Plasminogen activator inhibitor type 1 derived peptide, EEIIMD, diminishes cortical infarct but fails to improve neurological function in aged rats following middle cerebral artery occlusion

Tan, Zhenjun; Li, Xinlan; Kelly, Kimberly A.; Rosen, Charles L.; Huber, Jason D.

doi:10.1016/j.brainres.2009.05.042

Cited by 27 publications

(29 citation statements)

References 38 publications

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“…This finding is also consistent with previous studies showing larger infarct volumes and less functional recovery in aged mice (DiNapoli et al, 2008; Dinapoli et al, 2006; Dong et al, 2014; Rosen et al, 2005; Tan et al, 2009). We found that the striatum was especially affected in the aged animals after stroke.…”

Section: Discussionsupporting

confidence: 93%

White matter injury and microglia/macrophage polarization are strongly linked with age-related long-term deficits in neurological function after stroke

Suenaga

Hu²,

Pu³

et al. 2015

Experimental Neurology

160

118

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Most of the successes in experimental models of stroke have not translated well to the clinic. One potential reason for this failure is that stroke mainly afflicts the elderly and the majority of experimental stroke studies rely on data gathered from young adult animals. Therefore, in the present study we established a reliable, reproducible model of stroke with low mortality in aged (18 month) male mice and contrasted their pathophysiological changes with those in young (2 month) animals. To this end, mice were subjected to permanent tandem occlusion of the left distal middle cerebral artery (dMCAO) with ipsilateral common carotid artery occlusion (CCAO). Cerebral blood flow (CBF) was evaluated repeatedly during and after stroke. Reduction of CBF was more dramatic and sustained in aged mice. Aged mice exhibited more severe long-term sensorimotor deficits, as manifested by deterioration of performance in the Rotarod and hanging wire tests up to 35d after stroke. Aged mice also exhibited significantly worse long-term cognitive deficits after stroke, as measured by the Morris water maze test. Consistent with these behavioral observations, brain infarct size and neuronal tissue loss after dMCAO were significantly larger in aged mice at 2d and 14d, respectively. The young versus aged difference in neuronal tissue loss, however, did not persist until 35d after dMCAO. In contrast to the transient difference in neuronal tissue loss, we found significant and long lasting deterioration of white matter in aged animals, as revealed by the loss of myelin basic protein (MBP) staining in the striatum at 35d after dMCAO. We further examined the expression of M1 (CD16/CD32) and M2 (CD206) markers in Iba-1+ microglia by double immunofluorescent staining. In both young and aged mice, the expression of M2 markers peaked around 7d after stroke whereas the expression of M1 markers peaked around 14d after stroke, suggesting a progressive M2-to-M1 phenotype shift in both groups. However, aged mice exhibited significantly reduced M2 polarization compared to young adults. Remarkably, we discovered a strong positive correlation between favorable neurological outcomes after dMCAO and MBP levels or the number of M2 microglia/macrophages. In conclusion, our studies suggest that the distal MCAO stroke model consistently results in ischemic brain injury with long-term behavioral deficits, and is therefore suitable for the evaluation of long-term stroke outcomes. Furthermore, aged mice exhibit deterioration of functional outcomes after stroke and this deterioration is linked to white matter damage and reductions in M2 microglia/macrophage polarization.

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Section: Discussionsupporting

confidence: 93%

White matter injury and microglia/macrophage polarization are strongly linked with age-related long-term deficits in neurological function after stroke

Suenaga

Hu²,

Pu³

et al. 2015

Experimental Neurology

160

118

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“…Indeed, 1 recent study has shown that coadministration of a plasminogen activator inhibitor type 1-derived peptide, EEIIMD, with tissue plasminogen activator, a drug currently used for thrombolysis in stroke units, produced no improvement in total infarct volume, edema formation, or functional outcome in aged rats. 14 Improvement of function under treatment may suggest a direct effect of G-CSF on recovery of motor function and may be similar to our recent findings showing that G-CSF is an essential factor for the development of normal running function in wild-type and G-CSF Ϫ/Ϫ mice. 9 Potential mechanisms include a relative shift in favor of activation (upregulation of NMDA receptors, downregulation of GABA receptors) and improved behavioral performance associated with G-CSF stimulation.…”

