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Glutathione and TRPM2 Inhibition Reduce Amyloid-Beta and Lipopolysaccharide-Induced Apoptosis, Inflammation, and
Orhan Akpınar1,2, Mustafa Nazıroğlu2,3,4,5
1Department of Medical Microbiology, Health Sciences Institute, University of Süleyman Demirel, Isparta, Türkiye.
Abstract:
Microglia cells impacted by inflammation and Alzheimer's disease produce toxic reactive oxygen species (ROS), emit signaling molecules, and death as a result of microglia being active due to excessive Ca2+ entering the cells. The TRPM2 channel plays a crucial role in Ca²⁺ permeability, inflammation, ROS, and apoptosis changes in the BV2 microglia cells, while glutathione (GSH) treatment reduces the changes through TRPM2 inhibition. However, the effect of TRPM2 inhibitors and GSH treatment on oxidative stress, inflammation, and apoptotic values in BV2 microglia cells activated with LPS and amyloid-beta (Aβ) has not been investigated yet. The study aimed to assess the effects of TRPM2 inhibition and GSH treatment on the values in BV2 cells activated with LPS and Aβ. BV2 cells were divided into five groups: control (CNT), LPS, Aβ, Aβ + LPS, and Aβ + LPS + GSH. Increased levels of inflammation biomarkers (TNF-α, IL-1β, and IL-6), intracellular Ca2+ level, cytosolic ROS, mitochondrial membrane dysfunction, cell death, apoptosis, caspases (caspase-3, -8, and -9), and TRPM2 current density were observed in the cells stimulated with LPS and Aβ. These values increased more when LPS and Aβ were incubated together. However, these apoptotic, inflammatory, and oxidant levels decreased in cells treated with GSH and TRPM2 blockers. In conclusion, the involvement of TRPM2 stimulation was demonstrated on Aβ and LPS-induced Ca2+ entry, oxidative stress, inflammation, and apoptosis parameters in microglia cells. TRPM2 inhibition by GSH treatment seems to be a potential source for the prevention of Aβ and LPS-induced oxidative stress, apoptosis, and inflammation.
Insights
Glutathione (GSH) treatment inhibits the TRPM2 channel, reducing inflammation, oxidative stress, and apoptosis in microglia cells activated by LPS and amyloid-beta (Aβ). This suggests GSH as a potential therapeutic for Alzheimer's disease and inflammation-related conditions.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia activation by inflammation and Alzheimer's disease (Aβ) involves excessive calcium (Ca²⁺) influx, leading to reactive oxygen species (ROS), inflammation, and apoptosis.
- The Transient Receptor Potential Melastatin 2 (TRPM2) channel is implicated in Ca²⁺ permeability, inflammation, ROS production, and apoptosis in BV2 microglia cells.
- Glutathione (GSH) has shown potential in mitigating these changes via TRPM2 inhibition, but its specific effects on LPS and Aβ-induced responses require investigation.
Purpose of the Study:
- To investigate the effects of TRPM2 inhibition and GSH treatment on oxidative stress, inflammation, and apoptosis in BV2 microglia cells stimulated with lipopolysaccharide (LPS) and Aβ.
- To assess the role of TRPM2 channels in mediating Ca²⁺ influx, ROS generation, and inflammatory responses induced by combined LPS and Aβ stimuli.
Main Methods:
- BV2 microglia cells were divided into five groups: control, LPS-only, Aβ-only, combined LPS+Aβ, and LPS+Aβ treated with GSH.
- Measurements included inflammation biomarkers (TNF-α, IL-1β, IL-6), intracellular Ca²⁺ levels, cytosolic ROS, mitochondrial membrane potential, cell death, apoptosis markers, caspase activity, and TRPM2 current density.
Main Results:
- LPS and Aβ stimulation significantly increased inflammation, Ca²⁺ influx, ROS production, mitochondrial dysfunction, cell death, apoptosis, and caspase activity in BV2 cells.
- Combined LPS and Aβ treatment exacerbated these effects.
- GSH treatment and TRPM2 blockers effectively reduced these elevated levels of inflammation, oxidative stress, and apoptosis.
Conclusions:
- TRPM2 channel activation is critically involved in LPS and Aβ-induced Ca²⁺ entry, oxidative stress, inflammation, and apoptosis in microglia.
- TRPM2 inhibition through GSH treatment presents a promising therapeutic strategy for preventing and mitigating Aβ and LPS-induced neuroinflammation and neuronal damage associated with Alzheimer's disease.
