title: 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.
authors.affiliation: Physiology-Pharmacology Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Allahtavakoli
authors.affiliation: Physiology-Pharmacology Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Amin
authors.affiliation: Department of Cardiology, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
authors.forename: Ali
authors.initials: A
authors.lastname: Esmaeeli-Nadimi
authors.affiliation: Physiology-Pharmacology Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
authors.forename: Ali
authors.initials: A
authors.lastname: Shamsizadeh
authors.affiliation: Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Kazemi-Arababadi
authors.affiliation: School of Natural Sciences, Eskitis Institute for Drug Discovery, Griffith University Nathan, Nathan, Qld, Australia.
authors.forename: Derek
authors.initials: D
authors.lastname: Kennedy
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001929:Brain Edema / Q000517:prevention & control; D002199:Capillary Permeability / Q000187:drug effects; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000633:toxicity; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D011994:Recombinant Proteins / Q000008:administration & dosage; D015912:Thrombolytic Therapy / Q000009:adverse effects; D013997:Time Factors; D061665:Time-to-Treatment; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000633:toxicity
chemical_list: D000975:Antioxidants; D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat; D001205:Ascorbic Acid