Effects of the sigma-1 receptor agonist 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)- piperazine dihydro-chloride on inflammation

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-1b), tumor necrosis factor alpha (TNF-a), interferon gamma (IFN-c), 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-a and IL-1b observed in primary cultures of microglia exposed to combined Hypoxia/Aglycemia, while the unspecific sigma receptor ligand 1,3-di-otolylguanidine (DTG) significantly decreased the production of nitrite and levels of TNF-a. 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. Citation: Ruscher K, Inácio AR, Valind K, Rowshan Ravan A, Kuric E, et al. (2012) Effects of the Sigma-1 Receptor Agonist 1-(3,4-Dimethoxyphenethyl)-4-(3Phenylpropyl)-Piperazine Dihydro-Chloride on Inflammation after Stroke. PLoS ONE 7(9): e45118. doi:10.1371/journal.pone.0045118 Editor: Christoph Kleinschnitz, Julius-Maximilians-Universität Würzburg, Germany Received April 13, 2012; Accepted August 14, 2012; Published September 18, 2012 Copyright: 2012 Ruscher et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study was supported by the Swedish Research Council (grant 2011-2684 (KR) and grant 2011-2652 (TW)), the EU 7th workprogram through the European Stroke Network (grant No 201024), the Pia Ståhls Foundation (TW), The Swedish Brain Fund (TW), the Greta och Johan Kocks Stiftelser (KR), the Thorsten och Elsa Segerfalk stiftelse (KR), the Kungliga Fysiografiska Sällskapet i Lund (KR) and the Anna-Lisa Rosenbergs fond (KR). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected] . These authors contributed equally to this work.