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Sigma receptor ligand, (+)-pentazocine, suppresses inflammatory responses of retinal microglia
Jing Zhao1, Yonju Ha2, Gregory I Liou3
1James and Jean Culver Vision Discovery Institute, Georgia Regents University, Augusta, Georgia, United States.
Purpose:
To evaluate the effects of the σ 1 receptor (σR1) agonist, (+)-pentazocine, on lipopolysaccharide (LPS)-induced inflammatory changes in retinal microglia cells.
Methods:
Retinal microglia cells were isolated from Sprague-Dawley rat pups. Cells were treated with LPS with or without (+)-pentazocine and with or without the σR1 antagonist BD1063. Morphologic changes were assayed. Cell viability was assessed by using MTT assay. Supernatant levels of tumor necrosis factor α (TNF-α), interleukin 10, (IL-10), monocyte chemoattractant protein-1 (MCP-1), and nitric oxide (NO) were determined. Reactive oxygen species (ROS) formation was assayed, and levels of mitogen-activated protein kinases (MAPKs) were analyzed by using Western blot.
Results:
The σR1 protein was expressed in retinal microglia. Incubation with LPS and/or (+)-pentazocine did not alter cell viability or σR1 protein levels. Incubation with LPS for 24 hours induced a marked change in microglial morphology and a significant increase in secreted levels of TNF-α, IL-10, MCP-1, and NO. Pretreatment with (+)-pentazocine inhibited the LPS-induced morphologic changes. Release of TNF-α, IL-10, MCP-1, and NO was reduced with (+)-pentazocine. Intracellular ROS formation was suppressed with (+)-pentazocine. Phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) was reduced in the presence of (+)-pentazocine. The σR1 antagonist BD1063 blocked the (+)-pentazocine-mediated inhibition of LPS-induced morphologic changes. In addition, BD1063 treatment blocked (+)-pentazocine-mediated suppression of LPS-induced TNF-α, IL-10, MCP-1, NO, and intracellular ROS release.
Conclusions:
Treatment with (+)-pentazocine suppressed inflammatory responses of retinal microglia and inhibited LPS-induced activation of ERK/JNK MAPK. In neurodegenerative disease, (+)-pentazocine may exert neuroprotective effects through manipulation of microglia.
Insights
(+)-pentazocine, a sigma 1 receptor agonist, reduces inflammation in retinal microglia cells. This compound may offer neuroprotection in neurodegenerative diseases by modulating microglial activity.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Retinal microglia play a crucial role in neuroinflammation.
- Lipopolysaccharide (LPS) is a potent inducer of inflammatory responses in microglia.
- Sigma 1 receptor (σR1) agonists are being investigated for their therapeutic potential.
Purpose of the Study:
- To investigate the effect of the σR1 agonist, (+)-pentazocine, on LPS-induced inflammation in retinal microglia.
- To determine the impact of (+)-pentazocine on microglial morphology, inflammatory mediator release, and MAPK signaling.
Main Methods:
- Retinal microglia were isolated and treated with LPS, (+)-pentazocine, and/or the σR1 antagonist BD1063.
- Assessed morphologic changes, cell viability (MTT assay), inflammatory cytokine levels (TNF-α, IL-10, MCP-1), nitric oxide (NO), reactive oxygen species (ROS), and MAPK phosphorylation (Western blot).
Main Results:
- LPS induced significant microglial activation, characterized by morphologic changes and increased release of TNF-α, IL-10, MCP-1, and NO.
- (+)-pentazocine pretreatment suppressed LPS-induced morphologic changes and reduced the release of inflammatory mediators and ROS.
- The σR1 antagonist BD1063 reversed the protective effects of (+)-pentazocine, confirming the involvement of the σR1 pathway.
- LPS-induced phosphorylation of ERK and JNK MAPKs was inhibited by (+)-pentazocine.
Conclusions:
- (+)-pentazocine effectively suppresses inflammatory responses in retinal microglia induced by LPS.
- The anti-inflammatory effects of (+)-pentazocine involve the inhibition of ERK/JNK MAPK signaling.
- (+)-pentazocine holds potential as a neuroprotective agent in neurodegenerative conditions through microglial modulation.
