Akt/GSK3β/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 GSK3 beta. 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 GSK3 beta remains active. Active GSK3 beta 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. Flurbipmfen 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 neuropmtection may occur through modulation of (Akt/GSK3 beta/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, PGE(2), 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-GSK3 beta, 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 Box 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/GSK3 beta/Nrf2/HO-1) and inhibition of COX-2.

Automated summary

The study found that flurbiprofen has a neuroprotective effect in a glutamate-induced excitotoxicity model, which may be achieved by reducing damage and activating the survival pathway.