Telmisartan ameliorates Aβ oligomer-induced inflammation via PPARγ/PTEN pathway in BV2 microglial cells.

Abstract

Telmisartan ameliorates inflammation in various brain disorders through angiotensin II type 1 receptor (AT1) blockade and peroxisome proliferator-activated receptor gamma (PPARγ) activation. Soluble β-amyloid oligomers (AβOs) play a causative role in neuronal dysfunction and memory loss in Alzheimer's disease. In addition to directly targeting neurons, AβOs may also activate microglia to trigger toxic proinflammatory responses. Here, we investigated whether and how telmisartan ameliorates inflammatory responses in AβO-stimulated microglia. A mouse-derived BV2 microglial cell line lacking AT1 expression was selected as an in vitro model. Telmisartan not only inhibited AβO-induced proinflammatory interleukin (IL)-1β and tumor necrosis factor-α (TNF-α) expression, but also increased anti-inflammatory IL-10 expression, which was not affected by AβO stimulation. Telmisartan also inhibited AβO-induced nuclear factor (NF)-κB activity and phosphorylation of Akt and ERK, two upstream regulators of NF-κB activation. These anti-inflammatory effects were antagonized by PPARγ inhibitor GW9662. In addition, telmisartan increased the expression of PTEN (phosphate and tensin homolog deleted on chromosome 10), a lipid and protein phosphatase; PPARγ inhibitor GW9662 reversed this effect, indicating that telmisartan-induced PTEN expression is PPARγ dependent. The PTEN inhibitor blocked the effects of telmisartan on Akt and ERK phosphorylation, NF-κB transcriptional activity, and IL-1β and TNF-α production, but failed to reverse IL-10 expression. This data indicates that telmisartan-induced IL-10 expression is PPARγ-dependent but PTEN-independent. Altogether, telmisartan ameliorated AβO-induced microglial inflammation by inhibiting NF-κB-mediated proinflammatory cytokine expression via the PPARγ/PTEN pathways and by increasing PPARγ-mediated anti-inflammatory IL-10 expression. Telmisartan may present a promising therapy for the treatment of AβO pathology.

• Authors: Ze-Fen Wang, Jie Li, Chao Ma, Chong Huang, Zhi-Qiang Li
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 171 Pg. 113674 (01 2020) ISSN: 1873-2968 [Electronic] England
• PMID: 31634455 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• 2-chloro-5-nitrobenzanilide
• Amyloid beta-Protein Precursor
• Angiotensin II Type 1 Receptor Blockers
• Anilides
• Cytokines
• Inflammation Mediators
• PPAR gamma
• PTEN Phosphohydrolase
• Telmisartan

Topics

• Amyloid beta-Protein Precursor (metabolism)
• Angiotensin II Type 1 Receptor Blockers (pharmacology)
• Anilides (pharmacology)
• Animals
• Cell Line
• Cytokines (metabolism)
• Humans
• Inflammation (metabolism, prevention & control)
• Inflammation Mediators (antagonists & inhibitors, metabolism)
• Mice
• Microglia (drug effects, metabolism)
• PPAR gamma (antagonists & inhibitors, metabolism)
• PTEN Phosphohydrolase (metabolism)
• Signal Transduction (drug effects)
• Telmisartan (pharmacology)