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1.  Functional recovery in aging mice after experimental stroke 
Brain, behavior, and immunity  2011;25(8):1689-1700.
Aging is a non modifiable risk factor for stroke. Since not all strokes can be prevented, a major emerging area of research is the development of effective strategies to enhance functional recovery after stroke. However, in the vast majority of pre-clinical stroke studies, the behavioral tests used to assess functional recovery have only been validated for use in young animals, or are designed for rats. Mice are increasingly utilized in stroke models but well validated behavioral tests designed for rats are not necessarily reproducible in mice. We examined a battery of behavioral tests to evaluate functional recovery in an aging murine model of stroke. We found that the vertical pole, hanging wire and open field can accurately assess acute behavioral impairments after stroke in both young and aging male mice, but animals recover rapidly on these tasks. The corner test can accurately and repeatedly differentiate stroke from sham animals up to 30 days post stroke and can be performed reliably in aging mice. Aging male mice had significantly worse behavioral impairment compared to young male mice in the first two weeks after stroke but eventually recovered to the same degree as young mice. In contrast, chronic infarct size, as measured by ipsilateral cerebral atrophy, was significantly lower in aging male mice compared to young male mice. Reactive gliosis, formation of glial scar, and an enhanced innate immune response was seen in the aging brain and may contribute to the delayed behavioral recovery seen in aged animals.
PMCID: PMC3191237  PMID: 21756996
Cerebral ischemia; Aging; Functional recovery; Cerebral blood flow (CBF); Cerebral atrophy; Microglia; Glial scar; Astrocytes; GFAP (glial fibrillary acid protein); Iba1
2.  Constraint-Induced Movement Therapy for Rehabilitation of Arm Dysfunction After Stroke in Adults 
Executive Summary
The purpose of this evidence-based analysis is to determine the effectiveness and cost of CIMT for persons with arm dysfunction after a stroke.
Clinical Need: Condition and Target Population
A stroke is a sudden loss of brain function caused by the interruption of blood flow to the brain (ischemic stroke) or the rupture of blood vessels in the brain (hemorrhagic stroke). A stroke can affect any number of areas including the ability to move, see, remember, speak, reason, and read and write. Stroke is the leading cause of adult neurological disability in Canada; 300,000 people or 1% of the population live with its effects. Up to 85% of persons experiencing a complete stroke have residual arm dysfunction which will interfere with their ability to live independently. Rehabilitation interventions are the cornerstone of care and recovery after a stroke.
Constraint-Induced Movement Therapy
Constraint-Induced Movement (CIMT) is a behavioural approach to neurorehabilitation based on the principle of ‘learned non-use’. The term is derived from studies in nonhuman primates in which somatosensory deafferentation of a single forelimb was performed and after which the animal then failed to use that limb. This failure to use the limb was deemed ‘learned non-use’. The major components of CIMT include: i) intense repetitive task-oriented training of the impaired limb ii) immobilization of the unimpaired arm, and iii) shaping. With regard to the first component, persons may train the affected arm for several hours a day for up to 10-15 consecutive days. With immobilization, the unaffected arm may be restrained for up to 90% of waking hours. And finally, with shaping, the difficulty of the training tasks is progressively increased as performance improves and encouraging feedback is provided immediately when small gains are achieved.
Research Question
What is the effectiveness and cost of CIMT compared with physiotherapy and/or occupational therapy rehabilitative care for the treatment of arm dysfunction after stroke in persons 18 years of age and older?
Research Methods
Literature Search
Search Strategy
A literature search was performed on January 21, 2011 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and the Cochrane Library, Centre for Reviews and Dissemination. (Appendix 1) A preliminary search completed in August 2010 found a Cochrane Systematic review published in 2009. As a result, the literature search for this evidence-based analysis was designed to include studies published from January 1, 2008 to January 21, 2011.
Inclusion Criteria
Systematic reviews of randomized controlled trials with or without meta-analysis.
Study participants 18 years of age and older with arm dysfunction after stroke.
Studies comparing the use of CIMT with occupational therapy and/or physiotherapy rehabilitative care (usual care) to improve arm function.
Studies which described CIMT as having the following three components: i) restraining unimpaired arm and/or wrist with a sling, hand splint or cast; ii) intensive training with functional task practice of the affected arm; iii) application of shaping methodology during training. No restriction was placed on intensity or duration of treatment otherwise.
Duration and intensity of therapy is equal in treatment and control groups.
Therapy beginning a minimum of one month after stroke.
Published between 2008 and 2011.
Exclusion Criteria
Narrative reviews, case series, case reports, controlled clinical trials.
Letters to the editor
Grey literature.
Non-English language publications.
