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1.  Delayed administration of a small molecule TrkB ligand promotes recovery after hypoxic- ischemic stroke 
Background and Purpose
Stroke is the leading cause of long-term disability in the United States, yet no drugs are available that are proven to improve recovery. Brain-derived neurotrophic factor (BDNF) stimulates neurogenesis and plasticity, processes that are implicated in stroke recovery. It binds to both the tropomyosin-related kinase B (TrkB) and p75 neurotrophin (p75NTR) receptors. However, BDNF is not a feasible therapeutic agent, and no small molecule exists that can reproduce its binding to both receptors. We tested the hypothesis that a small molecule (LM22A-4) that selectively targets TrkB would promote neurogenesis and functional recovery after stroke.
Methods
Four-month-old mice were trained on motor tasks prior to stroke. After stroke, functional test results were used to randomize mice into two equally, and severely, impaired groups. Beginning 3 days after stroke, mice received LM22A-4 or saline vehicle daily for ten weeks.
Results
LM22A-4 treatment significantly improved limb swing speed and accelerated the return to normal gait accuracy after stroke. LM22A-4 treatment also doubled both the number of new mature neurons and immature neurons adjacent to the stroke. Drug-induced differences were not observed in angiogenesis, dendritic arborization, axonal sprouting, glial scar formation, or neuroinflammation.
Conclusion
A small molecule agonist of TrkB improves functional recovery from stroke and increases neurogenesis when administered beginning three days after stroke. These findings provide proof-of-concept that targeting of TrkB alone is capable of promoting one or more mechanisms relevant to stroke recovery. LM22A-4 or its derivatives might therefore serve as “pro-recovery” therapeutic agents for stroke.
doi:10.1161/STROKEAHA.111.641878
PMCID: PMC3383889  PMID: 22535263
Stroke recovery; neurotrophin; small molecule
2.  Distal Hypoxic stroke: A new mouse model of stroke with high throughput, low variability and a quantifiable functional deficit 
Journal of Neuroscience Methods  2012;207(1):31-40.
C57BL/6J are the most commonly used strain of mouse for stroke experiments but vascular anatomy of the Circle of Willis within this strain is extremely variable and the cortex has extensive collateralization. This causes large variability in stroke models that target the middle cerebral artery proximally and confers resistance to ischemia in those that target it distally. We tested the hypothesis that by combining distal middle cerebral artery occlusion with 1 hour of hypoxia, we could generate a large lesion that causes a behavioral deficit with low variability. We found that this new distal hypoxic (DH) model of stroke generates a lesion with a volume of 25% of the ipsilateral hemisphere, extends to the motor cortex and causes a behavioral deficit. It also has a very clear border, exceptionally low variability, and can be performed by a single surgeon on up to 30 animals a day. Moreover, survivability is 100% in young adult animals, the model can be performed on old animals, and therapeutic intervention can reduce infarct volume. Therefore DH stroke is an excellent complement to existing stroke models and could be used for preclinical studies in C57BL/6J mice.
doi:10.1016/j.jneumeth.2012.03.003
PMCID: PMC3348433  PMID: 22465679
New Mouse Stroke Model; Cerebral Ischemia; Hypoxia; Circle of Willis Variability
3.  Stratification substantially reduces behavioral variability in the hypoxic–ischemic stroke model 
Brain and Behavior  2012;2(5):698-706.
Stroke is the most common cause of long-term disability, and there are no known drug therapies to improve recovery after stroke. To understand how successful recovery occurs, dissect candidate molecular pathways, and test new therapies, there is a need for multiple distinct mouse stroke models, in which the parameters of recovery after stroke are well defined. Hypoxic–ischemic stroke is a well-established stroke model, but behavioral recovery in this model is not well described. We therefore examined a panel of behavioral tests to see whether they could be used to quantify functional recovery after hypoxic–ischemic stroke. We found that in C57BL/6J mice this stroke model produces high mortality (approximately one-third) and variable stroke sizes, but is fast and easy to perform on a large number of mice. Horizontal ladder test performance on day 1 after stroke was highly and reproducibly correlated with stroke size (P < 0.0001, R2 = 0.7652), and allowed for functional stratification of mice into a group with >18% foot faults and 2.1-fold larger strokes. This group exhibited significant functional deficits for as long as 3 weeks on the horizontal ladder test and through the last day of testing on automated gait analysis (33 days), rotarod (30 days), and elevated body swing test (EBST) (36 days). No deficits were observed in an automated activity chamber. We conclude that stratification by horizontal ladder test performance on day 1 identifies a subset of mice in which functional recovery from hypoxic–ischemic stroke can be studied.
