0000000000331247
AUTHOR
Wolf-rüdiger Schäbitz
Different postischemic protein expression of the GABA_{A} receptor α2 subunit and the plasticity-associated protein MAP1B after treatment with BDNF versus G-CSF in the rat brain
Purpose Recent data indicate that both brain-derived neurotrophic factor (BDNF) and granulocyte-colony stimulating factor (G-CSF) exert substantial neuroregenerative effects and improve functional outcome after ischemic stroke. In the present study, we checked for potential differences in the postischemic modulation of various excitatory and inhibitory neurotransmitter receptors as well as various marker molecules for structural plasticity by BDNF versus G-CSF. Methods Adult male Wistar rats were subjected to photothrombotic ischemia and subsequently treated with NaCl, BDNF or G-CSF, respectively. After 6 weeks, postischemic protein expression of the NR1, GluR1 and alpha2 subunit of the NMD…
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…
Semaphorin 6A Improves Functional Recovery in Conjunction with Motor Training after Cerebral Ischemia
Stroke is a major health problem in industrialized societies. Despite numerous attempts at developing acute stroke therapies aimed at minimizing acute infarct development, the only approved therapy so far is recombinant tissue plasminogen activator (rtPA). In recent years, the attention of the stroke community has therefore also put increased emphasis on understanding processes of post-stroke recovery, and their potential exploitability for therapeutic purposes. The brain has a remarkable ability to adapt to changes after stroke. Mechanisms that contribute to this plasticity are re-mapping and expansion of cortical areas to neighboring regions of functional motor cortex areas after injury […
Principles and requirements for stroke recovery science
The disappointing results in bench-to-bedside translation of neuroprotective strategies caused a certain shift in stroke research towards enhancing the endogenous recovery potential of the brain. One reason for this focus on recovery is the much wider time window for therapeutic interventions which is open for at least several months. Since recently two large clinical studies using d-amphetamine or fluoxetine, respectively, to enhance post-stroke neurological outcome failed again it is a good time for a critical reflection on principles and requirements for stroke recovery science. In principal, stroke recovery science deals with all events from the molecular up to the functional and behav…
A new model of thromboembolic stroke in the posterior circulation of the rat
The prognosis of vertebrobasilar occlusion is grave and therapeutic options are limited. The aim of the present study was to develop a new model of embolic hindbrain ischemia in the rat that closely resembles the clinical situation and that can be used to study pathophysiology and treatment options. After thoracotomy in 20 male Wistar rats, 15 animals received an injection of in vitro prepared autologous blood clots into the left vertebral artery. Five animals without clot injection served as controls. Neurological deficits were assessed in all animals 2 h after embolism. After 2 h, five animals were sacrificed to measure cerebral blood flow (CBF) by iodo-antipyridine autoradiography, and t…
Fostering Poststroke Recovery: Towards Combination Treatments.
Despite countless experimental studies demonstrating neuroprotective effects in the treatment of acute ischemic stroke, they all could not live up their promises when it came to translation into patients. Recent research therefore increasingly shifted to therapies enhancing poststroke recovery with the important advantage of a much wider time window up to several months. To further increase poststroke recovery, the combination of different therapy principles is a logical step. However, several burning questions concerning the modus of combination are unresolved. This review will briefly mention the principle poststroke recovery approaches and discuss the mostly used combination designs. In …
Long-term gene expression changes in the cortex following cortical ischemia revealed by transcriptional profiling
Cerebral ischemia evokes changes in gene expression time-dependently after the ischemic event. Most studies on transcriptional changes following ischemia have centered on relatively early postischemic time points, and detected multiple genes relevant to neuronal cell death. However, functional outcome after ischemia depends critically on adaptations of the postischemic brain. Plasticity may derive from network-inherent changes, or from the formation of new nerve cells in the CNS. We have screened for gene expression changes up to 3 weeks following a limited photothrombotic cortical insult in the rat sensorimotor cortex by using the sensitive restriction-mediated differential display (RMDD) …
Endocannabinoids mediate neuroprotection after transient focal cerebral ischemia.
The endocannabinoids anandamide (AEA) and palmitoylethanolamide (PEA) act as endogenous protective factors of the brain, using different pathways of neuroprotection against neuronal damage. Although several in vivo and in vitro studies confirmed the neuroprotective efficacy of endocannabinoids, no experimental settings compare and explore the neuroprotective potential of AEA and PEA in an acute stroke model. In this study, we investigated the neuroprotective potential by infarct measurement after high (30 mg/kg body weight) and low dosage administration (10 mg/kg body weight) of the endocannabinoid PEA in 49 male Wistar rats. In additions we studied infarct volumes of 22 male Wistar rats re…
Meta-analysis of the efficacy of different training strategies in animal models of ischemic stroke.
Background and Purpose— Although several studies have shown beneficial effects of training in animal stroke models, the most effective training strategy and the optimal time to initiate training have not been identified. The present meta-analysis was performed to compare the efficacy of different training strategies and to determine the optimal time window for training in animal stroke models. Methods— We searched the literature for studies analyzing the efficacy of training in animal models of ischemic stroke. Training was categorized into forced physical training, voluntary physical training, constraint-induced movement therapy, and skilled reaching training. Two reviewers independently …