Outcomes of Interest
Primary Outcome
Arm motor function: Action Research Arm Test (ARAT)
Secondary Outcome
Arm motor impairment: Fugl-Meyer Motor Assessment (FMA)
Activities of daily living (ADL): Functional Independence Measure (FIM), Chedoke Arm and Hand Inventory
Perceived motor function: Motor Activity Log (MAL) Amount of Use (AOU) and Quality of Movement (QOM) scales
Quality of Life: Stroke Impact Scale (SIS)
Summary of Findings
A significant difference was found in our primary outcome of arm motor function measured with the Action Research Arm Test in favour of CIMT compared with usual care delivered with the same intensity and duration. Significant differences were also found in three of the five secondary outcome measures including Arm Motor Impairment and Perceived Motor Function Amount of Use and Quality of Use. There was a nonsignificant effect found with the FIM score and the quality of life Stroke Impact Scale outcome measure. The nonsignificant effect found with the scale score and the quality of life score may be a factor of a nonresponsive outcome measure (FIM scale) and/or a type II statistical error from an inadequate sample size. The quality of evidence was moderate for arm motor function and low for all other outcome measures except quality of life, which was very low.
Summary of Results*
CI, Confidence Intervals; n, Sample Size
PMCID: PMC3377570  PMID: 23074418
3.  Long-term behavioral assessment of function in an experimental model for ischemic stroke 
Journal of neuroscience methods  2011;196(2):247-257.
Middle cerebral artery occlusion (MCAO) in rats is a well-studied experimental model for ischemic stroke leading to brain infarction and functional deficits. Many preclinical studies have focused on a small time window after the ischemic episode to evaluate functional outcome for screening therapeutic candidates. Short evaluation periods following injury have led to significant setbacks due to lack of information on the delayed effects of treatments, as well as short-lived and reversible neuroprotection, so called false-positive results. In this report, we evaluated long-term functional deficit for 90 days after MCAO in two rat strains with two durations of ischemic insult, in order to identify the best experimental paradigm to assess injury and subsequent recovery. Behavioral outcomes were measured pre-MCAO followed by weekly assessment post-stroke. Behavioral tests included the 18-point composite neurological score, 28-point neuroscore, rearing test, vibrissae-evoked forelimb placing test, foot fault test and the CatWalk. Brain lesions were assessed to correlate injury to behavior outcomes at the end of study. Our results indicate that infarction volume in Sprague-Dawley rats was dependent on occlusion duration. In contrast, the infarction volume in Wistar rats did not correlate with the duration of ischemic episode. Functional outcomes were not dependent on occlusion time in either strain; however, measureable deficits were detectable long-term in limb asymmetry, 18- and 28-point neuroscores, forelimb placing, paw swing speed, and gait coordination. In conclusion, these behavioral assays, in combination with an extended long-term assessment period, can be used for evaluating therapeutic candidates in preclinical models of ischemic stroke.
PMCID: PMC3539723  PMID: 21256866
Ischemic stroke; CatWalk; long-term functional recovery; middle cerebral artery occlusion; rat strain
4.  Motor Imagery After Stroke 
Annals of neurology  2009;66(5):604-616.
Neuroplasticity is essential for recovery after stroke and is the target for new stroke therapies. During recovery from subcortical motor stroke, brain activations associated with movement may appear normal despite residual functional impairment. This raises an important question: how far does recovery of motor performance depend on the processes that precede movement execution involving the premotor and prefrontal cortex, rather than recovery of the corticospinal system alone?
We examined stroke patients with functional magnetic resonance imaging while they either imagined or executed a finger-thumb opposition sequence. In addition to classical analyses of regional activations, we studied neuroplasticity in terms of differential network connectivity using structural equation modeling. The study included 8 right-handed patients who had suffered a left-hemisphere subcortical ischemic stroke with paresis, and 13 age-matched healthy controls.
With good functional recovery, the regional activations had returned to normal in patients. However, connectivity within the extended motor network remained abnormal. These abnormalities were seen predominantly during motor imagery and correlated with motor performance.
Our results indicate that neuroplasticity can manifest itself as differences in connectivity among cortical areas remote from the infarct, rather than in the degree of regional activation. Connection strengths between nodes of the cortical motor network correlate with motor outcome. The altered organization of connectivity of the prefrontal areas may reflect the role of the prefrontal cortex in higher order planning of movement. Our results are relevant to the assessment and understanding of emerging physical and neurophysiological therapies for stroke rehabilitation.
PMCID: PMC3791355  PMID: 19938103
5.  Blood Biomarkers of Ischemic Stroke 
Neurotherapeutics  2011;8(3):349-360.
This review provides a summary of the protein and RNA biomarkers that have been studied for the diagnosis and assessment of ischemic stroke. Many of the biomarkers identified relate to the pathophysiology of ischemic stroke, including ischemia of CNS tissue, acute thrombosis and inflammatory response. These biomarkers are summarized by their intended clinical application in ischemic stroke including diagnosis, prediction of stroke severity and outcome, and stratification of patients for stroke therapy. Among the biomarkers discussed are recent whole genome studies using RNA expression profiles to diagnose ischemic stroke and stroke etiology. Though many candidate blood based biomarkers for ischemic stroke have been identified, none are currently used in clinical practice. With further well designed study and careful validation, the development of blood biomarkers to improve the care of patients with ischemic stroke may be achieved.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-011-0050-4) contains supplementary material, which is available to authorized users.
