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However, it is unclear whether hyperhomocysteinemia contributes to disease pathology by inducing an inflammatory response. The current study investigates whether exposure of primary cultures from rat and mice cortical neurons to high levels of homocysteine induces the expression and release of the proinflammatory prostanoid, Prostaglandin E2 (PGE2). Using enzymatic assays and immunoblot analysis we show concurrent increase in the activity of cytosolic phospholipase A2 (cPLA2) and level of cyclooxygenase\u20102 (COX2), two enzymes involved in PGE2 biosynthesis. The findings also show an increase in PGE2 release from neurons. Pharmacological inhibition of GluN2A\u2010containing NMDAR (GluN2A\u2010NMDAR) with NVP\u2010AAM077 significantly reduces homocysteine\u2010induced cPLA2 activity, COX2 expression, and subsequent PGE2 release. Whereas, inhibition of GluN2B\u2010containing NMDAR (GluN2A\u2010NMDAR) with Ro 25\u20106981 has no effect. Complementary studies in neuron cultures obtained from wild type and GluN2A knockout mice show that genetic deletion of GluN2A subunit of NMDAR attenuates homocysteine\u2010induced neuronal increase in cPLA2 activity, COX2 expression, and PGE2 release. Pharmacological studies further establish the role of both extracellular\u2010regulated kinase\/mitogen\u2010activated protein kinase and p38 MAPK in homocysteine\u2010GluN2A NMDAR\u2010dependent activation of cPLA2\u2010COX2\u2010PGE2 pathway. Collectively, these findings reveal a novel role of GluN2A\u2010NMDAR in facilitating homocysteine\u2010induced proinflammatory response in neurons.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc14775-fig-0008-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.14775","type":"journal-article","created":{"date-parts":[[2019,5,24]],"date-time":"2019-05-24T16:25:46Z","timestamp":1558715146000},"page":"44-55","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Role of GluN2A NMDA receptor in homocysteine\u2010induced prostaglandin E2 release from neurons"],"prefix":"10.1111","volume":"150","author":[{"given":"Sathyanarayanan","family":"Rajagopal","sequence":"first","affiliation":[{"name":"Department of Neurology University of New Mexico Health Sciences Center University of New Mexico Albuquerque New Mexico USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashley Anne","family":"Fitzgerald","sequence":"additional","affiliation":[{"name":"Department of Neurology University of New Mexico Health Sciences Center University of New Mexico Albuquerque New Mexico USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satya Narayan","family":"Deep","sequence":"additional","affiliation":[{"name":"Department of Neurology University of New Mexico Health Sciences Center University of New Mexico Albuquerque New Mexico USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Surojit","family":"Paul","sequence":"additional","affiliation":[{"name":"Department of Neurology University of New Mexico Health Sciences Center University of New Mexico Albuquerque New Mexico USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8459-5560","authenticated-orcid":false,"given":"Ranjana","family":"Poddar","sequence":"additional","affiliation":[{"name":"Department of Neurology University of New Mexico Health Sciences Center University of New Mexico Albuquerque New Mexico USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,6,20]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.3988\/jcn.2014.10.4.281"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-894X(02)00074-4"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.1999.00399.x"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1385\/MN:26:2-3:283"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1101\/lm.777308"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2006.04280.x"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.108.521898"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-012-0769-2"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11011-010-9188-8"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.1.264"},{"key":"e_1_2_7_12_1","first-page":"7","article-title":"The glutamate receptor ion channels","volume":"51","author":"Dingledine R.","year":"1999","journal-title":"Pharmacol. 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