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

P. Srivastava,Y. K. Dhuriya,Vivek Kumar,A. Srivastava,Richa Gupta,R. Shukla,R. Yadav,Hari N. Dwivedi,A. Pant,V. Khanna

Published 2018 in Neurotoxicology

ABSTRACT

HIGHLIGHTSProtective role of curcumin in arsenic induced NMDA receptor alterations investigated.Sodium arsenite decreased expression of BDNF, pAkt, pErk ½, pGSK3&bgr; and pCREB.Curcumin protected sodium arsenite induced changes via PI3/Akt/MAPK pathway in hippocampus.Impaired cognitive deficits by sodium arsenite in rats also recovered by curcumin. ABSTRACT Protective efficacy of curcumin in arsenic induced NMDA receptor dysfunctions and PI3K/Akt/ GSK3&bgr; signalling in hippocampus has been investigated in vivo and in vitro. Exposure to sodium arsenite (in vivo – 20mg/kg, body weight p.o. for 28 days; in vitro – 10&mgr;M for 24h) and curcumin (in vivo – 100mg/kg body weight p.o. for 28 days; in vitro – 20&mgr;M for 24h) 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&agr;, PSD‐95 and SynGAP both in vivo and in vitro. Decreased levels of BDNF, pAkt, pERK1/2, pGSK3&bgr; 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&bgr; neuronal survival pathway, known to regulate various cellular events. Treatment of hippocampal cultures with pharmacological inhibitors for ERK1/2, GSK3&bgr; and Akt individually inhibited levels of CREB and proteins associated with PI3K/Akt/GSK3&bgr; 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&bgr; and BDNF in arsenic induced cognitive deficits in hippocampus.

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