PMCID: PMC3250275  PMID: 21671123
Ischemic stroke; Biomarker
6.  Delayed Treatment with a Novel Neurotrophic Compound Reduces Behavioral Deficits in Rabbit Ischemic Stroke 
Journal of neurochemistry  2010;116(1):122-131.
Acute ischemic stroke is a major risk for morbidity and mortality in our aging population. Currently only one drug, the thrombolytic tissue plasminogen activator, is approved by the FDA to treat stroke. Therefore, there is a need to develop novel drugs that promote neuronal survival following stroke. We have synthesized a novel neuroprotective molecule called CNB-001 that has neurotrophic activity, enhances memory, and blocks cell death in multiple toxicity assays related to ischemic stroke. In this study, we tested the efficacy of CNB-001 in a rigorous rabbit ischemic stroke model and determined the molecular basis of its in vivo activity. CNB-001 has substantial beneficial properties in an in vitro ischemia assay and improves the behavioral outcome of rabbit ischemic stroke even when administered 1 h after the insult, a therapeutic window in this model comparable to tissue plasminogen activator. In addition, we elucidated the protein kinase pathways involved in neuroprotection. CNB-001 maintains the calcium-calmodulin-dependent kinase signaling pathways associated with neurotrophic growth factors that are critical for the maintenance of neuronal function. On the basis of its in vivo efficacy and novel mode of action, we conclude that CNB-001 has a great potential for the treatment of ischemic stroke as well as other CNS pathologies.
PMCID: PMC3004475  PMID: 21054387
ischemia; trophic factor; neuroprotection; models; drugs; protein kinases
7.  Association of inflammatory gene polymorphisms with ischemic stroke in a Chinese Han population 
Inflammatory mechanisms are important in stroke risk, and genetic variations in components of the inflammatory response have been implicated as risk factors for stroke. We tested the inflammatory gene polymorphisms and their association with ischemic stroke in a Chinese Han population.
A total of 1,124 ischemic stroke cases and 1,163 controls were genotyped with inflammatory panel strips containing 51 selected inflammatory gene polymorphisms from 35 candidate genes. We tested the genotype-stroke association with logistic regression model.
We found two single nucleotide polymorphisms (SNPs) in CCL11 were associated with ischemic stroke. After adjusting for multiple testing using false discovery rate (FDR) with a 0.20 cut-off point, CCL11 rs4795895 remained statistically significant. We further stratified the study population by their hypertension status. In the hypertensive group, CCR2 rs1799864, CCR5 rs1799987 and CCL11 rs4795895 were nominally associated with increased risk of stroke. In the non-hypertensive group, CCL11 rs3744508, LTC4S rs730012, FCER1B rs569108, TGFB1 rs1800469, LTA rs909253 and CCL11 rs4795895 were associated with ischemic stroke. After correction for multiple testing, CCR2 rs1799864 and CCR5 rs1799987 remained significant in the hypertensive group, and CCL11 rs3744508, LTC4S rs730012, FCER1B rs569108, TGFB1 rs1800469, LTA rs909253 remained significant in the non-hypertensive group.
Our results indicate that inflammatory genetic variants are associated with increased risk of ischemic stroke in a Chinese Han population, particularly in non-hypertensive individuals.
PMCID: PMC3464807  PMID: 22769019
Association study; Hypertension; Inflammatory gene; Ischemic stroke
8.  Intracarotid administration of human bone marrow mononuclear cells in rat photothrombotic ischemia 
Increasing evidence suggests that cell therapy improves functional recovery in experimental models of stroke and myocardial infarction. So far only small pilot trials tested the effects of cell therapy in stroke patients, whereas large clinical trials were conducted in patients with ischemic heart disease. To investigate the therapeutic benefit of cell therapy to improve the recovery after stroke, we determined the efficacy of bone marrow derived mononuclear cells, which were shown to improve the recovery in experimental and clinical acute myocardial infarction studies, in a rat stroke model.
Adult male Wistar rats were randomly assigned to receive either five million human bone marrow mononuclear cells (hBMC) or placebo intraarterially 3 days after photothrombotic ischemia. For immunosuppression the animals received daily injections of cyclosporine throughout the experiment, commencing 24 hours before the cell transplantation. A battery of behavioral tests was performed before and up to 4 weeks after ischemia.
Body temperature and body weight revealed no difference between groups. Neurological deficits measured by the Rotarod test, the adhesive-removal test and the cylinder test were not improved by hBMC transplantation compared to placebo.
This study demonstrates that hBMC do not improve functional recovery when transplanted intraaterially 3 days after the onset of focal cerebral ischemia. A possible reason for the failed neurological improvement after cell therapy might be the delayed treatment initiation compared to other experimental stroke studies that showed efficacy of bone marrow mononuclear cells.
