title: Upregulation of protein phosphatase 2A and NR3A-pleiotropic effect of simvastatin on ischemic stroke rats.
abstract: Ca(2+) influxes are regulated by the functional state of N-methyl-D-aspartate receptors (NMDARs). Dephosphorylation of NMDARs subunits decreases Ca(2+) influxes. NR3, a novel subunit of NMDARs, also decreases Ca(2+) influxes by forming new NMDARs with NR1 and NR2. It is meaningful to uncover whether protein phosphatase 2A (PP2A) and NR3A play a role in the protective effect of Simvastatin on ischemic stroke. In the present study, the Sprague-Dawley rats were pretreated with Simvastatin for 7 days before middle cerebral artery occlusion was performed to mimic ischemic stroke. The results showed that Simvastatin decreased brain ischemic infarct area significantly while increasing the expression levels of PP2A and NR3A, thus dephosphorylating the serine sites of NR1 (ser896 and ser897) along with increased enzymatic activities of PP2A. The protein levels of NR3A decreased as the enzymatic activities of PP2A were inhibited by okadaic acid. The results indicated that Simvastatin could protect the cerebrum from ischemic injury through a signaling mechanism involving elevated levels of PP2A and NR3A, and that PP2A might involve in the regulatory mechanism of NR3A expression.
authors.affiliation: Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Minxia
authors.initials: M
authors.lastname: Zhu
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.forename: Dongshu
authors.initials: D
authors.lastname: Du
authors.forename: Chunmei
authors.initials: C
authors.lastname: Xia
authors.forename: Linlin
authors.initials: L
authors.lastname: Shen
authors.forename: Danian
authors.initials: D
authors.lastname: Zhu
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D058685:Genetic Pleiotropy / Q000187:drug effects*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000201:enzymology / Q000473:pathology; D008297:Male; D019319:Okadaic Acid / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D020521:Stroke / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: C409466:NR1 NMDA receptor; C464437:NR3A NMDA receptor; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D019319:Okadaic Acid; D019821:Simvastatin; D054648:Protein Phosphatase 2