Thrombolysis of cerebral clot embolism in rat

Brinker, Gerrit; Franke, Claudia; Hoehn, Mathias; Uhlenküken, Ulla; Ka, Hossmann

doi:10.1097/00001756-199911080-00004

Cited by 38 publications

(30 citation statements)

References 7 publications

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“…However, the success of the tissue plasminogen activator (tPA) trial with a 3-hour time window [7] shows that such studies are possible. It is noteworthy that tPA is also effective in animal stroke models within the same time frame [8], supporting the idea that animals and humans may be similar in the time their window of opportunity is open. Most investigated compounds act on the early events in the neurodegenerative cascade.…”

Section: Therapeutic Windowmentioning

confidence: 81%

Thrombolysis and Neuroprotection in Cerebral Ischemia

Gutiérrez¹,

Tejedor

Leciñana

et al. 2006

Cerebrovasc Dis

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Stroke is a major cause of death and disability worldwide. The resulting burden on society grows with the increase in the incidence of stroke. The term brain attack was introduced to describe the acute presentation of stroke and emphasize the need for urgent action to remedy the situation. Though a large number of therapeutic agents, like thrombolytics, NMDA receptor antagonists, calcium channel blockers and antioxidants, have been used or are being evaluated, there is still a large gap between the benefits of these agents and the properties of an ideal drug for stroke. So far, only thrombolysis with rtPA within a 3-hour time window has been shown to improve the outcome of patients with ischemic stroke. Understanding the mechanisms of injury and neuroprotection in these diseases is important to target news sites for treating ischemia. Better evaluation of the drugs and increased similarity between the results of animal experimentation and in the clinical setting requires critical assessment of the selection of animal models and the parameters to be evaluated. Our laboratory has employed a rat embolic stroke model to investigate the combination of rtPA with citicoline as compared to monotherapy alone and investigated whether neuroprotection should be provided before or after thrombolysis in order to achieve a greater reduction of ischemic brain damage.

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Section: Therapeutic Windowmentioning

confidence: 81%

Thrombolysis and Neuroprotection in Cerebral Ischemia

Gutiérrez¹,

Tejedor

Leciñana

et al. 2006

Cerebrovasc Dis

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“…6 Furthermore, Brinker and colleagues 8 showed that HTs can reliably be induced in SHR by means of the presently used animal model and timing conditions for treatment. Thus, although rtPA treatment is performed at this time point, no confounding effect by any treatment success would hide the bleeding aspects of our study.…”

Section: Animal Preparationmentioning

confidence: 99%

“…However, basing pretreatment decisions on such signatures may lead both to unjustified inclusions and exclusions of stroke patients: unjustified inclusions because hemorrhages have been observed in undamaged brain 5 and unjustified exclusions because thrombolytic protection of the penumbra may lead to the significant reduction of final lesion size, even if the infarct core is irreversibly damaged and cannot be salvaged. 6,7 This raises the question of whether hemorrhages can be predicted by MRI irrespective of the severity of the ischemic injury.…”

mentioning

confidence: 99%

Prediction of Hemorrhagic Transformation After Thrombolytic Therapy of Clot Embolism

