PI3K/Akt/GSK3 beta induced CREB activation ameliorates arsenic mediated alterations in NMDA receptors and associated signaling in rat hippocampus: Neuroprotective role of curcumin

摘要

Protective efficacy of curcumin in arsenic induced NMDA receptor dysfunctions and PI3K/Akt/ GSK3 beta signalling in hippocampus has been investigated in vivo and in vitro. Exposure to sodium arsenite (in vivo - 20 mg/kg, body weight p.o. for 28 days; in vitro - 10 mu M for 24 h) and curcumin (in vivo - 100 mg/kg body weight p.o. for 28 days; in vitro - 20 mu M for 24 h) was carried out alone or simultaneously. Treatment with curcumin ameliorated sodium arsenite induced alterations in the levels of NMDA receptors, its receptor subunits and synaptic proteins - pCaMKII alpha, PSD-95 and SynGAP both in vivo and in vitro. Decreased levels of BDNF, pAkt, pERK1/2, pGSK3 beta and pCREB on sodium arsenite exposure were also protected by curcumin. Curcumin was found to decrease sodium arsenite induced changes in hippocampus by modulating PI3K/Akt/GSK3 beta neuronal survival pathway, known to regulate various cellular events. Treatment of hippocampal cultures with pharmacological inhibitors for ERK1/2, GSK3 beta and Akt individually inhibited levels of CREB and proteins associated with PI3K/Akt/GSK3 beta pathway. Simultaneous treatment with curcumin was found to improve sodium arsenite induced learning and memory deficits in rats assessed by water maze and Y-maze. The results provide evidence that curcumin exercises its neuroprotective effect involving PI3K/Akt pathway which may affect NMDA receptors and downstream signalling through TrK beta and BDNF in arsenic induced cognitive deficits in hippocampus. (C) 2018 Elsevier B.V. All rights reserved.