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

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Sigma Receptor Ligand, (Þ)-Pentazocine, Suppresses Inflammatory Responses of Retinal Microglia Retinal Cell Biology Sigma Receptor Ligand, (þ)-Pentazocine, Suppresses Inflammatory Responses of Retinal Microglia Jing Zhao,1–3 Yonju Ha,*,1,3 Gregory I. Liou,1,2 Graydon B. Gonsalvez,3 Sylvia B. Smith,1–3 and Kathryn E. Bollinger1–3 1James and Jean Culver Vision Discovery Institute, Georgia Regents University, Augusta, Georgia, United States 2Department of Ophthalmology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States 3Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States Correspondence: Kathryn E. Bollin- PURPOSE. To evaluate the effects of the r 1 receptor (rR1) agonist, (þ)-pentazocine, on ger, Department of Ophthalmology, lipopolysaccharide (LPS)–induced inflammatory changes in retinal microglia cells. Medical College of Georgia, Georgia Regents University, 1120 15th Street, METHODS. Retinal microglia cells were isolated from Sprague-Dawley rat pups. Cells were BA 2320, Augusta, GA 30912, USA; treated with LPS with or without (þ)-pentazocine and with or without the rR1 antagonist [email protected]. BD1063. Morphologic changes were assayed. Cell viability was assessed by using MTT assay. Current affiliation: *Department of Supernatant levels of tumor necrosis factor a (TNF-a), interleukin 10, (IL-10), monocyte Ophthalmology and Visual Sciences, chemoattractant protein-1 (MCP-1), and nitric oxide (NO) were determined. Reactive oxygen University of Texas Medical Branch, species (ROS) formation was assayed, and levels of mitogen-activated protein kinases (MAPKs) Galveston, Texas, United States. were analyzed by using Western blot. Submitted: July 14, 2013 RESULTS. The rR1 protein was expressed in retinal microglia. Incubation with LPS and/or (þ)- Accepted: April 29, 2014 pentazocine did not alter cell viability or rR1 protein levels. Incubation with LPS for 24 hours Citation: Zhao J, Ha Y, Liou GI, induced a marked change in microglial morphology and a significant increase in secreted Gonsalvez GB, Smith SB, Bollinger KE. levels of TNF-a, IL-10, MCP-1, and NO. Pretreatment with (þ)-pentazocine inhibited the LPS- Sigma receptor ligand, (þ)-pentazo- induced morphologic changes. Release of TNF-a, IL-10, MCP-1, and NO was reduced with (þ)- cine, suppresses inflammatory re- pentazocine. Intracellular ROS formation was suppressed with (þ)-pentazocine. Phosphor- sponses of retinal microglia. Invest ylation of extracellular signal–regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) was Ophthalmol Vis Sci. 2014;55:3375– reduced in the presence of (þ)-pentazocine. The rR1 antagonist BD1063 blocked the (þ)- 3384. DOI:10.1167/iovs.13-12823 pentazocine–mediated inhibition of LPS-induced morphologic changes. In addition, BD1063 treatment blocked (þ)-pentazocine–mediated suppression of LPS-induced TNF-a, IL-10, MCP- 1, NO, and intracellular ROS release. CONCLUSIONS. Treatment with (þ)-pentazocine suppressed inflammatory responses of retinal microglia and inhibited LPS-induced activation of ERK/JNK MAPK. In neurodegenerative disease, (þ)-pentazocine may exert neuroprotective effects through manipulation of microglia. Keywords: microglia, neuron–glia interactions, optic nerve, sigma receptor icroglia are the resident macrophages of the retina and degeneration share neuroinflammation as a common pathologic M brain.1 These cells are activated in response to inflamma- component.11–13 In addition, many studies indicate that strategies tory stimuli such as the bacterial endotoxin lipopolysaccharide for decreasing chronic inflammation prove therapeutic.14,15 (LPS). Microglia activation causes intracellular production of Therefore, microglia-mediated responses to inflammatory stimuli reactive oxygen species (ROS) and release of bioactive are treatment targets for vision-threatening diseases. molecules including tumor necrosis factor a (TNF-a), nitric The r receptors are classified into two subtypes (rR1 and oxide (NO), interleukin 10 (IL-10), and monocyte chemo- rR2), and ligands for these receptors show variable specificity.16 attractant protein-1 (MCP-1).2 The mitogen-activated protein rR1 has been cloned and its sequence does not share homology kinase (MAPK) subgroup members including extracellular with other known mammalian proteins.16 rR1 is a transmem- signal–regulated kinase (ERK), c-Jun N-terminal kinase (JNK), brane protein found in the endoplasmic reticulum that is and p38 MAPK have been implicated in control of expression of ubiquitously expressed throughout the nervous system and these immune-related factors within microglia.3–5 visceral organs. Within the eye, rR1 is expressed in cornea, iris– In brain and retina, microglial secreted factors cause ciliary body, lens, retina, and