PMCID: PMC2828442  PMID: 20298535
9.  Post-Stroke Inhibition of Induced NADPH Oxidase Type 4 Prevents Oxidative Stress and Neurodegeneration 
PLoS Biology  2010;8(9):e1000479.
The identification of NOX4 as a major source of oxidative stress in stroke and demonstration of dramatic protection after stroke in mice by NOX4 deletion or NOX inhibition, opens up new avenues for treatment.
Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox4−/−) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox4−/− mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy.
Author Summary
Stroke is the second leading cause of death worldwide. Today, only one approved therapy exists—a drug that breaks down blood clots—the effectiveness of which is moderate, and it can only be used in about 10% of patients because of contraindications. New therapeutic strategies that are translatable to humans and more rigid thresholds of relevance in pre-clinical stroke models are needed. One candidate mechanism is oxidative stress, which is the damage caused by reactive oxygen species (ROS). Antioxidant approaches that specifically target ROS have thus far failed in clinical trials. For a more effective approach, we focus here on targeting ROS at its source by investigating an enzyme involved in generating ROS, known as NADPH oxidase type 4, or NOX4. We found that NOX4 causes oxidative stress and death of nerve cells after a stroke. Deletion of the NOX4-coding gene in mice, as well as inhibiting the ROS-generating activity of NOX with a pharmacological inhibitor, reduces brain damage and improves neurological function, even when given hours after a stroke. Importantly, neuroprotection was preserved in old male and female Nox4−/− mice as well as in Nox4−/− mice subjected to permanent ischemia. NOX4 thus represents a most promising new therapeutic target for reducing oxidative stress in general, and in brain injury due to stroke in particular.
PMCID: PMC2943442  PMID: 20877715
10.  Role of stress-inducible protein-1 in recruitment of bone marrow derived cells into the ischemic brains 
EMBO Molecular Medicine  2013;5(8):1227-1246.
Stress-inducible protein-1 (STI-1) is the proposed ligand for the cellular prion protein (PrPC), which is thought to facilitate recovery following stroke. Whether STI-1 expression is affected by stroke and how its signalling facilitates recovery remain elusive. Brain slices from patients that died of ischemic stroke were collected for STI-1 immunohistochemistry. These findings were compared to results from cell cultures, mice with or without the PrPC knockout, and rats. Based on these findings, molecular and pharmacological interventions were administered to investigate the underlying mechanisms and to test the possibility for therapy in experimental stroke models. STI-1 was upregulated in the ischemic brains from humans and rodents. The increase in STI-1 expression in vivo was not cell-type specific, as it was found in neurons, glia and endothelial cells. Likewise, this increase in STI-1 expression can be mimicked by sublethal hypoxia in primary cortical cultures (PCCs) in vitro, and appear to have resulted from the direct binding of the hypoxia inducible factor-1α (HIF-1α) to the STI-1 promoter. Importantly, this STI-1 signalling promoted bone marrow derived cells (BMDCs) proliferation and migration in vitro and recruitment to the ischemic brain in vivo, and augmenting its signalling facilitated neurological recovery in part by recruiting BMDCs to the ischemic brain. Our results thus identified a novel mechanism by which ischemic insults can trigger a self-protective mechanism to facilitate recovery.
This work identifies HIF-1α-mediated transcription of STI-1 and PrPc interaction as leading to BMDCs recruitment into ischemic brains following stroke in both patients and animal models of stroke, highlighting novel neuroprotective possibilities.
PMCID: PMC3944463  PMID: 23836498
bone marrow derived cells (BMDCs); cell trafficking; hypoxia inducible factor 1α (HIF-1α); stress inducible protein type 1 (STI-1); stroke
11.  Stress-induced glucocorticoid receptor activation determines functional recovery following ischemic stroke 
A major consequence of stroke is permanent motor disturbance, such as postural imbalance and loss of skilled movement. The degree of neuronal and functional loss and subsequent recovery after stroke is influenced by hypothalamic-pituitary-adrenal axis activation and the response to glucocorticoid hormones. This study investigated if recovery after stroke is related to glucocorticoid receptor (GR) activation in a rat model of stroke.
Adult male rats were pre-trained and tested in a skilled reaching task and received a focal ischemic motor cortex lesion. One group of animals received daily restraint stress starting one week pre-lesion up to three weeks post-lesion. Immuno-histochemical analysis of GR expression was performed to determine receptor activation.
Stress reduced reaching success in naïve animals and diminished recovery of limb use. Exaggerated functional loss in stressed rats was related to increased GR activation in the lesion hemisphere as indicated by nuclear GR location.
These findings provide a mechanistic link between stress-induced motor disability and GR activation in a rat model of stroke. The elevated receptor activation proposes synergistic effects of stress and stroke to modulate the impact of glucocorticoids on motor system function at the genomic level. The modulation of GR biosynthesis may alter responsiveness to stroke treatment and compromise recovery.