Neumann-Haefelin

Brinker

Uhlenküken

et al. 2002

Stroke

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Background and Purpose-Thrombolytic treatment of stroke carries the risk of hemorrhagic transformation. Therefore, the potential of MRI for prediction of recombinant tissue plasminogen activator (rtPA)-induced bleeding is explored to identify patients in whom rtPA treatment may provoke such complications. Methods-Spontaneously hypertensive rats (SHR) (nϭ9) were submitted to middle cerebral artery (MCA) clot embolism, followed 3 hours later by intra-arterial infusion of 10 mg/kg rtPA. Untreated SHR (nϭ9) were infused with saline. MRI imaging was performed before treatment and included apparent diffusion coefficient (ADC), T2, and perfusion mapping and contrast enhancement with gadolinium-DTPA. The distribution of intracerebral hemorrhages was studied 3 days later by histological staining. Results-Clot embolism led to the rapid decline of ADC in the territory of the occluded artery. Tissue lesion volume derived from ADC imaging increased by 155Ϯ69% in the untreated animals and by 168Ϯ87% in the treated animals (PϭNS), determined on the histological sections after 3 days. This same lesion growth in both groups indicated absence of therapeutic effect after 3-hour treatment delay. Hemorrhagic transformations were significantly more frequent in treated SHR (PϽ0.05). In untreated rats, hemorrhages were found in the border zone of the ischemic territory; in treated animals, hemorrhagic transformations occurred in the ischemic core region. rtPA-induced hemorrhages were predicted by a disturbance of the blood-brain barrier in 3 of 4 animals before treatment by Gd-DTPA contrast enhancement but not by ADC, T2, or perfusion imaging. The region of contrast enhancement colocalized with subsequent bleeding in these animals. Conclusions-The disturbance of blood-brain barrier but not of other MR parameters allows risk assessment for hemorrhagic transformation induced by subsequent thrombolytic treatment.

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“…27 The evaluation of the dynamics of the ADC changes confirmed our earlier observation that the reduction of the biochemical lesion volume is not due to the reversal of the initial ischemic injury but to the prevention of infarct growth. 9,28 This explains why the therapeutic efficacy declines with increasing treatment delay. In fact, comparison of ADC recordings after different treatment delays revealed that rtPA freezes the lesion volume at the level it has reached when treatment begins.…”

Section: Rtpa-induced Reduction Of Tissue Injurymentioning

confidence: 99%

“…In fact, comparison of ADC recordings after different treatment delays revealed that rtPA freezes the lesion volume at the level it has reached when treatment begins. 28 Because up to this time ADC volume steadily expands, the salvageable tissue mass declines accordingly.…”

Section: Rtpa-induced Reduction Of Tissue Injurymentioning

confidence: 99%

Thrombolytic Treatment of Clot Embolism in Rat

Niessen

Hilger

Hoehn

et al. 2002

Stroke

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Background and Purpose-We sought to test the hypothesis that intra-arterial recombinant tissue plasminogen activator (rtPA) treatment of thromboembolic stroke is more efficient than intravenous application. Methods-Rats were embolized by intracarotid injection of autologous fibrin-rich blood clots. One hour later rtPA (10 mg/kg) was infused either intravenously (nϭ8) or intra-arterially (nϭ8). Control rats (nϭ8) received intra-arterial infusion of saline. Treatment was monitored by MR perfusion-weighted imaging and apparent diffusion coefficient (ADC) imaging, and outcome was evaluated by comparing incidence of hemorrhages and lesion volumes of ATP and pH. Results-Clot embolism led to a decline of perfusion-weighted imaging signal intensity in the middle cerebral artery territory to Ͻ40% of control. Both intra-arterial and intravenous treatment significantly improved blood flow in cerebral cortex but not in caudate putamen. In untreated animals, ATP and pH lesion volumes were 510.3Ϯ94.5 and 438.6Ϯ39.2 mm 3 at 7 hours after clot embolism, respectively. Both intravenous and intra-arterial rtPA treatment produced hemorrhagic complications but reduced ATP lesion size to 296.2Ϯ136.1 and 370.3Ϯ103.7 mm 3 and reduced pH lesion size to 263.3Ϯ114.6 and 303.3Ϯ103.0 mm 3 , respectively (PϽ0.05 for untreated versus treated rats; no difference between intravenous and intra-arterial treatment). ADC imaging revealed that lesion reduction was due to inhibition of infarct growth but not to reversal of primary injury. Conclusions-This

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Thrombolysis of cerebral clot embolism in rat

Cited by 38 publications

References 7 publications

Thrombolysis and Neuroprotection in Cerebral Ischemia

Thrombolysis and Neuroprotection in Cerebral Ischemia

Prediction of Hemorrhagic Transformation After Thrombolytic Therapy of Clot Embolism

Thrombolytic Treatment of Clot Embolism in Rat

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