In Vivo Animal Stroke Models

Tajiri, Naoki; Dailey, Travis; Metcalf, Christopher; Mosley, Yusef I.; Lau, Tsz; Staples, Meaghan; Loveren, Harry van; Kim, Seung Up; Yamashima, Tetsumori; Yasuhara, Takao; Date, Isao; Kaneko, Yuji; Borlongan, Cesario V.

doi:10.1007/s12975-012-0241-2

Cited by 45 publications

(34 citation statements)

References 123 publications

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“…G-CSFR, previously reported to be expressed on neurons, is also expressed on other cells of the neurovascular unit, supporting it as a promising therapeutic target (Leak et al, 2014). Combined with the limitations from the AX2000 clinical trial, this study warrants continued research on G-CSF treatment, possibly by using large animal models (Ramanantsoa et al, 2013; Tajiri et al, 2013) following the guidelines for effective translational research (Chen et al, 2014; Lapchak et al, 2013;), as well as examining G-CSF’s neuroprotective effects after ischemic brain injury in another clinical trial. Finally, future clinical trials should examine G-CSF’s effects after hypoxic ischemia in newborns.…”

Section: Discussionmentioning

confidence: 97%

G-CSF attenuates neuroinflammation and stabilizes the blood–brain barrier via the PI3K/Akt/GSK-3β signaling pathway following neonatal hypoxia-ischemia in rats

McBride

Doycheva

et al. 2015

Experimental Neurology

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Objective Neonatal hypoxia occurs in approximately 60% of premature births and is associated with a multitude of neurological disorders. While various treatments have been developed, translating them from bench to bedside has been limited. We previously showed G-CSF administration was neuroprotective in a neonatal hypoxia-ischemia rat pup model, leading us to hypothesize that G-CSF inactivation of GSK-3β via the PI3K/Akt pathway may attenuate neuroinflammation and stabilize the Blood-Brain Barrier (BBB). Methods P10 Sprague-Dawley rat pups were subjected to unilateral carotid artery ligation followed by hypoxia for 2.5 hours. We assessed inflammation by measuring expression levels of IKKβ, NF-κB, TNF-α, IL-1β, IL-10, and IL-12, as well as neutrophil infiltration. BBB stabilization was evaluated by measuring Evans blue extravasation, and Western blot analysis of Claudin-3, Claudin-5, ICAM-1 and VCAM-1. Measurements and Main Results First, the time course study showed that p-β-Catenin/β-Catenin, IKKβ, and NF-κB expression levels peaked at 48 hours post-HI. Knockdown of GSK-3β with siRNA prevented the HI-induced increase of p-β-Catenin/β-Catenin, IKKβ, and NF-κB expression levels 48 hours after HI. G-CSF treatment reduced brain water content and neuroinflammation by downregulating IKKβ, NF-κB, TNF-α, IL-1β, and IL-12 and upregulating IL-10, thereby reducing neutrophil infiltration. Additionally, G-CSF stabilizes the BBB by downregulating VCAM-1 and ICAM-1, as well as upregulating Claudins 3 and 5 in endothelial cells. G-CSFR knockdown by siRNA and Akt inhibition by Wortmannin reversed G-CSF’s neuroprotective effects. Conclusions We demonstrate G-CSF plays a pivotal role in attenuating neuroinflammation and BBB disruption following HI by inactivating GSK-3β through the PI3K/Akt pathway.

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Section: Discussionmentioning

confidence: 97%

G-CSF attenuates neuroinflammation and stabilizes the blood–brain barrier via the PI3K/Akt/GSK-3β signaling pathway following neonatal hypoxia-ischemia in rats

McBride

Doycheva

et al. 2015

Experimental Neurology

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“…However, quantification of TUNEL positive neurons would have certainly strengthened our hypothesis. Further studies are necessary for clinical translation (Bahjat et al, 2013; Lapchak, 2013; Tajiri et al, 2013). …”

Section: Discussionmentioning

confidence: 99%

Cannabinoid receptor type 2 agonist attenuates apoptosis by activation of phosphorylated CREB–Bcl-2 pathway after subarachnoid hemorrhage in rats

