Telmisartan attenuated LPS-induced neuroinflammation in human IMR-32 neuronal cell line via SARM in AT1R independent mechanism.

Abstract

AIM:

The aim of this study was to find the protective role of Telmisartan (TS) in LPS intoxicated neuronal cells and elucidate the possible neuroprotective mechanism of action.

MAIN METHODS:

TLR4 and AT1R specific primers were designed and used in rtPCR to confirm the receptor expression in IMR-32 and Neuro2A cell lines. The protective effect of TS was assayed by MTT assay. The mechanism of action of TS was elucidated by assessing the expression and activation of TLR4 specific adaptor proteins SARM and MyD88, phosphorylated NFκB, PPARγ, MAPK p38, c-JNK, ERK by Western blotting. Selective PPARγ antagonist GW9662 was used to confirm the link between PPARγ activation and TLR4 mediated NFκB inflammatory mechanisms. The pro-inflammatory cytokines TNFα, IL1β, and IL-6 and anti-inflammatory cytokine IL10 release were measured by ELISA.

KEY FINDINGS:

IMR-32 cells expressed TLR4 receptor and Neuro2A cells expressed both AT1R and TLR4 receptors. TS significantly protected both the cell lines from LPS intoxication. TS significantly suppressed the TLR4 mediated inflammatory response by PPARγ and SARM protein activation and the effect was reversed significantly by selective PPARγ antagonist GW9662, confirming the existence of link between PPARγ activation and TLR4 mediated inflammation via SARM.

SIGNIFICANCE:

LPS intoxicated human neuronal IMR-32 cells can be a good in vitro model to study inflammatory mediated neurodegeneration due to TLR4 receptor expression. Our study strongly recommends that the PPARγ activating pleiotropic effect of TS is responsible for the protective effect in LPS induced TLR4 mediated inflammation via SARM adaptor protein in the IMR-32 cell line.

• Authors: Prathab Balaji Saravanan, Muthusamy V Shanmuganathan, Muthiah Ramanathan
• Journal: Life sciences (Life Sci) Vol. 130 Pg. 88-96 (Jun 01 2015) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 25816983 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• 2-chloro-5-nitrobenzanilide
• Angiotensin II Type 1 Receptor Blockers
• Anilides
• Armadillo Domain Proteins
• Benzimidazoles
• Benzoates
• Cytokines
• Cytoskeletal Proteins
• Inflammation Mediators
• Lipopolysaccharides
• Neuroprotective Agents
• Receptor, Angiotensin, Type 1
• SARM1 protein, human
• TLR4 protein, human
• Toll-Like Receptor 4
• Telmisartan

Topics

• Angiotensin II Type 1 Receptor Blockers (pharmacology)
• Anilides (pharmacology)
• Armadillo Domain Proteins (metabolism)
• Benzimidazoles (pharmacology)
• Benzoates (pharmacology)
• Cell Line
• Cytokines (metabolism)
• Cytoskeletal Proteins (metabolism)
• Enzyme-Linked Immunosorbent Assay
• Humans
• Inflammation (prevention & control)
• Inflammation Mediators (metabolism)
• Lipopolysaccharides (toxicity)
• Neurons (drug effects, pathology)
• Neuroprotective Agents (pharmacology)
• Receptor, Angiotensin, Type 1 (drug effects, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Telmisartan
• Toll-Like Receptor 4