PMCID: PMC2954925  PMID: 20858282
Future neurology  2013;8(2):193-203.
Stem cell therapy for adult stroke has reached limited clinical trials. Here, we provide translational research guidance on stem cell therapy for neonatal hypoxic-ischemic brain injury requiring a careful consideration of clinically relevant animal models, feasible stem cell sources, and validated safety and efficacy endpoint assays, as well as a general understanding of modes of action of this cellular therapy. To this end, we refer to existing translational guidelines, in particular the recommendations outlined in the consortium of academicians, industry partners and regulators called Stem cell Therapeutics as an Emerging Paradigm for Stroke or STEPS. Although the STEPS guidelines are directed at enhancing the successful outcome of cell therapy in adult stroke, we highlight overlapping pathologies between adult stroke and neonatal hypoxic-ischemic brain injury. We are, however, cognizant that the neonatal hypoxic-ischemic brain injury displays disease symptoms distinct from adult stroke in need of an innovative translational approach that facilitates the entry of cell therapy in the clinic. Finally, insights into combination therapy are provided with the vision that stem cell therapy may benefit from available treatments, such as hypothermia, already being tested in children diagnosed with hypoxic-ischemic brain injury.
PMCID: PMC3615569  PMID: 23565051
cerebral palsy; stem cells; hypothermia; neurorestoration; translational; consortium; combination therapy
13.  Neurological Disorders in a Murine Model of Chronic Renal Failure 
Toxins  2014;6(1):180-193.
Cardiovascular disease is highly prevalent in patients with chronic renal failure (CRF). However, data on the impact of CRF on the cerebral circulatory system are scarce—despite the fact that stroke is the third most common cause of cardiovascular death in people with CRF. In the present study, we examined the impact of CRF on behavior (anxiety), recognition and ischemic stroke severity in a well-defined murine model of CRF. We did not observe any significant increases between CRF mice and non-CRF mice in terms of anxiety. In contrast, CRF mice showed lower levels of anxiety in some tests. Recognition was not impaired (vs. controls) after 6 weeks of CRF but was impaired after 10 weeks of CRF. Chronic renal failure enhances the severity of ischemic stroke, as evaluated by the infarct volume size in CRF mice after 34 weeks of CRF. Furthermore, neurological test results in non-CRF mice tended to improve in the days following ischemic stroke, whereas the results in CRF mice tended to worsen. In conclusion, we showed that a murine model of CRF is suitable for evaluating uremic toxicity and the associated neurological disorders. Our data confirm the role of uremic toxicity in the genesis of neurological abnormalities (other than anxiety).
PMCID: PMC3920256  PMID: 24394639
ischemic stroke; chronic renal failure; recognition; anxiety
14.  Enhanced Neurogenesis and Cell Migration following Focal Ischemia and Peripheral Stimulation in Mice 
Developmental neurobiology  2008;68(13):1474-1486.
Peripheral stimulation and physical therapy can promote neurovascular plasticity and functional recovery after CNS disorders such as ischemic stroke. Using a rodent model of whisker-barrel cortex stroke, we have previously demonstrated that whisker activity promotes angiogenesis in the penumbra of the ischemic barrel cortex. This study explored the potential of increased peripheral activity to promote neurogenesis and neural progenitor migration toward the ischemic barrel cortex.
Three days after focal barrel cortex ischemia in adult mice, whiskers were manually stimulated (15 min × 3 times/day) to enhance afferent signals to the ischemic barrel cortex. 5-bromo-2′-deoxyuridine (BrdU, i.p.) was administered once daily to label newborn cells. At 14 days after stroke, whisker stimulation significantly increased vascular endothelial growth factor (VEGF) and stromal derived factor-1 (SDF-1) expression in the penumbra. The whisker stimulation animals showed increased doublecortin (DCX) positive and DCX/BrdU-positive cells in the ipsilateral corpus of the white matter but no increase in BrdU-positive cells in the subventricular zone, suggesting a selective effect on neuroblast migration. Neurogenesis indicated by neuronal nuclear protein (NeuN) and BrdU double staining was also enhanced by whisker stimulation in the penumbra at 30 days after stroke. Local cerebral blood flow was better recovered in mice that received whisker stimulation. It is suggested that the enriched microenvironment created by specific peripheral stimulation increases regenerative responses in the post-ischemic brain and may benefit long-term functional recovery from ischemic stroke.
PMCID: PMC2756802  PMID: 18777565
Neurogenesis; Ischemic stroke; Barrel cortex; Whisker stimulation; Cell migration
15.  Stem Cell Mediation of Functional Recovery after Stroke in the Rat 
PLoS ONE  2010;5(9):e12779.
Regenerative strategies of stem cell grafting have been demonstrated to be effective in animal models of stroke. In those studies, the effectiveness of stem cells promoting functional recovery was assessed by behavioral testing. These behavioral studies do, however, not provide access to the understanding of the mechanisms underlying the observed functional outcome improvement.