doi:10.1002/brb3.77
PMCID: PMC3489820  PMID: 23139913
Behavior; hypoxic–ischemic stroke; motor recovery; mouse model
4.  Proof of concept: pharmacological preconditioning with a Toll-like receptor agonist protects against cerebrovascular injury in a primate model of stroke 
Cerebral ischemic injury is a significant portion of the burden of disease in developed countries; rates of mortality are high and the costs associated with morbidity are enormous. Recent therapeutic approaches have aimed at mitigating the extent of damage and/or promoting repair once injury has occurred. Often, patients at high risk of ischemic injury can be identified in advance and targeted for antecedent neuroprotective therapy. Agents that stimulate the innate pattern recognition receptor, Toll-like receptor 9, have been shown to induce tolerance (precondition) to ischemic brain injury in a mouse model of stroke. Here, we demonstrate for the first time that pharmacological preconditioning against cerebrovascular ischemic injury is also possible in a nonhuman primate model of stroke in the rhesus macaque. The model of stroke used is a minimally invasive transient vascular occlusion, resulting in brain damage that is primarily localized to the cortex and as such, represents a model with substantial clinical relevance. Finally, K-type (also referred to as B-type) cytosine-guanine-rich DNA oligonucleotides, the class of agents employed in this study, are currently in use in human clinical trials, underscoring the feasibility of this treatment in patients at risk of cerebral ischemia.
doi:10.1038/jcbfm.2011.6
PMCID: PMC3099644  PMID: 21285967
CpG ODN; ischemia; neuroprotection; nonhuman primate; stroke; Toll-like receptors
5.  TGFβ signaling in the brain increases with aging and signals to astrocytes and innate immune cells in the weeks after stroke 
Background
TGFβ is both neuroprotective and a key immune system modulator and is likely to be an important target for future stroke therapy. The precise function of increased TGF-β1 after stroke is unknown and its pleiotropic nature means that it may convey a neuroprotective signal, orchestrate glial scarring or function as an important immune system regulator. We therefore investigated the time course and cell-specificity of TGFβ signaling after stroke, and whether its signaling pattern is altered by gender and aging.
Methods
We performed distal middle cerebral artery occlusion strokes on 5 and 18 month old TGFβ reporter mice to get a readout of TGFβ responses after stroke in real time. To determine which cell type is the source of increased TGFβ production after stroke, brain sections were stained with an anti-TGFβ antibody, colocalized with markers for reactive astrocytes, neurons, and activated microglia. To determine which cells are responding to TGFβ after stroke, brain sections were double-labelled with anti-pSmad2, a marker of TGFβ signaling, and markers of neurons, oligodendrocytes, endothelial cells, astrocytes and microglia.
Results
TGFβ signaling increased 2 fold after stroke, beginning on day 1 and peaking on day 7. This pattern of increase was preserved in old animals and absolute TGFβ signaling in the brain increased with age. Activated microglia and macrophages were the predominant source of increased TGFβ after stroke and astrocytes and activated microglia and macrophages demonstrated dramatic upregulation of TGFβ signaling after stroke. TGFβ signaling in neurons and oligodendrocytes did not undergo marked changes.
Conclusions
We found that TGFβ signaling increases with age and that astrocytes and activated microglia and macrophages are the main cell types that undergo increased TGFβ signaling in response to post-stroke increases in TGFβ. Therefore increased TGFβ after stroke likely regulates glial scar formation and the immune response to stroke.
doi:10.1186/1742-2094-7-62
PMCID: PMC2958905  PMID: 20937129
6.  A New Model of Cortical Stroke in the Rhesus Macaque 
Primate models are essential tools for translational research in stroke, but are reportedly inconsistent in their ability to produce cortical infarcts of reproducible size. Here we report a new stroke model using a transorbital, reversible, two-vessel occlusion approach in male rhesus macaques that produces consistent and reproducible cortical infarcts. The right middle cerebral artery (MCA) (distal to the orbitofrontal branch), and both anterior cerebral arteries (ACA) were occluded with vascular clips. Bilateral occlusion of the ACA was critical for reducing collateral flow to the ipsilateral cortex. Reversible ischemia were induced for 45, 60, or 90 minutes (n=2/timepoint) and infarct volume and neurological outcome were evaluated. The infarcts were located predominantly in the cortex and increased in size with extended duration of ischemia determined by T2-weighted MRI. Infarct volume measured by 2,3,5-triphenyl tetrazolium chloride (TTC) and cresyl violet staining corroborated MRI results. Neurological deficit scores worsened gradually with longer occlusion times. A subset of animals (n=5) underwent 60 minutes of ischemia resulting in consistent infarct volumes primarily located to the cortex which correlated well with neurological deficit scores. This approach offers promise for evaluating therapeutic interventions in stroke.
doi:10.1038/jcbfm.2009.43
PMCID: PMC2828874  PMID: 19384334
Cerebral ischemia; MRI; Neurological deficit; Non-human primate; Rhesus macaque; Stroke
7.  Neuropharmacology – Special Issue on Cerebral Ischemia Mechanisms of Ischemic Brain Damage – Review Article 
Neuropharmacology  2008;55(3):310-318.
Each year in the United States approximately 700,000 individuals are afflicted with a stroke and currently there are almost 2 million survivors of stroke living in the US with prolonged disability. In China 1.5 million people die from stroke each year and in developed nations stroke is the third leading cause of death, only surpassed by heart disease and cancer. Brain injury following stroke results from the complex interplay of multiple pathways including excitotoxicity, acidotoxicity, ionic imbalance, oxidative/nitrative stress, inflammation, apoptosis and peri-infarct depolarization. Here, we discuss the underlying pathophysiology of this devastating disease and reveal the intertwined pathways that are the target of therapeutic intervention.
doi:10.1016/j.neuropharm.2008.01.005
PMCID: PMC2603601  PMID: 18308346

Results 1-7 (7)