1-(3-4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine-dihydrochloride and Inflammation

Accumulating evidence has shown that astrocytes play a critical role in neuroinflammation and protection against oxidative stress. In this study, we investigated the effects of sigma-1 receptor (Sig-1R) activation on lipopolysaccharide (LPS)-induced inflammatory reactions and oxidative/nitrosative stress in cultured astrocytes. We found that SA4503, a selective Sig-1R agonist, attenuated LPS-induced inflammatory reactions and oxidative/nitrosative stress by downregulating the expression of iNOS and tumor necrosis factor α (TNF-α) and upregulating glutathione (GSH) in cultured astrocytes. To investigate the mechanism by which SA4503 caused these effects, we then examined the expression of nuclear factor erythroid-derived 2-like 2 (Nrf2) and heme oxygenase-1 (HO-1) through western blotting. The results revealed that SA4503 treatment increased Nrf2 and HO-1 expression significantly. These results suggested that the antioxidative/nitrosative stress and anti-inflammatory effects of Sig-1R activation in astrocytes were partially mediated by Nrf2 and HO-1 activation.

Topics: Animals; Astrocytes; Cells, Cultured; Heme Oxygenase (Decyclizing); Inflammation; Lipopolysaccharides; NF-E2-Related Factor 2; Nitric Oxide; Nitrosative Stress; Nootropic Agents; Oxidative Stress; Piperazines; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptors, sigma; Sigma-1 Receptor; Signal Transduction

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.

Topics: Animals; CD11b Antigen; Cytokines; Hypoxia-Ischemia, Brain; Infarction, Middle Cerebral Artery; Inflammation; Inflammation Mediators; Macrophages; Male; Microglia; Nitrites; Piperazines; Proliferating Cell Nuclear Antigen; Rats; Rats, Wistar; Receptors, sigma; Recovery of Function; Sigma-1 Receptor; Stroke