Fujii

Sherchan

Soejima

et al. 2014

Experimental Neurology

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Early brain injury (EBI) which comprises of vasogenic edema and apoptotic cell death is an important component of subarachnoid hemorrhage (SAH) pathophysiology. This study evaluated whether Cannabinoid receptor type 2 (CB2R) agonist, JWH133, attenuates EBI after SAH and whether CB2R stimulation reduces pro-apoptotic caspase-3 via up-regulation of cAMP response element-binding protein (CREB)-Bcl-2 signaling pathway. Male Sprague Dawley rats (n=123) were subjected to SAH by endovascular perforation. Rats received vehicle or JWH133 at 1 hour after SAH. Neurological deficits and brain water content were evaluated at 24 hours after SAH. Western blot was performed to quantify phosphorylated CREB (pCREB), Bcl-2, and cleaved caspase-3 levels. Neuronal cell death was evaluated with terminal deoxynucleotidyl transferase-mediated uridine 5′-triphosphate-biotin nick end-labeling staining. Additionally, CREB siRNA was administered to manipulate the proposed pathway. JWH133 (1.0 mg/kg) improved neurological deficits and reduced brain water content in left hemisphere 24 hours after SAH. JWH133 significantly increased activated CREB (pCREB) and Bcl-2 levels and significantly decreased cleaved caspase-3 levels in left hemisphere 24 hours after SAH. CREB siRNA reversed the effects of treatment. TUNEL positive neurons in the cortex were reduced with JWH133 treatment. Thus, CB2R stimulation attenuated EBI after SAH possibly through activation of pCREB-Bcl-2 pathway.

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“…Furthermore, using functional imaging and functional connectivity analyses, motor circuitry can be functionally evaluated (52–54). Thus, the structural, functional and behavioral effects of a therapeutic intervention on an injured brain’s plasticity, regeneration and repair can be measured in vivo in a non-invasive and objective way, assessing the gray and white matter (50,55). …”

Section: Neuroimaging Prepares the Ground For Clinical Translationmentioning

confidence: 99%

Advancing Research in Regeneration and Repair of the Motor Circuitry: Non-Human Primate Models and Imaging Scales as the Missing Links for Successfully Translating Injectable Therapeutics to the Clinic

Tsintou¹

2016

Int J Stem Cell Res Ther

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Regeneration and repair is the ultimate goal of therapeutics in trauma of the central nervous system (CNS). Stroke and spinal cord injury (SCI) are two highly prevalent CNS disorders that remain incurable, despite numerous research studies and the clinical need for effective treatments. Neural engineering is a diverse biomedical field, that addresses these diseases using new approaches. Research in the field involves principally rodent models and biologically active, biodegradable hydrogels. Promising results have been reported in preclinical studies of CNS repair, demonstrating the great potential for the development of new treatments for the brain, spinal cord and peripheral nerve injury. Several obstacles stand in the way of clinical translation of neuroregeneration research. There seems to be a key gap in the translation of research from rodent models to human applications, namely non-human primate models, which constitute a critical bridging step. Applying injectable therapeutics and multimodal neuroimaging in stroke lesions using experimental rhesus monkey models is an avenue that a few research groups have begun to embark on. Understanding and assessing the changes that the injured brain or spinal cord undergoes after an intervention with biodegradable hydrogels in non-human primates seem to represent critical preclinical research steps. Existing innovative models in non-human primates allow us to evaluate the potential of neural engineering and injectable hydrogels. The results of these preliminary studies will pave the way for translating this research into much needed clinical therapeutic approaches. Cutting edge imaging technology using Connectome scanners represents a tremendous advancement, enabling the in vivo, detailed, high-resolution evaluation of these therapeutic interventions in experimental animals. Most importantly, they also allow quantifiable and clinically meaningful correlations with humans, increasing the translatability of these innovations to the bedside.

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In Vivo Animal Stroke Models

Cited by 45 publications

References 123 publications

G-CSF attenuates neuroinflammation and stabilizes the blood–brain barrier via the PI3K/Akt/GSK-3β signaling pathway following neonatal hypoxia-ischemia in rats

G-CSF attenuates neuroinflammation and stabilizes the blood–brain barrier via the PI3K/Akt/GSK-3β signaling pathway following neonatal hypoxia-ischemia in rats

Cannabinoid receptor type 2 agonist attenuates apoptosis by activation of phosphorylated CREB–Bcl-2 pathway after subarachnoid hemorrhage in rats

Advancing Research in Regeneration and Repair of the Motor Circuitry: Non-Human Primate Models and Imaging Scales as the Missing Links for Successfully Translating Injectable Therapeutics to the Clinic

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