Combination Therapy of Rosiglitazone, a Peroxisome Proliferator‐Activated Receptor‐γ Ligand, and NMDA Receptor Antagonist (MK‐801) on Experimental Embolic Stroke in Rats

Abstract

Peroxisome proliferator-activated receptor-γ (PPAR-γ ) 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-γ 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.

Peroxisome Proliferator‐Activated Receptors: “Key” Regulators of Neuroinflammation after Traumatic Brain Injury

“…PPARs have also been shown to attenuate adaptive immune responses by inhibiting helper T cell functions and by mediating apoptosis of B cells [41, 42]. PPARs are activated by naturally ocurring fatty acid derivatives, eicosanoides, and by synthetic pharmacological agents, such as fibrates (PPAR α ) and glitazones (PPAR γ ) [18, 22, 43]. PPAR ligands have been shown to exert anti-inflammatory activities in various cell types by inhibiting the gene expression for proinflammatory cytokines, metalloproteinases, and hepatic acute-phase proteins.…”

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

“…To compensate for the effect of brain oedema, the corrected infarct volume was calculated as follows: corrected infarct area = measured infarct area 9 {1À[(ipsilateral hemisphere area-contralateral hemisphere area)/contralateral hemisphere]}. Brain oedema was determined using the following formula: oedema = (volume of left hemisphere volume of right hemisphere)/volume of right hemisphere [21]. The brain oedema was reported as percentages.…”

Rosiglitazone infusion therapy following minimally invasive surgery for intracerebral hemorrhage evacuation decreases matrix metalloproteinase-9 and blood–brain barrier disruption in rabbits

“…RSG, an agonist of peroxisome proliferator-activated receptor-gamma (PPARγ), has been demonstrated to be effective in the treatment of ischemic stroke [28,29]. There are a few studies that have reported the role of RSG in the treatment of ICH [19,30], thus demonstrating that RSG promotes hematoma resolution, decreases neuronal damage, and improves functional recovery.…”