Methodology/Principal Findings
In order to address the underlying mechanisms of stem cell mediated functional improvement, this functional improvement after stroke in the rat was investigated for six months after stroke by use of fMRI, somatosensory evoked potentials by electrophysiology, and sensorimotor behavior testing. Stem cells were grafted ipsilateral to the ischemic lesion. Rigorous exclusion of spontaneous recovery as confounding factor permitted to observe graft-related functional improvement beginning after 7 weeks and continuously increasing during the 6-month observation period. The major findings were i) functional improvement causally related to the stem cells grafting; ii) tissue replacement can be excluded as dominant factor for stem cell mediated functional improvement; iii) functional improvement occurs by exclusive restitution of the function in the original representation field, without clear contributions from reorganization processes, and iv) stem cells were not detectable any longer after six months.
A delayed functional improvement due to stem cell implantation has been documented by electrophysiology, fMRI and behavioral testing. This functional improvement occurred without cells acting as a tissue replacement for the necrotic tissue after the ischemic event. Combination of disappearance of grafted cells after six months on histological sections with persistent functional recovery was interpreted as paracrine effects by the grafted stem cells being the dominant mechanism of cell activity underlying the observed functional restitution of the original activation sites. Future studies will have to investigate whether the stem cell mediated improvement reactivates the original representation target field by using original connectivity pathways or by generating/activating new ones for the stimulus.
PMCID: PMC2943902  PMID: 20877642
16.  Effects of Fast Functional Electrical Stimulation Gait Training on Mechanical Recovery in Post-Stroke Gait 
Artificial organs  2011;35(3):217-220.
Stroke leads to gait impairments that can negatively influence quality of life. Functional electrical stimulation (FES) applied during fast walking is an effective gait rehabilitation strategy that can lead to improvements in gait performance, walking speed and endurance, balance, activity, and participation post-stroke. The effect of FastFES gait training on mechanical energy utilization is not well understood. The objective of this study was to test the effects of 12-weeks of FastFES gait training on mechanical recovery indices of post-stroke gait. Kinematic data were collected from 11 stroke survivors before and after 12-weeks of FastFES training. Mechanical recovery was calculated from the positive changes in vertical, anterior-posterior, and medial-lateral components of COM energy. The average mechanical recovery increased from 34.5% before training to 40.0% after training. The increase was statistically significant (p=.014). The average self-selected walking speed increased from 0.4m/s to 0.7m/s after the 12-week FastFES training. The results indicate that the subjects were better able to generate and utilize the external mechanical energy of walking after FastFES gait training. FastFES gait training has the capacity to increase the gait speed, improve the mechanical recovery, and reduce the mechanical energy expenditure of stroke survivors when they walk.
PMCID: PMC3081781  PMID: 21401663
Functional electrical stimulation; stroke; gait; mechanical recovery; training
17.  Estrogen enhances neurogenesis and behavioral recovery after stroke 
Stroke is a leading cause of permanent disability and death. It is well accepted that the principal mammalian estrogen (E2), 17-β estradiol, provides robust neuroprotection in a variety of brain injury models in animals of both sexes. E2 enhances neurogenesis after stroke in the subventricular zone; however, it is unknown if these cells survive long-term or enhance functional recovery. In this study, we examined stroke-induced neurogenesis in male, gonadally intact female, and ovariectomized female mice 2 and 6 weeks after stroke. Treatment with 17-β estradiol increased 5-bromo-2′-deoxyuridine-labeled cells at both time points in both the dentate gyrus and subventricular zone; the majority were colabeled with doublecortin at 2 weeks and with NeuN at 6 weeks. Stroke-induced neurogenesis was reduced in estrogen receptor knockout mice, as well as in mice lacking the gene for aromatase, which converts testosterone into E2. Improved behavioral deficits were seen in E2-treated mice, suggesting that E2-induced increases in poststroke neurogenesis contribute to poststroke recovery.
PMCID: PMC3049534  PMID: 20940729
aromatase; brain-derived neurotrophic factor; estrogen receptor; middle cerebral artery occlusion; neurogenesis
18.  Magnetic Resonance Imaging to Visualize Stroke and Characterize Stroke Recovery: A Review 
The global burden of stroke continues to grow. Although stroke prevention strategies (e.g., medications, diet, and exercise) can contribute to risk reduction, options for acute interventions (e.g., thrombolytic therapy for ischemic stroke) are limited to the minority of patients. The remaining patients are often left with profound neurological disabilities that substantially impact quality of life, economic productivity, and increase caregiver burden. In the last decade, however, the future outlook for such patients has been tempered by movement toward the view that the brain is capable of reorganizing after injury. Many now view brain recovery after stroke as an area of scientific research with large potential for therapeutic advances, far into the future (Broderick and William, 2004). As a probe of brain anatomy, function and physiology, magnetic resonance imaging (MRI) is a non-invasive and highly versatile modality that promises to play a particularly important role in such research. Here we provide a basic review of MRI physical principles and applications for assessing stroke, looking toward the future role MRI may play in improving stroke rehabilitation methods and stroke recovery.
