Premature cellular proliferation following cortical infarct in aged rats

Popa‐Wagner, Aurel; Badan, Irina; Dinca, Ivona; Suofu, Yalikun; Vintilescu, Raluca; Walker, Lary C.; Keesler, Christoff

doi:10.1038/sj.jcbfm.9591524.0215

Cited by 9 publications

(12 citation statements)

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“…As a thrombolytic agent, r-tPA has direct and deleterious effects on the neurovascular unit that substantially increases death rate and infarct volume and causes severe hemorrhage when administered intravenously following an MCAO in a delayed fashion. Recent studies indicate that aged rats were more severely impaired following ischemic stroke than younger rats with diminished functional recovery (Popa-Wagner et al, 2006a; Popa-Wagner et al, 2006b; Popa-Wagner et al, 2007). Clinically, increased age negatively affects spontaneous recovery of stroke patients and is a primary risk factor for fragility of the blood brain barrier and hemorrhagic transformation following thrombolytic therapy (Fisher et al, 2009).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…The highest incidence of stroke occurs in aged individuals and considerable evidence exists demonstrating that aging may alter many physiological and metabolic processes in the nervous system that may play a role in plasticity and cortical reorganization (Badan et al, 2003, 2004; Dinse, 2005; Li and Carmichael, 2006; Li et al, 2005; Popa-Wagner et al, 2006, 2007a, 2007b; Wang et al, 2003). While there are conflicting data in regards to the effects of age on stroke size and the mechanisms of recovery, numerous studies have demonstrated age-related differences in functional recovery and the cytological response to stroke (Badan et al, 2003; Buga et al, 2008; Davis et al, 1995; Nagayama et al, 1999;Popa-Wagner et al, 2006, 2007a, 2007b; Wang et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Recovery from ischemia in the middle-aged brain: a nonhuman primate model

Moore¹,

Killiany²,

Pessina³

et al. 2012

Neurobiology of Aging

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Studies of recovery from stroke mainly utilize rodent models and focus primarily on young subjects despite the increased prevalence of stroke with age and the fact that recovery of function is more limited in the aged brain. In the present study, a nonhuman primate model of cortical ischemia was developed to allow the comparison of impairments in young and middle-aged monkeys. Animals were pretrained on a fine motor task of the hand and digits and then underwent a surgical procedure to map and lesion the hand-digit representation in the dominant motor cortex. Animals were retested until performance returned to preoperative levels. To assess the recovery of grasp patterns, performance was videotaped and rated using a scale adapted from human occupational therapy. Results demonstrated that the impaired hand recovers to baseline in young animals in 65–80 days and in middle-aged animals in 130–150 days. However, analysis of grasp patterns revealed that neither group recover preoperative finger thumb grasp patterns, rather they develop compensatory movements.

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“…Reactive microglia, characterized by cellular hypertrophy, accumulate in the boundary zone next to the ischemic core (Biran et al, 2006;Carruthers and Suzuki, 2007;Morioka et al, 1991;Pforte et al, 2005;Popa-Wagner et al, 2006). In addition, expression of a number of microglial cytokines and chemokines can exacerbate ischemic injury (Chew et al, 2006;Lai and Todd, 2006;Stoll and Jander, 1999).…”

Section: Introductionmentioning

confidence: 98%

Cell cycle inhibition attenuates microglial proliferation and production of IL‐1β, MIP‐1α, and NO after focal cerebral ischemia in the rat

Zhang

Chen

et al. 2008

Glia

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We recently showed that suppressing cell cycle progression inhibited reactive astrogliosis and promoted neuronal survival in an acute focal cerebral ischemia rat model. However, it remains unclear whether and to what extent the beneficial effects of cell cycle inhibition might also be attributed to the inhibition of microglial proliferation and cytokine/chemokine production. In this study, we showed that application of the cell cycle inhibitor roscovitine before middle carotid artery occlusion (MCAO) in the rat inhibited microglial proliferation and cytokine/chemokine production, and reduced the number of cell-cycle-related proteins including cyclin A, cyclin B, and cyclin E. All of these microglia-related changes may contribute to roscovitine's effect on reducing neuronal apoptosis and infarct volume, thus improving neurological scores. Using the BV-2 microglia cell line, we showed that roscovitine not only inhibited oxygen-glucose deprivation (OGD) induced cell cycle activation by arresting the cells at G1/S and G2/M in a dose-dependent manner, but it also inhibited interleukin-1 beta (IL-1beta), macrophage inflammatory protein-1alpha (MIP-1alpha), and nitric oxide (NO) production. These results suggest that cell cycle modulation results in neuroprotection in ischemia, mediated at least in part through inhibition of microglia proliferation and production of inflammatory cytokines such as IL-1beta, MIP-1alpha, and NO.

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Premature cellular proliferation following cortical infarct in aged rats

Cited by 9 publications

References 0 publications

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

Recovery from ischemia in the middle-aged brain: a nonhuman primate model

Cell cycle inhibition attenuates microglial proliferation and production of IL‐1β, MIP‐1α, and NO after focal cerebral ischemia in the rat

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