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Our previous work has demonstrated that gp120 enhanced excitatory postsynaptic currents (EPSCs) mediated by\n                    <jats:italic>N<\/jats:italic>\n                    \u2010methyl\u2010\n                    <jats:sc>d<\/jats:sc>\n                    \u2010aspartate receptors (NMDARs) and caused neural injury. However, the relationship between gp120, NMDARs and HAND is still unclear. Several lines of evidence indicate that double\u2010stranded RNA\u2010activated protein kinase (PKR) is involved in NMDA\u2010induced cerebral ischaemia and retinal damage, but because its role in neuropathology is still debated, we examined whether PKR links oxidative stress and endoplasmic reticulum (ER) stress to exert a deleterious role in the rat model with gp120\u2010induced dementia. In this study, we found that NMDAR antagonist memantine or PKR inhibitor C16 improved gp120\u2010induced learning and memory impairment and inhibited gp120\u2010induced PKR activity. Furthermore, memantine or C16 was found to attenuate gp120\u2010induced neuroinflammation, oxidative stress, ER stress and its downstream IRE1\u03b1\/JNK pathway. Additionally, memantine or C16 evidently inhibited apoptotic pathways by reducing the Bax and caspase\u20103, \u20108, \u20109 expressions and increasing Bcl\u20102 expression. So the NMDA receptor antagonists could alleviate HIV\/gp120\u2010induced dementia in the rat model by altering PKR level. In conclusion, this study demonstrates that NMDARs play a key role in HIV\/gp120\u2010induced hippocampal damage and cognitive dysfunction through PKR\u2010mediated oxidative stress, ER stress, and IRE1\u03b1\/JNK signalling pathway in rats, and implicating PKR inhibitors could provide a novel neuroprotective strategy for HAND via inhibiting ER stress and its downstream IRE1\u03b1 signalling pathway.\n                  <\/jats:p>","DOI":"10.1111\/ejn.15688","type":"journal-article","created":{"date-parts":[[2022,5,11]],"date-time":"2022-05-11T11:51:32Z","timestamp":1652269892000},"page":"3806-3824","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["NMDA receptor antagonists engender neuroprotection against gp120\u2010induced cognitive dysfunction in rats through modulation of PKR activation, oxidative stress, ER stress and IRE1\u03b1 signal 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