On Ischemic Brain Injury in Genetically Altered Mice

Ginsberg, Myron D.

doi:10.1161/01.atv.19.11.2581

Cited by 11 publications

(3 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is important because minor differences in the extent of decline of CBF during the 2-hour period of MCAO may result in major differences in infarct volume. 19 Consistent with CBF data, our dynamic diffusion-weighted MRI data demonstrated that the initial ischemic lesion volumes were relatively the same before treatment. However, evolution of the ischemic lesion was significantly reduced in animals treated with neuroserpin in combination with tPA compared with animals treated with tPA alone.…”

Section: Discussionsupporting

confidence: 82%

Adjuvant Treatment With Neuroserpin Increases the Therapeutic Window for Tissue-Type Plasminogen Activator Administration in a Rat Model of Embolic Stroke

et al. 2002

View full text Add to dashboard Cite

Background-After stroke, the thrombolytic effect of tissue-type plasminogen activator (tPA) in the intravascular space is beneficial, whereas its extravascular effect on ischemic neurons is deleterious. We tested the hypothesis that neuroserpin, a natural inhibitor of tPA, reduces tPA-induced neuronal toxicity and increases its therapeutic window for treatment of embolic stroke. Methods and Results-Rats were subjected to embolic middle cerebral artery occlusion (MCAO). Ischemic brains were treated with neuroserpin in combination with recombinant human tPA (nϭ7), tPA alone (nϭ7), or saline (nϭ9). Neuroserpin (20 L of 16 mol/L active neuroserpin) was intracisternally injected 3 hours and tPA (10 mg/kg) was intravenously administered 4 hours after ischemia. MRI measurements were performed to study blood brain barrier (BBB) leakage and ischemic lesion volume. Administration of tPA alone 4 hours after ischemia significantly (PϽ0.05) increased BBB leakage in the ischemic core measured by Gd-DTPA-enhanced MRI compared with rats treated with saline. However, treatment with neuroserpin in combination with tPA significantly (PϽ0.05) reduced BBB leakage, brain edema, and ischemic lesion volume compared with rats treated with tPA alone, although ischemic lesion volumes were the same in both groups before the treatment. Immunostaining revealed that MCAO resulted in reduction of neuroserpin immunoreactivity in the ipsilateral hemisphere after 2 to 6 hours of ischemia. Zymographic assay showed increased plasminogen activity in areas with BBB leakage in rats treated with tPA. Conclusions-Administration of neuroserpin after stroke is neuroprotective, seemingly because it blocks the extravascular effect of tPA, leading to subsequent decrease in stroke volume and widening of the therapeutic window for the thrombolytic effect of tPA. (Circulation. 2002;106:740-745.)

show abstract

Section: Discussionsupporting

confidence: 82%

Adjuvant Treatment With Neuroserpin Increases the Therapeutic Window for Tissue-Type Plasminogen Activator Administration in a Rat Model of Embolic Stroke

et al. 2002

View full text Add to dashboard Cite

show abstract

“…However, contradictory data was collected in another study, where tPA deficient mice had larger infarcts after transient focal cerebral ischemia (Tabrizi et al, 1999). Although the exact reason for these variable results is not known, differences in genetic background of the mice used are likely to play a significant role (Ginsberg, 1999).…”

Section: Neurotoxicity In Animal Modelsmentioning

confidence: 99%

The Neurotoxicity of Tissue Plasminogen Activator?

Kaur

Zhao

Klein

et al. 2004

J Cereb Blood Flow Metab

240

185

View full text Add to dashboard Cite

Abstract:Tissue plasminogen activator (tPA), a fibrin specific activator for the conversion of plasminogen to plasmin, stimulates thrombolysis and rescues ischemic brain by restoring blood flow. However, emerging data suggests that under some conditions, both tPA and plasmin, which are broad spectrum protease enzymes, are potentially neurotoxic if they reach the extracellular space. Animal models suggest that in severe ischemia with injury to the blood brain barrier (BBB) there is injury attributed to the protease effects of this exogenous tPA. Besides clot lysis per se, tPA may have pleiotropic actions in the brain, including direct vasoactivity, cleaveage of the N-methyl-Daspartate (NMDA) NR1 subunit, amplification of intracellular Ca ++ conductance, and activation of other extracellular proteases from the matrix metalloproteinase (MMP) family, e.g. MMP-9. These effects may increase excitotoxicity, further damage the BBB, and worsen edema and cerebral hemorrhage. If tPA is effective and reverses ischemia promptly, the BBB remains intact and exogenous tPA remains within the vascular space. If tPA is ineffective and ischemia is prolonged, there is the risk that exogenous tPA will injure both the neurovascular unit and the brain. Methods of neuroprotection, which prevent tPA toxicity or additional mechanical means to open cerebral vessels, are now needed.

show abstract

“…In models of traumatic brain injury, initial data show that tPA knockouts are protected in terms of smaller cortical lesions and reduced edema (Mori et al, 2001). This variability in outcomes is likely related to complex issues regarding genetic backgrounds of the contributing strains and the specific conditions for each model of brain injury (Schauwecker and Steward, 1997; Ginsberg, 1999).…”

Section: Acute Brain Injurymentioning

confidence: 99%

Extracellular proteolysis in brain injury and inflammation: Role for plasminogen activators and matrix metalloproteinases

Wang

Cuzner

2002

J of Neuroscience Research

297

211

View full text Add to dashboard Cite

The role of intracellular proteases (e.g., calpains and caspases) in the pathophysiology of neuronal cell death has been extensively investigated. More recently, accumulating data have suggested that extracellular proteolysis also plays a critical role. The two major systems that modify the extracellular matrix in brain are the plasminogen activator (PA) and matrix metalloproteinase (MMP) axes. This Mini-Review delineates major pathways of PA and MMP action after stroke, brain trauma, and chronic inflammation. Deleterious effects include the disruption of blood-brain barrier integrity, amplification of inflammatory infiltrates, demyelination, and possibly interruption of cell-cell and cell-matrix interactions that may trigger cell death. In contrast, PA-MMP actions may contribute to extracellular proteolysis that mediates parenchymal and angiogenic recovery after brain injury. As the mechanisms of deleterious vs. potentially beneficial PA and MMP actions become better defined, it is hoped that new therapeutic targets will emerge for ameliorating the sequelae of brain injury and inflammation.

show abstract

On Ischemic Brain Injury in Genetically Altered Mice

Cited by 11 publications

References 51 publications

Adjuvant Treatment With Neuroserpin Increases the Therapeutic Window for Tissue-Type Plasminogen Activator Administration in a Rat Model of Embolic Stroke

Adjuvant Treatment With Neuroserpin Increases the Therapeutic Window for Tissue-Type Plasminogen Activator Administration in a Rat Model of Embolic Stroke

The Neurotoxicity of Tissue Plasminogen Activator?

Extracellular proteolysis in brain injury and inflammation: Role for plasminogen activators and matrix metalloproteinases

Contact Info

Product

Resources

About