Effect of Delayed Thrombolysis with rt-PA in a Rat Embolic Stroke Model

Overgaard, Karsten; Sereghy, Tomas; Pedersen, H.; Boysen, Gudrun

doi:10.1038/jcbfm.1994.58

Cited by 62 publications

(26 citation statements)

References 22 publications

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“…14 The only partial exception to this is a report by Sakurama et al, 19 in which treatment with tPA as long as 6 hours after stroke significantly reduced lesion development but failed to improve the neurological status of the treated animals. The model or technical distinctions responsible for the various reported treatment windows are not clear but likely reflect thromboembolic model differences in emboli preparation or surgical technique.…”

Section: Discussionmentioning

confidence: 81%

Inhibition of Factor IX(a) Is Protective in a Rat Model of Thromboembolic Stroke

Toomey

Valocik

Koster

et al. 2002

Stroke

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Background and Purpose-Although used clinically to prevent stroke, there are few examples of anticoagulant investigations in the treatment of acute thromboembolic stroke in animal models. The treatment of thromboembolic stroke in experimental models has been investigated almost exclusively around the use of tissue plasminogen activator (tPA). In this study, using a rat thromboembolic stroke model, we investigated the use of an inhibitory anti-factor IX(a) monoclonal antibody (SB 249417) for the treatment of thromboembolic stroke and compared its efficacy to that of tPA. Methods-Stroke was initiated by delivering 6 clots into the internal carotid artery. After 2, 4, or 6 hours, rats received either intravenous vehicle, 10.0 mg/kg tPA, or 1.0, 2.0, or 3.0 mg/kg SB 249417. At 24 hours after stroke, infarct volumes and neurological deficits were assessed. Results-Treatment with tPA 2, 4, or 6 hours after stroke reduced infarct volumes by 35% (PϭNS), 45%, and 39%, respectively. tPA treatment did not improve neurological deficits at any time point. Treatment with SB 249417 (3.0 mg/kg) 2, 4, or 6 hours after stroke reduced infarct volumes by 44%, 50%, and 13% (PϭNS), respectively. Neurological deficits were reduced by 49%, 42%, and 13% (PϭNS), respectively. Neither mortality nor hemorrhage was affected by either treatment. Conclusions-The data indicate that the inhibition of factor IX(a) within 4 hours of thromboembolic stroke produced a more favorable outcome than tPA. When treatment was initiated 6 hours after stroke, the benefits of factor IX(a) inhibition were lost, whereas tPA continued to suppress lesion development, albeit without a corresponding improvement in functional deficits. This study suggests that cerebral ischemia and the resultant perfusion deficit are exacerbated by the activation of blood coagulation and that anticoagulants like SB 249417 may find utility in the treatment of ischemic stroke. (Stroke. 2002;33:578-585.)

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Section: Discussionmentioning

confidence: 81%

Inhibition of Factor IX(a) Is Protective in a Rat Model of Thromboembolic Stroke

Toomey

Valocik

Koster

et al. 2002

Stroke

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“…The protection exerted by NS-398 is not attributable to effects on body temperature, arterial pressure, blood gases, plasma glucose, or hematocrit, because these parameters were monitored and did not differ between treated and untreated groups. It is also unlikely that NS-398 reduced cerebral ischemic damage by improving postischemic blood flow, because at the time when the NS-398 treatment was instituted, i.e., 6 hr after ischemia, vascular-hemodynamic factors no longer influence tissue outcome (Overgard et al, 1994;Zhang and Iadecola, 1994a). Effects of NS-398 on platelet aggregation are also unlikely, because platelets contain COX-1 and not COX-2 (Klein et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Cyclo-Oxygenase-2 Gene Expression in Neurons Contributes to Ischemic Brain Damage