Section: Discussionsupporting

confidence: 90%

Effects of Granulocyte-Colony Stimulating Factor After Stroke in Aged Rats

Popa‐Wagner

Stöcker

Bălșeanu

et al. 2010

Stroke

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Background and Purpose-In aged humans, stroke is a major cause of disability for which no neuroprotective measures are available. Granulocyte-colony stimulating factor (G-CSF), a member of the cytokine family of growth factors, promotes brain neurogenesis and improves functional outcome after stroke in young animals. We tested the hypothesis that G-CSF provides a restorative therapeutic benefit in aged animals. Methods-Focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery in 19-to 20-month-old male Sprague-Dawley rats. One hour after reperfusion, the aged rats were treated daily with 15 g/kg G-CSF and for 15 days total. Rats were behaviorally tested and the brains removed for analysis at 28 days poststroke. Results-G-CSF treatment after stroke exerted a robust and sustained beneficial effect on survival rate and running function. Transient improvement after G-CSF treatment could be observed for coordinative motor function on the inclined plane test and for working memory in the radial-arm maze test. At the cellular level, G-CSF treatment increased the number of proliferating cells in the subventricular zone and dentate gyrus and also increased the number of newborn neurons in the subventricular zone ipsilateral to the lesion. Conclusions-These results suggest that G-CSF treatment in aged rats has a survival-enhancing capacity and a beneficial effect on functional outcome, most likely through supportive cellular processes such as neurogenesis.

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“…The protective effect of r-tPA over placebo (saline) was lost at 6 h following ischemic stroke. The main finding of this study, taking into account prior findings demonstrating a protective effect of r-tPA when administered at 2 hours after ischemic stroke (DiNapoli et al ., 2008; Tan et a l., 2009), was that r-tPA in combination with the recombinant human apyrase (APT102) safely extended the time window for r-tPA out to 6 h after ischemic stroke in aged female rats. This study showed that co-administration of APT102 with r-tPA significantly reduced mortality rate, decreased infarct volume and cerebral hemorrhage, and improved neurological functional outcome at 24 h following MCAO as compared to subjects treated with r-tPA alone.…”

Section: Discussionmentioning

confidence: 99%

“…Rats were given a reversible embolic MCAO as previously described (Dinapoli et al, 2006; DiNapoli et al, 2008; Tan et al, 2009). Briefly, rats were anesthetized with 2% isoflurane in a mixture of 30% oxygen and 70% nitrous oxide.…”

Section: Methodsmentioning

confidence: 99%

Combination treatment of r-tPA and an optimized human apyrase reduces mortality rate and hemorrhagic transformation 6h after ischemic stroke in aged female rats

Tan

Turner

et al. 2014

European Journal of Pharmacology

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Recombinant tissue plasminogen activator (r-tPA) is the only FDA-approved drug treatment for ischemic stroke and must be used within 4.5 hours. Thrombolytic treatment with r-tPA has deleterious effects on the neurovascular unit that substantially increases the risk of intracerebral hemorrhage if administered too late. These therapeutic shortcomings necessitate additional investigation into agents that can extend the therapeutic window for safe use of thrombolytics. In this study, combination of r-tPA and APT102, a novel form of human apyrase/ADPase, was investigated in a clinically-relevant aged-female rat embolic ischemic stroke model. We propose that successfully extending the therapeutic window of r-tPA administration would represent a significant advance in the treatment of ischemic stroke due to a significant increase in the number of patients eligible for treatment. Results of our study showed significantly reduced mortality from 47% with r-tPA alone to 16% with co-administration of APT102 and r-tPA. Co-administration decreased cortical (47±5% vs 29±5%), striatal (50±2%, vs 40±3%) and total (48±3%vs 33±4%) hemispheric infarct volume compared to r-tPA alone. APT102 improved neurological outcome (8.9±0.6, vs 6.8±0.8) and decreased hemoglobin extravasation in cortical tissue (1.9±0.1 mg/dlvs 1.4±0.1 mg/dl) striatal tissue (2.1±0.3 mg/dl vs 1.4±0.1 mg/dl) and whole brain tissue (2.0±0.2 mg/dl vs 1.4±0.1 mg/dl). These data suggest that APT102 can safely extend the therapeutic window for r-tPA mediated reperfusion to 6 h following experimental stroke without increased hemorrhagic transformation. APT102 offers to be a viable adjunct therapeutic option to increase the number of clinical patients eligible for thrombolytic treatment after ischemic stroke.

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Plasminogen activator inhibitor type 1 derived peptide, EEIIMD, diminishes cortical infarct but fails to improve neurological function in aged rats following middle cerebral artery occlusion

Cited by 27 publications

References 38 publications

White matter injury and microglia/macrophage polarization are strongly linked with age-related long-term deficits in neurological function after stroke

White matter injury and microglia/macrophage polarization are strongly linked with age-related long-term deficits in neurological function after stroke

Effects of Granulocyte-Colony Stimulating Factor After Stroke in Aged Rats

Combination treatment of r-tPA and an optimized human apyrase reduces mortality rate and hemorrhagic transformation 6h after ischemic stroke in aged female rats

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