optic nerve. Cell types throughout pleiotropic effects on immunoregulation and inflammation. the retina that contain rR1 include ganglion cells, inner nuclear However, microglia activation via inflammatory stimuli can lead layer cells, photoreceptors, and retinal pigment epithelium.17,18 to chronic neuroinflammation and enhanced neuronal injury.6,7 Within the nervous system, rR1 has been shown to regulate Several pathologic conditions are exacerbated by neuroinflam- several processes including N-methyl-D-aspartate receptor and mation, including stroke, Alzheimer’s disease, Parkinson’s disease, Kþ channel activity,19 neuritogenesis,20,21 L-type voltage-gated and traumatic brain injury.8–10 Within the eye, disease states calcium channel activity,22,23 and microglial activity.24 However, including glaucoma, diabetic retinopathy, and age-related macular the complete endogenous function of this protein is not known. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc. www.iovs.org j ISSN: 1552-5783 3375 Downloaded from tvst.arvojournals.org on 09/23/2021 Sigma Receptor Ligand and Retinal Microglia IOVS j June 2014 j Vol. 55 j No. 6 j 3376 FIGURE 1. Characterization of cultured retinal microglia cells. (A) Retinas were dissected from rat pups and retinal microglia cells were purified and cultured. The cells were fixed and probed with an antibody against Iba1, a microglia-specific marker (green). The cells were counterstained with DAPI to label DNA (blue) as a marker for nuclei. A merged image is also shown. Scale bar:50lm. (B) Cells that stained positively for Iba1 were counted and represented as a fraction of the total cell population. More than 90% of the cells expressed Iba1. Ligands for rR1 have shown neuroprotective properties in Sigma-Aldrich Corp. (St. Louis, MO, USA). The rR1 antagonist several animal models including amyotrophic lateral sclerosis BD1063 was purchased from Tocris Bioscience (Bristol, UK). (ALS),25 stroke,26 and diabetic retinopathy.27 In addition to Dulbecco’s modified Eagle’s medium (DMEM)/F12 culture neuroprotection, rR1 activation has been associated with medium, Hanks’ balanced salt solution (HBSS), 0.125% trypsin, decreased reactive gliosis in both the ALS mouse model and the penicillin/streptomycin, MTT Cell Proliferation Assay Kit, Griess rat stroke injury model.26,28 Evidence also suggests that some Reagent Kit, CellROX Green Reagent, MCP-1 ELISA Kit, and rR1 ligands can repress activation of the MAPK/ERK pathway Alexa Fluor 488–labeled goat anti-mouse IgG antibody were within cortical neurons.29 purchased from Invitrogen (Grand Island, NY, USA). Cellgro Recent work has shown that r receptors modulate the complete medium was purchased from Cellgro (Manassas, VA, activation of CNS-derived primary microglia. Treatment with USA). Tumor necrosis factor a ELISA kits and IL-10 ELISA kits the nonspecific rR1/R2 ligand 1,3-di-o-tolylguanidine (DTG) were purchased from R&D Systems (Minneapolis, MN, USA). p- decreased the LPS-stimulated microglial release of inflammato- ERK, ERK, p-p38, p38, p-JNK, JNK polyclonal antibodies, and ry mediators including NO, TNF-a, and IL-10.24 It is not known horseradish peroxidase (HRP)-conjugated anti-rabbit IgG and whether this effect results from rR1 or rR2 activation. In HRP-conjugated anti-mouse IgG were purchased from Cell addition, the effect of rR1 activation on neuroinflammation in Signaling Technology (Danvers, MA, USA). glyceraldehyde-3- the retina is not known. Further, the existence of rR1 within phosphate dehydrogenase (GAPDH) monoclonal antibody was retinal microglia has never been reported. purchased from Millipore (Billerica, MA, USA). Iba1 monoclonal The present study was undertaken to investigate the activity antibody was purchased from Abcam (Cambridge, MA, USA). of the rR1-specific agonist (þ)-pentazocine on retina-derived, SuperSignal West Pico chemiluminescent substrate was pur- LPS-stimulated, primary microglia. Our results showed that chased from Thermo Scientific (Waltham, MA, USA). rR1 rabbit exposure of retinal microglia to LPS led to release of TNF-a, polyclonal antibody was raised from a peptide sequence and 30 NO, IL-10, and ROS as well as morphologic changes in the cells, generated within the laboratory of Sylvia Smith, PhD. and activation of ERK/JNK MAPK pathways. These effects were inhibited by (þ)-pentazocine. From these results, we Primary Rat Retinal Microglia Culture suggest that the rR1 agonist pentazocine has the potential to Experiments requiring animals adhered to the ARVO Statement serve as a therapeutic modulator for neuroinflammatory for the Use of Animals in Ophthalmic and Vision Research. responses within the retina. Microglia cells were isolated from retinas of SD rats, according to previously published protocols31 with minor modifications.
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