et al. 1997

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Cyclo-oxygenase-2 (COX-2), a rate-limiting enzyme for prostanoid synthesis, is induced during inflammation and participates in inflammation-mediated cytotoxicity. Cerebral ischemia is followed by an inflammatory reaction that plays a role in the evolution of the tissue damage. We studied whether COX-2 is induced after cerebral ischemia and if so, whether such expression contributes to ischemic brain damage. The middle cerebral artery was occluded in rats, and the ischemic area was sampled for analysis 3-96 hr later. COX-2 mRNA was determined by the competitive reverse-transcription PCR. COX-2 mRNA was upregulated in the ischemic hemisphere, but not contralaterally, beginning 6 hr after ischemia. The upregulation reached a maximum at 12 hr, at which time a fivefold induction of the message occurred. Twenty-four hours after ischemia, the concentration of prostaglandin E 2 was elevated in the injured brain by 292 Ϯ 57% (n ϭ 6). COX-2 immunoreactivity was observed in neurons at the medial edge of the ischemic area. Administration of the COX-2 inhibitor NS-398 attenuated the elevation in prostaglandin E 2 in the postischemic brain and reduced the volume of the infarct by 29 Ϯ 6% ( p Ͻ 0.05). Thus, cerebral ischemia leads to upregulation of COX-2 message, protein, and reaction products in the injured hemisphere. The data implicate COX-2 in the mechanisms of delayed neuronal death at the infarct border and provide the rationale for neuroprotective strategies employing COX-2 inhibitors.

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“…Cerebral protection from tPA has been shown in earlier stroke studies [7][8][9] that led to clinical trials with tPA. 4 -6 Unwanted side effects of tPA treatment for stroke were also noted, including a higher rate of intracerebral hemorrhage, 28 downstream displacement of thrombolysed material, breakdown of the blood-brain barrier, and reperfusion injury.…”

Section: Discussionmentioning

confidence: 99%

Tissue Plasminogen Activator (tPA) Deficiency Exacerbates Cerebrovascular Fibrin Deposition and Brain Injury in a Murine Stroke Model

Tabrizi

Wang

Seeds

et al. 1999

ATVB

118

105

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Abstract-Although the serine protease, tissue plasminogen activator (tPA), is approved by the US Food and Drug Administration for therapy to combat focal cerebral infarction, the basic concept of thrombolytic tPA therapy for stroke was challenged by recent studies that used genetically manipulated tPA-deficient (tPAϪ/Ϫ) mice, which suggested that tPA mediates ischemic neuronal damage. However, those studies were potentially flawed because the genotypes of tPAϪ/Ϫ and wild-type control mice were not entirely clear, and ischemic neuronal injury was evaluated in isolation of tPA effects on brain thrombosis. Using mice with appropriate genetic backgrounds and a middle cerebral artery occlusion stroke model with nonsiliconized thread, which does lead to microvascular thrombus formation, in the present study we determined the risk for cerebrovascular thrombosis and neuronal injury in tPAϪ/Ϫ and genetically matched tPAϩ/ϩ mice subjected to transient focal ischemia. Cerebrovascular fibrin deposition and the infarction volume were increased by 8.2-and 6.7-fold in tPAϪ/Ϫ versus tPAϩ/ϩ mice, respectively, and these variables were correlated with reduced cerebral blood flow up to 58% (PϽ0.05) and impaired motor neurological score by 70% (PϽ0.05). Our findings indicate that tPA deficiency exacerbates ischemia-induced cerebrovascular thrombosis and that endogenous tPA protects the brain from an ischemic insult, presumably through its thrombolytic action. In addition, our study emphasizes the importance of appropriate genetic controls in murine stroke research. (Arterioscler Thromb Vasc Biol.

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Effect of Delayed Thrombolysis with rt-PA in a Rat Embolic Stroke Model

Cited by 62 publications

References 22 publications

Inhibition of Factor IX(a) Is Protective in a Rat Model of Thromboembolic Stroke

Inhibition of Factor IX(a) Is Protective in a Rat Model of Thromboembolic Stroke

Cyclo-Oxygenase-2 Gene Expression in Neurons Contributes to Ischemic Brain Damage

Tissue Plasminogen Activator (tPA) Deficiency Exacerbates Cerebrovascular Fibrin Deposition and Brain Injury in a Murine Stroke Model

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