title: Combination therapy of rosiglitazone, a peroxisome proliferator-activated receptor-gamma ligand, and NMDA receptor antagonist (MK-801) on experimental embolic stroke in rats.
abstract: Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists have been found to have potent anti-inflammatory actions and suggested as potential therapies for brain ischaemia. Glutamate is the most common excitatory neurotransmitter in the central nervous system and is released excessively during ischaemia. Stroke therapy will require combinations of drug classes, because no single drug class has yet been proven efficacious in human beings. The present study was conducted to assess whether N-methyl-d-aspartate (NMDA) receptor antagonist (MK-801) treatment can improve recovery from ischaemic brain injury and whether rosiglitazone, a PPAR-gamma ligand, can increase its neuroprotective effect in an embolic model of stroke. Stroke was induced in rats by embolizing a preformed clot into the middle cerebral artery. Rosiglitazone (0.1 mg/kg, intraperitoneally) and MK-801 (0.1 mg/kg, intravenously) were injected immediately after embolization. Forty-eight hours later, the brains were removed, sectioned and stained with triphenyltetrazolum chloride and analysed by a commercial image processing software programme. Rosiglitazone and MK-801 alone or in combination decreased infarct volume by 49.16%, 50.26% and 81.32%, respectively (P < 0.001). Moreover, the combination therapy significantly decreased the infarct volume when compared to any drug used alone (P < 0.05). MK-801 reduced the brain oedema by 68% compared to the control group (P < 0.05), but rosiglitazone or combination did not show any significant effect. The drugs alone or in combination also demonstrated improved neurological function, but combination therapy was more effective on neurological deficits improving. Our data show that the combination of MK-801 and rosiglitazone is more neuroprotective in thromboembolic stroke than given alone; this effect perhaps represents a possible additive effect in the brain infarction.
authors.affiliation: Department of Physiology and Pharmacology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran. alahtavakoli@razi.tums.ac.ir
authors.forename: Mohammad
authors.initials: M
authors.lastname: Allahtavakoli
authors.forename: Alireza
authors.initials: A
authors.lastname: Shabanzadeh
authors.forename: Ali
authors.initials: A
authors.lastname: Roohbakhsh
authors.forename: Aliasghar
authors.initials: A
authors.lastname: Pourshanazari
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001777:Blood Coagulation; D001921:Brain / Q000473:pathology; D002544:Cerebral Infarction / Q000188:drug therapy / Q000473:pathology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000627:therapeutic use*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006993:Hypnotics and Sedatives; D020766:Intracranial Embolism / Q000150:complications* / Q000523:psychology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D047495:PPAR gamma / Q000187:drug effects*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D000077154:Rosiglitazone; D020521:Stroke / Q000188:drug therapy* / Q000209:etiology* / Q000523:psychology; D045162:Thiazolidinediones / Q000627:therapeutic use*
chemical_list: D006993:Hypnotics and Sedatives; D018696:Neuroprotective Agents; D047495:PPAR gamma; D016194:Receptors, N-Methyl-D-Aspartate; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D016291:Dizocilpine Maleate; D004121:Dimethyl Sulfoxide