Time Window of Fibroblast Growth Factor-18—Mediated Neuroprotection after Occlusion of the Middle Cerebral Artery in Rats*

Ellsworth, Jeff L.; Garcia, Richard U.; Yu, Jin; Kindy, Mark S.

doi:10.1097/01.wcb.0000100063.36077.cd

Cited by 15 publications

(9 citation statements)

References 42 publications

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“…After 60 minutes ischemia, the suture was removed for a 24h period of reperfusion before sacrifice, as consistent with previous literature (3, 4, 21, 22). Blood pressure, temperature, and ipsilateral cerebral blood flow(measured by laser Doppler), were measured before, during and after ischemia as previously described (23, 24). Mice with ischemic blood flow less than 25% were included in our studies.…”

Section: Methodsmentioning

confidence: 99%

Pathogenic Natural Antibodies Propagate Cerebral Injury Following Ischemic Stroke in Mice

Elvington

Atkinson

Kulik

et al. 2012

The Journal of Immunology

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112

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Self-reactive natural antibodies initiate injury following ischemia and reperfusion of certain tissues, but their role in ischemic stroke is unknown. We investigated neoepitope expression in the post-ischemic brain, and the role of natural antibodies in recognizing these epitopes and mediating complement-dependent injury. A novel IgM mAb recognizing a subset of phospholipids (C2) and a previously characterized anti-annexin IV mAb (B4) were used to reconstitute and characterize injury in antibody deficient Rag1−/− mice after 60 minutes of middle cerebral artery occlusion and reperfusion. Reconstitution with C2 or B4 mAb in otherwise protected Rag1−/− mice restored injury to that seen in wild-type mice, as demonstrated by infarct volume, demyelination and neurological scoring. IgM deposition was demonstrated in both wild-type mice and reconstituted Rag1−/− mice, and IgM co-localized with the complement activation fragment, C3d, following B4 mAb reconstitution. Further, recombinant annexin IV significantly reduced infarct volumes in wild-type mice and in Rag1−/− mice administered normal mouse serum, demonstrating that a single antibody reactivity is sufficient to develop cerebral ischemia reperfusion injury in the context of an entire natural antibody repertoire. Finally, C2 and B4 mAbs bound to hypoxic, but not normoxic, human endothelial cells in vitro. Thus, the binding of pathogenic natural IgM to post-ischemic neoepitopes initiates complement-dependent injury following murine cerebral ischemia and reperfusion and, based also on previous data investigating IgM reactivity in human serum, there appears to be a similar recognition system in both mouse and man.

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Section: Methodsmentioning

confidence: 99%

Pathogenic Natural Antibodies Propagate Cerebral Injury Following Ischemic Stroke in Mice

Elvington

Atkinson

Kulik

et al. 2012

The Journal of Immunology

Self Cite

112

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show abstract

“…Brain temperature was monitored for 1 hour prior to ischemia to 6 hours following ischemia and was recorded at 30-minute intervals. Each mouse was anesthetized and the external carotid artery (ECA) and common carotid artery (CCA) were isolated (Gary et al, 1998; Mattson et al, 2000; Dubal et al, 2001; Ellsworth et al, 2003; Ellsworth et al, 2004). The left common carotid artery (CCA) was exposed through a midline incision in the neck.…”

Section: Methodsmentioning

confidence: 99%

Motoneuronotrophic factor analog GM6 reduces infarct volume and behavioral deficits following transient ischemia in the mouse

Zhu

Ko³

et al. 2008

Brain Research

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Motoneuronotrophic factor (MNTF) is an endogenous neurotrophin that is highly specific for the human nervous system, and some of the observed effects of MNTF include motoneuron differentiation, maintenance, survival, and reinnervation of target muscles and organs. MNTF is a neuro-signaling molecule that binds to specific receptors. Using In Silico Analysis, one of the active sites of MNTF was identified as an analog of six amino acids (GM6). The effect of chemically synthesized GM6 on ischemic stroke was studied in the middle cerebral artery occlusion (MCAo) mouse model. Mice were subjected to 1 hour of ischemia followed by 24 hours of reperfusion. Mice were injected intravenously with a bolus of GM6, at various doses (1 and 5 mg/kg) immediately after the start of reperfusion and examined for changes in physiological parameters, neurological deficits and infarct volume. GM6 was able to penetrate the blood brain barrier, and at both 1 and 5 mg/kg showed a significant protection from infarct damage, which translated to improvement of neurological deficits. Administration of GM6 demonstrated no changes in HR, BP, pO2, pCO2, or pH. A significant increase over the control group in CBF after reperfusion was observed with GM6 administration, which helped to mitigate the ischemic effect caused by the blockage of blood flow. The time window of treatment was assessed at various times following cerebral ischemia with GM6 demonstrating a significant protective effect up to 6–12 hours post ischemia. In addition, GM6 increased neurogenesis, and decreased apoptosis and inflammation in the mouse brain following cerebral ischemic injury. These data suggest that GM6 is neuroprotective to the brain following IV injection in the mouse model of MCAo.

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“…Each mouse was anesthetized and the external carotid artery (ECA) and common carotid artery were isolated. 36,37 The left common carotid artery was exposed through a midline incision in the neck. The superior thyroid and occipital arteries were electrocoagulated and divided.…”

Section: Animal Studiesmentioning

confidence: 99%

Nanoparticles for Targeted Delivery of Antioxidant Enzymes to the Brain after Cerebral Ischemia and Reperfusion Injury

Xiang

Maximov

et al. 2013

J Cereb Blood Flow Metab

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118

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Stroke is one of the major causes of death and disability in the United States. After cerebral ischemia and reperfusion injury, the generation of reactive oxygen species (ROS) and reactive nitrogen species may contribute to the disease process through alterations in the structure of DNA, RNA, proteins, and lipids. We generated various nanoparticles (liposomes, polybutylcyanoacrylate (PBCA), or poly(lactide-co-glycolide) (PLGA)) that contained active superoxide dismutase (SOD) enzyme (4,000 to 20,000 U/kg) in the mouse model of cerebral ischemia and reperfusion injury to determine the impact of these molecules. In addition, the nanoparticles were untagged or tagged with nonselective antibodies or antibodies directed against the N-methyl-Daspartate (NMDA) receptor 1. The nanoparticles containing SOD protected primary neurons in vitro from oxygen-glucose deprivation (OGD) and limited the extent of apoptosis. The nanoparticles showed protection against ischemia and reperfusion injury when applied after injury with a 50% to 60% reduction in infarct volume, reduced inflammatory markers, and improved behavior in vivo. The targeted nanoparticles not only showed enhanced protection but also showed localization to the CA regions of the hippocampus. Nanoparticles alone were not effective in reducing infarct volume. These studies show that targeted nanoparticles containing protective factors may be viable candidates for the treatment of stroke.

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Time Window of Fibroblast Growth Factor-18—Mediated Neuroprotection after Occlusion of the Middle Cerebral Artery in Rats*

Cited by 15 publications

References 42 publications

Pathogenic Natural Antibodies Propagate Cerebral Injury Following Ischemic Stroke in Mice

Pathogenic Natural Antibodies Propagate Cerebral Injury Following Ischemic Stroke in Mice

Motoneuronotrophic factor analog GM6 reduces infarct volume and behavioral deficits following transient ischemia in the mouse

Nanoparticles for Targeted Delivery of Antioxidant Enzymes to the Brain after Cerebral Ischemia and Reperfusion Injury

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