Human Recombinant Tissue-Plasminogen Activator (Alteplase): Why Not Use the ‘Human’ Dose for Stroke Studies in Rats?

Haelewyn, Benoît; Risso, Jean-Jacques; Abraini, Jacques H.

doi:10.1038/jcbfm.2010.33

Cited by 44 publications

(41 citation statements)

References 15 publications

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“…In the second experiment, 20 rats were randomly divided into four equal groups as noted above, and these animals were used for the evaluation of BBB permeability and levels of MMP-9. The dose of r-tPA and AA was selected based on the other investigations [14,18] and our preliminary results. The drugs were applied at 5 hr after the stroke onset.…”

Section: Methodsmentioning

confidence: 99%

Ascorbic Acid Reduces the Adverse Effects of Delayed Administration of Tissue Plasminogen Activator in a Rat Stroke Model

Allahtavakoli

Amin

Esmaeeli-Nadimi

et al. 2015

Basic Clin Pharmacol Toxicol

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Delayed treatment of stroke with recombinant tissue plasminogen activator (r-tPA) induces overexpression of matrix metalloproteinase 9 (MMP-9) which leads to breakdown of the blood-brain barrier (BBB) and causes more injuries to the brain parenchyma. In this study, the effect of ascorbic acid (AA), an antioxidant agent, on the delayed administration of r-tPA in a rat model of permanent middle cerebral artery occlusion (MCAO) was investigated. Forty male rats were randomly divided into four groups: untreated control rats (ischaemic animals), AA-treated (500 mg/kg; 5 hr after stroke) rats, r-tPA-treated (5 hr after stroke 1 mg/kg) rats and rats treated with the combination of AA and r-tPA. Middle cerebral artery occlusion was induced by occluding the right middle cerebral artery (MCA). Infarct size, BBB, brain oedema and the levels of MMP-9 were measured at the end of study. Neurological deficits were evaluated at 24 and 48 hr after stroke. Compared to the control or r-tPA-treated animals, AA alone (p < 0.001) or in combination with r-tPA (p < 0.05) significantly decreased infarct volume. Ascorbic acid alone or r-tPA + AA significantly reduced BBB permeability (p < 0.05), levels of MMP-9 (p < 0.05 versus control; p < 0.01 versus r-tPA) and brain oedema (p < 0.001) when compared to either the control or the r-tPA-treated animals. Latency to the removal of sticky labels from the forepaw was also significantly decreased after the administration of AA + r-tPA (p < 0.05) at 24 or 48 hr after stroke. Based on our data, acute treatment with AA may be considered as a useful candidate to reduce the side effects of delayed application of r-tPA in stroke therapy. Ischaemic brain injury (IBI) is one of the most common causes of mortality and morbidity in the world [1,2]. Ischaemic brain injury is accompanied by several side effects, including brain oedema, destruction of blood-brain barrier (BBB), inflammation and induction of oxidative stress [3]. Oxidative stress in turn leads to oedema and more destruction of BBB which causes additional brain damage [4]. Reperfusion with thrombolytic recombinant tissue plasminogen activator (r-tPA) remains the only treatment proved to be safe and effective when given within 3-4.5 hr after ischaemia onset [5]. It has been shown that delayed use of r-tPA leads to hyperperfusion which results in the accumulation of free radicals and the up-regulation of matrix metalloproteinases (MMPs) including 7] and these events lead to more injuries to the brain parenchyma. Under normal conditions, the endogenous and exogenous antioxidants scavenge free radicals and inhibit the harmful effects of oxidative stress [8]. Previous investigations revealed that after IBI, the concentrations of glutathione and ascorbic acid (AA) are decreased, while free radicals are increased [9,10], suggesting that increasing the concentration of AA, which may act as an antioxidant under these conditions, could be considered as new therapeutic strategy for treatment of IBI [11].One vitamer form of AA, vitamin C, is a...

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Section: Methodsmentioning

confidence: 99%

Ascorbic Acid Reduces the Adverse Effects of Delayed Administration of Tissue Plasminogen Activator in a Rat Stroke Model

Allahtavakoli

Amin

Esmaeeli-Nadimi

et al. 2015

Basic Clin Pharmacol Toxicol

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“…A single clot measuring 40 mm in length was injected in a volume of 50 l saline solution through a polyethylene-10 catheter directed into the internal carotid artery up to 2 mm after the pterygopalatine-internal carotid artery bifurcation, as detailed previously. 29 After a 45-min period of occlusion during which all rats were given medical air, the catheter was removed from the internal carotid artery to the external carotid artery, and the rats were given tPA in the form of Actilyse at 0.9 mg/kg (a dose shown to be as clinically relevant as that of 10 mg/kg, which is often used in rodents 31 ) in 1 ml saline solution (10% bolus plus 90% perfusion over a 45-min period) with either medical air (n ϭ 5) or 75 vol% nitrous oxide (n ϭ 5). Then, all animals were given medical air again.…”

