very late antigen-4 blockade by monoclonal antibodies improved outcome in models of moderate stroke lesions by inhibiting cerebral leukocyte invasion and neurotoxic cytokine production without increasing the susceptibilit…
Effects of levosimendan on hemodynamics, local cerebral blood flow, neuronal injury, and neuroinflammation after asphyctic cardiac arrest in rats.
Despite advances in cardiac arrest treatment, high mortality and morbidity rates after successful cardiopulmonary resuscitation are still a major clinical relevant problem. The post cardiac arrest syndrome subsumes myocardial dysfunction, impaired microcirculation, systemic inflammatory response, and neurological impairment. The calcium-sensitizer levosimendan was able to improve myocardial function and initial resuscitation success after experimental cardiac arrest/cardiopulmonary resuscitation. We hypothesized that levosimendan exerts beneficial effects on cerebral blood flow, neuronal injury, neurological outcome, and inflammation 24 hours after experimental cardiac arrest/cardiopulmonar…
Postischemic Brain Infiltration of Leukocyte Subpopulations Differs among Murine Permanent and Transient Focal Cerebral Ischemia Models
Cellular and humoral inflammations play important roles in ischemic brain injury. The effectiveness of immunomodulatory therapies may critically depend on the chosen experimental model. Our purpose was to compare the post-ischemic neuroinflammation among murine permanent and transient middle cerebral artery occlusion (MCAO) models. Permanent MCAO was induced by transtemporal electrocoagulation and 30 minutes or 90 minutes transient MCAO was induced by intraluminal filament in C57BL/6 mice. Infiltration of leukocyte subpopulations was quantified by immunohistochemistry and fluorescence-activated cell sorting. Cerebral cytokine and adhesion molecule expression was measured by real-time polyme…