PMCID: PMC3664317  PMID: 23750149
stroke; stroke recovery; magnetic resonance imaging; diffusion; perfusion; functional MRI; arterial spin labeling; review
19.  Experimental pediatric arterial ischemic stroke model reveals sex-specific estrogen signaling 
Background and Purpose
Pediatric stroke, birth-18 years, is a significant cause of long-term disability in the United States, however there is currently little experimental data on the pathophysiology of childhood stroke due to lack of animal models. We developed a novel mouse model of experimental childhood-onset arterial ischemic stroke (AIS) in order to characterize the sex-specific response of the adolescent brain to cerebral ischemia and assess the neuroprotective effect of estrogen at this developmental stage.
Postnatal day 20–25 (P20-25) mice were subjected to 90 minutes experimental stroke via the intraluminal filament middle cerebral artery occlusion (MCAO) model and ischemic damage assessed 22 hr after reperfusion. Real-time quantitative RT-PCR (qPCR) was performed 22 hr after MCAO to determine the effects of ischemia and estrogen treatment on the pro-apoptotic gene Bax.
Ischemic injury did not differ between male and female juvenile (P20-25) mice following MCAO. However, estrogen reduced ischemic injury in female mice, while having no effect in juvenile males. No differences in estrogen receptor expression was observed between P20 males and females. In contrast, estrogen minimized the ischemia-induced increase in the pro-apoptotic gene Bax in female mice, while having no effect on Bax induction in the male brain.
Focal ischemia has fundamentally different effects in the juvenile brain compared to the adult, as evidenced by the lack of gender difference in ischemic injury in the murine P20-25 MCAO model and the sexually dimorphic response to estrogen neuroprotection.
PMCID: PMC3930081  PMID: 23349190
childhood stroke; estrogen; cerebral ischemia; Bax, Bcl-2
20.  Increased Cerebral Matrix Metalloprotease -9 Activity is Associated with Compromised Recovery in the Diabetic db/db Mouse Following a Stroke 
Journal of neurochemistry  2011;119(5):1029-1040.
Diabetes is a major risk factor of stroke and is associated with increased frequency of stroke and a poorer prognosis for recovery. In earlier studies we have utilized Type 2 diabetic mouse models of stroke and demonstrated that diabetic db/db and ob/ob mice experience larger infarct volumes and impaired recovery associated with greater infiltration of macrophage following hypoxic-ischemic (H/I) insult than their heterozygous non-diabetic db/+ & ob/+ littermates. To obtain a better understanding of the pathogenesis of the impaired recovery, we have investigated the role of matrix metalloproteases and their endogenous inhibitors in the breakdown of the blood-brain barrier (BBB) following H/I. Diabetic db/db mice showed a significant and more rapid increase in MMP-9 mRNA, protein and gelatinolytic activity compared to db/+, which resulted in an increased degradation of occludin & collagen IV and subsequently an increased BBB permeability and greater infiltration of neutrophils into the infarct area. The expression of the MMPs, especially in the db/+ mice, is preceded by an elevated expression of their endogenous tissue inhibitors of metalloproteases (TIMPs) 1, 2, & 3, while in the db/db mice, a lower expression of the TIMPs is associated with greater MMP 3 & 9 expression. These results suggest that an imbalance in the MMPs/TIMPs cascade in the diabetic mouse, particularly MMP-9, results in a greater neutrophil invasion, a compromised BBB and consequently a greater insult.
PMCID: PMC3217107  PMID: 21923664
Stroke; Type 2 Diabetes; Metalloproteases; Tissue Inhibitors of Metalloproteases; Blood-Brain Barrier; Neutrophil
21.  Animal Models of Ischemic Stroke. Part One: Modeling Risk Factors 
Ischemic stroke is one of the leading causes of long-term disability and death in developed and developing countries. As emerging disease, stroke related mortality and morbidity is going to step up in the next decades. This is both due to the poor identification of risk factors and persistence of unhealthy habits, as well as to the aging of the population. To counteract the estimated increase in stroke incidence, it is of primary importance to identify risk factors, study their effects, to promote primary and secondary prevention, and to extend the therapeutic repertoire that is currently limited to the very first hours after stroke. While epidemiologic studies in the human population are essential to identify emerging risk factors, adequate animal models represent a fundamental tool to dissect stroke risk factors to their molecular mechanism and to find efficacious therapeutic strategies for this complex multi- factorial disorder. The present review is organized into two parts: the first part deals with the animal models that have been developed to study stroke and its related risk factors and the second part analyzes the specific stroke models. These models represent an indispensable tool to investigate the mechanisms of cerebral injury and to develop novel therapies.
PMCID: PMC2928914  PMID: 20802809
Aging; animal model; atherosclerosis; hypercholesterolemia; hyperhomocysteinemia; hypertension; ischemic stroke; risk factor.
