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

Abstract

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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