Neuroprotective effect of the new thiadiazolidinone NP00111 against oxygen-glucose deprivation in rat hippocampal slices: Implication of ERK1/2 and PPARγ receptors

Abstract

Thiadiazolidinones (TDZDs) are small molecules that inhibit glycogen synthase kinase 3-β (GSK3-β) activity in a non competitive manner to ATP. NP00111, a new TDZD, besides causing inhibition of GSK-3β, has also shown to be an agonist of PPARγ . Since phosphorylation and consequent inhibition of GSK-3β by PI-3K/Akt and agonism of PPARγ have shown to afford neuroprotection in several in vitro and in vivo models, we have studied the potential neuroprotective effect of NP00111 in an “ in vitro” model of ischemia–reperfusion. NP00111, at the concentration of 10 μM, significantly protected adult rat hippocampal slices subjected to oxygen and glucose deprivation (OGD) for 1 h followed by 3 h re-oxygenation, measured as lactic dehydrogenase (LDH) released to the extracellular media. The protective effects of NP00111 were more pronounced during the re-oxygenation period in comparison to the OGD period. Other GSK-3β inhibitors like lithium or AR-A014418 did not afford protection in this model. However, the PPARγ agonist rosiglitazone was protective at 3 μM. Protection afforded by NP00111 and rosiglitazone were prevented by the PPARγ antagonist GW9662, suggesting that both NP00111 and rosiglitazone were preventing cell death caused by oxygen-glucose deprivation via activation of PPARγ. NP00111 increased by two fold phosphorylation of ERK1/2 and its protective effects were lost when the hippocampal slices were co-incubated with the mitogen-activated protein kinase (MAPK) inhibitor PD98059. In conclusion, the novel TDZD NP00111 was protective against OGD in rat hippocampal slices by a mechanism related to phosphorylation of ERK1/2 via activation of PPARγ.