1,721,110 research outputs found
Effects of recombinant tissue plasminogen activator after intraluminal thread occlusion in mice - Role of hemodynamic alterations
No full textBackground and Purpose-It has been suggested that recombinant tissue plasminogen activator (rtPA) may cause an aggravation of injury after transient focal ischemia via excitotoxic side effects. Such rtPA toxicity would be of major clinical significance since rtPA is increasingly used in stroke treatment. This study was conducted to evaluate the effects of dose, application time, and hemodynamic changes after intravenous rtPA treatment in focal ischemia. Methods-Mice were subjected to a 90-minute episode of middle cerebral artery thread occlusion, and rtPA effects were assessed by laser-Doppler flowmetry, [C-14]iodoantipyrine autoradiography, and triphenyltetrazolium chloride staining. Results and Conclusions-We provide evidence that rtPA provokes complex hemodynamic alterations in the ischemic brain tissue, which include an initial hyperperfusion and a more delayed hypoperfusion response. Changes are most pronounced in the periphery of the ischemic infarct, where regional blood flow drops below critical thresholds of tissue viability. Our observations suggest that changes of perfusion may at least partly explain the rtPA-induced increase of infarct size, which has previously been reported and which we also confirmed in the present experiments. Notably, both the secondary hypoperfusion and increase of infarct volume were abolished when rtPA-treated animals received additional heparin infusions. This finding suggests that a secondary hypercoagulability may compromise brain perfusion after rtPA delivery. Accordingly, early treatment with heparin might help to prevent the rtPA-induced changes
Tissue Plasminogen Activator-Induced Ischemic Injury Is Reversed by NMDA Antagonist MK-801 in vivo
No full textIn vitro studies suggested that tissue plasminogen activator (t-PA) may aggravate ischemic injury by enhancing N-methyl-D-aspartate (NMDA) receptor signalling. It remained unclear whether NMDA signalling is also relevant for t-PA toxicity in vivo. We herein examined effects of intravenous t-PA (10 mg/kg), administered alone or in combination with the NMDA antagonist MK-801 (0.2 mg/kg), following 90 min of middle cerebral artery occlusion in mice. In our study, MK-801 alone, administered intra-peritoneally, neither affected infarct volume nor brain swelling at 24 h after reperfusion. t-PA significantly increased infarct size, in accordance with previous findings. t-PA-induced ischemic injury was completely abolished and brain swelling markedly reduced when t-PA-treated animals received additional MK-801 injections. To elucidate how t-PA influences brain damage, we examined actions of t-PA on the expression of NO synthases by immunohistochemistry, showing that t-PA does not influence neuronal NO synthase, but increases inducible NO synthase in ischemic areas. The effect of t-PA on inducible NO synthase levels was completely reversed after cotreatment with MK-801. Our study provides in vivo evidence in a model of focal cerebral ischemia that t-PA-induced brain injury involves an NMDA receptor-dependent mechanism. Copyright (C) 2005 S. Karger AG, Base
Effects of pinealectomy and melatonin on the retrograde degeneration of retinal ganglion cells in a novel model of intraorbital optic nerve transection in mice
No full textThe effects of pinealectomy and of intraperitoneally administered melatonin on the retrograde degeneration of retinal ganglion cells (RGCs) were examined in a novel model of optic nerve (ON) transection in C57BL/6J mice. RGCs were prelabeled with the fluorescent tracer 1,1'-dioctadecyl-3,3,3',3'-tetramethyl indocarbocyanine perchlorate (Di-I), and the ON was cut inside the orbital cavity 7 days later. The degree of RGC injury was assessed by counting viable Di-I labeled RGCs in various locations of the retina. In unlesioned control eyes, a mean ganglion cell density of 1891 +/- 30/mm(2) (mean +/- S.E.M.) was determined. The cell density markedly declined at 14 days after axotomy (295 +/- 9 cells/mm(2); 15.6% of contralateral). Sham-pinealectomy did not influence the density of RGCs at 14 days after ON transection (382 +/- 37 cells/mm(2)). In pinealectomized animals, on the other hand, the RGC number was significantly reduced as compared with untreated and sham-pinealectomized animals (91 +/- 33 RGCs/mm(2)). The effect of pinealectomy was reversed after i.p. administration of melatonin (4 mg/kg bw bolus followed by continuous infusion of 8 mg/kg bw/day) (286 +/- 27 cells/mm(2)) In nonpinealectomized. animals., on the contrary, i.p. melatonin did not influence the RGC density (344 +/- 20 cells/mm(2)). The present results suggest that endogenous melatonin prevents the delayed degeneration of adult central nervous system (CNS) neurons in vivo, and that exogenous substitution of melatonin may be useful to protect injured neurons against cell death under conditions of melatonin deficiency, e.g. in the aged brain, when melatonin synthesis and secretion have decreased
The role of small extracellular vesicles in cerebral and myocardial ischemia-Molecular signals, treatment targets, and future clinical translation
No full textThe heart and the brain mutually interact with each other, forming a functional axis that is disturbed under conditions of ischemia. Stem cell-derived extracellular vesicles (EVs) show great potential for the treatment of ischemic stroke and myocardial infarction. Due to heart-brain interactions, therapeutic actions of EVs in the brain and the heart cannot be regarded in an isolated way. Effects in each of the two organs reciprocally influence the outcome of the other. Stem cell-derived EVs modulate a large number of signaling pathways in both tissues. Upon ischemia, EVs prevent delayed injury, promote angiogenesis, enhance parenchymal remodeling, and enable functional tissue recovery. The therapeutic effects greatly depend on EV cargos, among which are noncoding RNAs like microRNAs (miRNAs) and proteins, which modulate cell signaling in a differential way that not always corresponds to each other in the two tissues. Interestingly, the same miRNA or protein localized in EVs can modulate different signaling pathways in the ischemic heart and brain, which may have diverse consequences for disease outcomes. Paying careful attention to unveiling these underlying mechanisms may provide new insights into tissue remodeling processes and identify targets for ischemic stroke and myocardial infarction therapies. Some of these mechanisms are discussed in this concise review, and consequences for the clinical translation of EVs are presented
