Akt / GSK3ß / Nrf2 / HO-1 pathway activation by flurbiprofen protects the hippocampal neurons in a rat model of glutamate excitotoxicity.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates redox homeostasis of the cell through regulation of the antioxidant response element genes transcription. Nrf2 also regulates the antiapoptotic Bcl-2 gene. Nrf2 degradation and nuclear translocation is regulated by upstream kinases Akt and GSK3ß. Glutamate excitotoxicity is a process of neuronal cells death due to excessive activation of glutamate receptors. Glutamate excitotoxicity participates in the pathophysiology of several acute and chronic neurological conditions. In addition, glutamate excitotoxicity interrupts the PI3K/Akt prosurvival pathway so GSK3ß remains active. Active GSK3ß increases Nrf2 degradation, decreases Nrf2 nuclear translocation and increases Nrf2 nuclear export which decreases the ARE genes transcription such as, SOD, GSH synthesis enzyme and HO-1. Also, Bcl-2 transcription decreases. Flurbiprofen is a COX inhibitor. Previous studies showed that it has a neuroprotective effect in neurodegeneration and in focal cerebral ischemia/reperfusion model. In our research we aimed to test the hypothesis that flurbiprofen may have a neuroprotective effect in a rat model of glutamate-induced excitotoxicity and this neuroprotection may occur through modulation of (Akt/GSK3ß/Nrf2/HO-1) pathway. Rats were divided into 4 groups; control, MSG (2.5 g/Kg, i.p), low dose FB (5 mg/kg, i.p) and high dose FB (10 mg/kg, i.p). We found that low and high doses FB decreased COX-2, PGE2, NO and MDA and increased SOD and GSH in brain compared to MSG group. High dose was more effective than low dose. Western blotting analysis in hippocampus tissue showed that high dose FB increased p-Akt, p-GSK3ß, nuclear Nrf2 and HO-1 and decreased cytosolic Nrf2 level in comparison with MSG group. Immunohistochemical analysis in hippocampus and cerebral cortex showed that high dose FB increased Bcl-2 and decreased Bax compared to MSG group. In addition, FB increased the number of intact neurons in hippocampus areas and cerebral cortex neurons and showed an anxiolytic-like action in OF and EPM tests. These findings suggest that FB has a neuroprotective effect in glutamate-induced excitotoxicity model through reduction of the glutamate excitotoxicity damage and activation of the survival pathway. These may occur due to modulation the survival pathway (Akt/GSK3ß/Nrf2/HO-1) and inhibition of COX-2.

Antidepressant-like effects of rosiglitazone, a PPARγ agonist, in the rat forced swim and mouse tail suspension tests.

Several studies have evaluated thiazolidinedione therapy as medical treatments for some central nervous system disorders, such as cognitive deficits associated with neurodegenerative disorders. However, there is limited data to support a direct role for peroxisome proliferator-activated receptor-γ agonists in depression. Therefore, the aim of this study was to investigate antidepressant-like activity of rosiglitazone using the mouse tail suspension test and the rat forced swimming test, two models sensitive to the effects of antidepressants. In the tail suspension test, 5 days of treatment with rosiglitazone (8.5 or 17 mg/kg, orally) reduced immobility time. In the forced swimming test, rosiglitazone (6 or 12 mg/kg, orally) treatment decreased immobility time and increased climbing. These effects were not accompanied by any alteration in locomotor activity in the open field test. Rosiglitazone treatment (6 or 12 mg/kg, orally) significantly reduced plasma corticosterone levels in rats. GW9662 significantly inhibited the rosiglitazone-induced reduction in the duration of immobility. In summary, this study suggests that rosiglitazone possesses a specific antidepressant-like activity in behavioral models and that this effect may be mediated by reduction of plasma corticosterone level.