title: Effects of the sigma-1 receptor agonist 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)-piperazine dihydro-chloride on inflammation after stroke.
abstract: Activation of the sigma-1 receptor (Sig-1R) improves functional recovery in models of experimental stroke and is known to modulate microglia function. The present study was conducted to investigate if Sig-1R activation after experimental stroke affects mediators of the inflammatory response in the ischemic hemisphere. Male Wistar rats were subjected to transient occlusion of the middle cerebral artery (MCAO) and injected with the specific Sig-1R agonist 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) or saline for 5 days starting on day 2 after MCAO. Treatment did not affect the increased levels of the pro-inflammatory cytokines interleukin 1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), interleukin 4 (IL-4), interleukin 5 (IL-5), and interleukin 13 (IL-13) in the infarct core and peri-infarct area after MCAO. In addition, treatment with SA4503 did not affect elevated levels of nitrite, TNF-α and IL-1β observed in primary cultures of microglia exposed to combined Hypoxia/Aglycemia, while the unspecific sigma receptor ligand 1,3-di-o-tolylguanidine (DTG) significantly decreased the production of nitrite and levels of TNF-α. Analysis of the ischemic hemisphere also revealed increased levels of ionized calcium binding adaptor molecule 1 (Iba1) levels in the infarct core of SA4503 treated animals. However, no difference in Iba1 immunoreactivity was detected in the infarct core. Also, levels of the proliferation marker proliferating cell nuclear antigen (PCNA) and OX-42 were not increased in the infarct core in rats treated with SA4503. Together, our results suggest that sigma-1 receptor activation affects Iba1 expression in microglia/macrophages of the ischemic hemisphere after experimental stroke but does not affect post-stroke inflammatory mediators.
authors.affiliation: Department of Clinical Sciences, Division of Neurosurgery, Laboratory for Experimental Brain Research, Wallenberg Neuroscience Center, Lund University, Lund, Sweden. karsten.ruscher@med.lu.se
authors.forename: Karsten
authors.initials: K
authors.lastname: Ruscher
authors.forename: Ana R
authors.initials: AR
authors.lastname: Inácio
authors.forename: Kristian
authors.initials: K
authors.lastname: Valind
authors.forename: Arman
authors.initials: A
authors.lastname: Rowshan Ravan
authors.forename: Enida
authors.initials: E
authors.lastname: Kuric
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Wieloch
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009573:Nitrites / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017480:Receptors, sigma / Q000819:agonists* / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects; D020521:Stroke / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000097605:Sigma-1 Receptor
chemical_list: D039481:CD11b Antigen; D016207:Cytokines; D018836:Inflammation Mediators; D009573:Nitrites; D010879:Piperazines; D018809:Proliferating Cell Nuclear Antigen; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C101789:SA 4503