Extracellular Vesicles as Diagnostic Tool in Transient Ischemic Attack and Ischemic Stroke
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Opportunities and Limitations of Vascular Risk Factor Models in Studying Plasticity-Promoting and Restorative Ischemic Stroke Therapies
No full textMajor efforts are currently made promoting neuronal plasticity and brain remodeling in the postacute stroke phase. Experimental studies evaluating new stroke therapies are mostly performed in rodents, which compared to humans exhibit a short lifespan. These studies widely employ young, otherwise healthy, rodents that lack the vascular risk factors and comorbidities of stroke patients. These risk factors compromise postischemic neurological recovery and brain plasticity and in several contexts reduce the brain responsiveness to recovery-inducing plasticity-promoting treatments. By examining risk factor models, which have hitherto been used for studying experimentally induced ischemic stroke, this review outlines the possibilities and limitations of risk factor models in the evaluation of plasticity-promoting and restorative stroke treatments
Animal models of ischemic stroke and their impact on drug discovery
No full textIntroduction: Representing the leading cause of long-term disability, ischemic stroke urgently needs further research and drug development. This review summarizes current animal models of ischemic stroke that can be used for drug discovery.
Areas covered: Several reproducible models of permanent and transient focal cerebral ischemia have been established in a variety of animal species including rats and mice, in which a brain-supplying artery, often the middle cerebral artery, is occluded by mechanical devices including sutures, clips and hooks, pharmacological agents or delivery of blot clots. The authors review existing literature about these models, outlining their utility for evaluating acute and post-acute stroke treatments. Since stroke is an age-related disease that strongly affects humans with vascular risk factors and co-morbidities, the authors give focus to strategies replicating risk factors in ischemic stroke models. Furthermore, the authors present models of spontaneous stroke.
Expert opinion: It is important that animal models mimic clinical conditions in a reliable and clinically relevant way, so here, they should replicate the pathophysiology of human stroke, stroke-associated risk factors and doses, times and modes of drug treatment. We propose that risk factor models should more widely be used in early drug discovery, if possible already during the identification of treatment targets.No Full Tex
Role of sleep-disordered breathing and sleep-wake disturbances for stroke and stroke recovery.
Full text linkBACKGROUND
Sleep-disordered breathing (SDB) and sleep-wake disturbances (SWD) are highly prevalent in stroke patients. Recent studies suggest that they represent both a risk factor and a consequence of stroke and affect stroke recovery, outcome, and recurrence.
METHODS
Review of literature.
RESULTS
Several studies have proven SDB to represent an independent risk factor for stroke. Sleep studies in TIA and stroke patients are recommended in view of the very high prevalence (>50%) of SDB (Class IIb, level of evidence B). Treatment of obstructive SDB with continuous positive airway pressure is recommended given the strength of the increasing evidence in support of a positive effect on outcome (Class IIb, level of evidence B). Oxygen, biphasic positive airway pressure, and adaptive servoventilation may be considered in patients with central SDB. Recently, both reduced and increased sleep duration, as well as hypersomnia, insomnia, and restless legs syndrome (RLS), were also suggested to increase stroke risk. Mainly experimental studies found that SWD may in addition impair neuroplasticity processes and functional stroke recovery. Treatment of SWD with hypnotics and sedative antidepressants (insomnia), activating antidepressants or stimulants (hypersomnia), dopaminergic drugs (RLS), and clonazepam (parasomnias) are based on single case observations and should be used with caution.
CONCLUSIONS
SDB and SWD increase the risk of stroke in the general population and affect short- and long-term stroke recovery and outcome. Current knowledge supports the systematic implementation of clinical procedures for the diagnosis and treatment of poststroke SDB and SWD on stroke units
Immunological and non-immunological effects of stem cell-derived extracellular vesicles on the ischaemic brain
No full textFollowing the implementation of thrombolysis and endovascular recanalization strategies, stroke therapy has profoundly changed in recent years. In spite of these advancements, a considerable proportion of stroke patients still exhibit functional impairment in the long run, increasing the need for adjuvant therapies that promote neurological recovery. Stem cell therapies have initially attracted great interest in the stroke field, since there were hopes that transplanted cells may allow for the replacement of lost cells. After the recognition that transplanted cells integrate poorly into existing neural networks and that they induce brain remodelling in a paracrine way by secreting a heterogeneous group of nanovesicles, these extracellular vesicles (EVs) have been identified as key players that mediate restorative effects of stem and progenitor cells in ischaemic brain tissue. We herein review restorative effects of EVs in stroke models and discuss immunological and non-immunological mechanisms that may underlie recovery of function
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