Section: Mcao Experiments With Intraischemic Nitrous Oxidementioning

confidence: 99%

Interactions between Nitrous Oxide and Tissue Plasminogen Activator in a Rat Model of Thromboembolic Stroke

et al. 2011

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Background: Preclinical evidence in rodents has suggested that inert gases, such as xenon or nitrous oxide, may be promising neuroprotective agents for treating acute ischemic stroke. This has led to many thinking that clinical trials could be initiated in the near future. However, a recent study has shown that xenon interacts with tissue-type plasminogen activator (tPA), a well-recognized approved therapy of acute

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“…Haelewyn et al showed that the dose of 0.9 mg/kg rtPA (the clinical dose in patients with stroke) is as appropriate as that of 10 mg/kg for preclinical stroke studies in rodents. 22 Aronowski et al found that 10-mg/kg dose of intravenous rtPA started 5 minutes after 180 minutes of MCAO was very toxic and resulted in severe bleeding and high mortality in animals and suggested that 5 mg/kg rtPA produced bleeding in approximately 85% to 90% of animals. 9 Accordingly, we used a total dose of 5 mg/kg (2.5 mg/kg bolus followed by 30-minute intravenous infusion at 5 mg/kg per hour) and rtPA was started 15 minutes after the onset of reperfusion.…”

Section: Discussionmentioning

confidence: 99%

“…Statistically significant effects were detected among all 3 groups when compared with the control: for forelimb foot fault placing ( Figure 3B; F [2,22] ϭ6.08, PϽ0.01), parallel bar traversing ( Figure 3C; F [2,22] ϭ14.75, PϽ0.01), and beam balance ( Figure 3D; F [2,22] ϭ22.70, PϽ0.01). The post hoc test indicated that significant improvements in motor behavior were achieved by each treatment in ischemic rats from 2 through 28 days after stroke.…”

Section: Ethanol In Combination With Hypothermiamentioning

confidence: 96%

Neuroprotective Effect of Acute Ethanol Administration in a Rat With Transient Cerebral Ischemia

Wang

et al. 2012

Stroke

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Background and Purpose-Ethanol consumption is inversely associated with the risk of ischemic stroke, suggesting a neuroprotective effect. In a rat model of transient cerebral ischemia, we identified ethanol as a possible treatment for acute ischemic stroke. Methods-Sprague-Dawley rats were subjected to middle cerebral artery occlusion for 2 hours. Five sets of experiments were conducted: to determine the dose-response effect of ethanol on brain infarction and functional outcome; to determine whether combining ethanol and hypothermia produces synergistic neuroprotection; to determine the therapeutic windows of opportunity for ethanol in stroke; to test whether ethanol promotes intracerebral hemorrhage in a hemorrhagic or ischemic stroke or after administration of thrombolytics; and to test the affect of ethanol on hypoxia-inducible factor-1␣ protein expression. Results-Ethanol at 1.5 g/kg reduced infarct volume and behavioral dysfunction when administered at 2, 3, or 4 hours after middle cerebral artery occlusion. The protective effect of ethanol was not improved when paired with hypothermia. Ethanol did not promote cerebral hemorrhage in hemorrhagic or ischemic stroke in combination with recombinant tissue-type plasminogen activator or urokinase. Ethanol treatment (1.5 g/kg) increased protein levels of hypoxiainducible factor-1␣ at 3 hours postreperfusion. Conclusions-Ethanol exerts a strong neuroprotective effect when administered up to 4 hours after ischemia, increases expression of hypoxia-inducible factor-1␣, and does not promote intracerebral hemorrhage when used with thrombolytics. Ethanol is a potential neuroprotectant for acute ischemic stroke. (Stroke. 2012;43:205-210.)

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Human Recombinant Tissue-Plasminogen Activator (Alteplase): Why Not Use the ‘Human’ Dose for Stroke Studies in Rats?

Cited by 44 publications

References 15 publications

Ascorbic Acid Reduces the Adverse Effects of Delayed Administration of Tissue Plasminogen Activator in a Rat Stroke Model

Ascorbic Acid Reduces the Adverse Effects of Delayed Administration of Tissue Plasminogen Activator in a Rat Stroke Model

Interactions between Nitrous Oxide and Tissue Plasminogen Activator in a Rat Model of Thromboembolic Stroke

Neuroprotective Effect of Acute Ethanol Administration in a Rat With Transient Cerebral Ischemia

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