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.

Sigma Receptor Ligand, (+)-Pentazocine, Suppresses Inflammatory Responses of Retinal Microglia

“…In addition, in models of rheumatoid arthritis and sepsis, a decrease in cytokine release was observed after treatment with the r ligands SR31747A and SSR 125329A, respectively. 39,40 However, Ruscher et al 28 have found that exposure of rat brain-derived microglia to the rR1 ligand SA4503 did not affect the release of proinflammatory mediators after combined hypoxia/aglycemia stimulation. To our knowledge, no previous reports address the effects of (þ)-pentazocine, specifically, on microglia.…”

“…27 In addition to neuroprotection, rR1 activation has been associated with decreased reactive gliosis in both the ALS mouse model and the rat stroke injury model. 26,28 Evidence also suggests that some rR1 ligands can repress activation of the MAPK/ERK pathway within cortical neurons. 29 Recent work has shown that r receptors modulate the activation of CNS-derived primary microglia.…”

Sigma-1 Receptors and Neurodegenerative Diseases: Towards a Hypothesis of Sigma-1 Receptors as Amplifiers of Neurodegeneration and Neuroprotection

“…Following cerebral ischemia, both necrotic and apoptotic cell death can be induced through complex interactions of pathological processes, including excitotoxicity and inflammation [8, 9]. Neuroprotective and neurorestorative effects of sigma-1 agonists (e.g., decreasing cell death, protecting against tissue damage, and increasing synaptic protein expression) have been shown in multiple animal models of stroke, including mouse [10], rat [11–16], gerbil [17] and cat [18]. In rat models of stroke, for example, decreased infarct volume as well as enhanced neuronal survival were observed following acute treatment with a sigma agonist 24 h after the onset of ischemia [14, 15].…”

Central inflammatory response to experimental stroke is inhibited by a neuroprotective dose of dietary soy

“…The significant down-regulation of IL13 in soy-fed rats was an unexpected result, as IL13 is traditionally considered an antiinflammatory cytokine. Previous studies revealed both increases (Ruscher et al, 2012) and decreases (Yu et al, 2010) in IL13 in response to ischemia, although the latter result reflects hippocampal injury in Mongolian gerbils. The lack of IL13 increase in the soy-fed animals may be interpreted as either a reduction of injury that fails to reach the threshold for IL13 activation or a reduction in potential deleterious effects of IL13.…”