22.  Human Adult Bone Marrow-Derived Somatic Cell Therapy Results in Functional Recovery and Axonal Plasticity Following Stroke in the Rat 
Experimental neurology  2008;211(2):588-592.
Stroke is the leading cause of adult disability in the United States. To date there is no satisfactory treatment for stroke once neuronal damage has occurred. Human adult bone marrow-derived somatic cells (hABM-SC) represent a homogenous population of CD49c/CD90 co-positive, non-hematopoietic cells that have been shown to secrete therapeutically relevant trophic factors and to support axonal growth in a rodent model of spinal cord injury. Here we demonstrate that treatment with hABM-SC after ischemic stroke in adult rats results in recovery of forelimb function on a skilled motor test, and that this recovery is positively correlated with increased axonal outgrowth of the intact, uninjured corticorubral tract. While the complete mechanism of repair is still unclear, we conclude that enhancement of structural neuroplasticity from uninjured brain areas is one mechanism by which hABM-SC treatment after stroke leads to functional recovery.
PMCID: PMC3932708  PMID: 18440506
23.  When right is all that's left: plasticity of right-hemisphere tracts in a young aphasic patient 
Using an adapted version of melodic intonation therapy (MIT), we treated an adolescent girl with a very large left-hemisphere lesion and severe nonfluent aphasia secondary to an ischemic stroke. At the time of her initial assessment 1.25 years after her stroke, she had reached a plateau in her recovery despite intense and long-term traditional speech-language therapy (approximately five times per week for more than one year). Following an intensive course of treatment with our adapted form of MIT, her performance improved on both trained and untrained phrases, as well as on speech and language tasks. These behavioral improvements were accompanied by functional MRI changes in the right frontal lobe as well as by an increased volume of white matter pathways in the right hemisphere. No increase in white matter volume was seen in her healthy twin sister, who was scanned twice over the same time period. This case study not only provides further evidence for MIT's effectiveness, but also indicates that intensive treatment can induce functional and structural changes in a right hemisphere fronto-temporal network.
PMCID: PMC3589758  PMID: 22524365
aphasia; melodic intonation therapy; brain plasticity; diffusion tensor imaging
24.  Acute hepatocyte growth factor treatment induces long-term neuroprotection and stroke recovery via mechanisms involving neural precursor cell proliferation and differentiation 
Hepatocyte growth factor (HGF) is an interesting candidate for acute stroke treatment as shown by continuous infusion or gene delivery protocols. However, little is known about HGF-mediated long-term effects. The present study therefore analyzed long-term effects of an acute intrastriatal HGF treatment (5 μg) after a 45-minute stroke, with regard to brain injury and neurologic recovery. Hepatocyte growth factor induced long-term neuroprotection as assessed by infarct volume and neuronal cell death analysis for as long as 4 weeks after stroke, which was associated with sustained neurologic recovery as evidenced by corner-turn and tight-rope tests. Analyzing underlying mechanisms of HGF-induced sustained neuroprotection, enhanced cell proliferation followed by increased neuronal differentiation of neural precursor cells (NPCs) was observed in the ischemic striatum of HGF-treated mice, which persisted for up to 4 weeks. In line with this, HGF promoted neurosphere formation as well as proliferation of NPC and decreased caspase-3-dependent hypoxic injury in vitro. Preservation of blood–brain barrier integrity 24 hours after stroke was furthermore noticed in animals receiving HGF, which was associated with the inhibition of matrix metalloproteases (MMP)-2 and MMP-9 at 4 and 24 hours, respectively. We suggest that sustained recruitment of proliferating cells together with improved neurovascular remodeling provides an explanation for HGF-induced long-term neuroprotection.
PMCID: PMC3099629  PMID: 21119693
cerebral ischemia; hepatocyte growth factor; matrix metalloproteases; neural precursor cells; neurogenesis; stroke
25.  Dialectics and Implications of Natural Neurotropic Autoantibodies in Neurological Disease and Rehabilitation 
The role of natural idiotypic (Id-Abs) and anti-idiotypic (AId-Abs) autoantibodies against neuro-antigens observed in different neurological disorders is not fully understood. In particular, limited experimental evidence has been provided concerning the qualitative and quantitative serological response after acute injuries of the central nervous system or during chronic mental diseases. In this study, we analyzed the specific Id-Abs and AId-Abs serological reactivities against 4 neuro-antigens in a large population of patients with ischemic stroke, schizophrenia, as well as healthy individuals. Patients with ischemic stroke were tested at different time points following the acute stroke episode and a correlation was attempted between autoantibodies response and different patterns of functional recovery. Results showed variable and detectable Id-Abs and AId-Abs in different proportions of all three populations of subjects. Among patients with different functional recovery after ischemic stroke, a difference in time-related trends of Id-Abs and AId-Abs was encountered. Our observations suggest that changes in the production of natural neurotropic Abs may engender a positive homeostatic, beside a possible pathogenic effect, in specific neurological disorders.
PMCID: PMC2270705  PMID: 15330451

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