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

Saravanan, Prathab Balaji; Shanmuganathan, Muthusamy V.; Ramanathan, Meena

doi:10.1016/j.lfs.2015.03.005

Cited by 19 publications

(6 citation statements)

References 41 publications

(6 reference statements)

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“…AT1 receptor stimulation enhances TLR gene expression in microglia and Telmisartan and several other ARBs reduce gene expression of several TLRs in many in vitro and in vivo models [13, 36, 150–157]. In addition, ARBs downregulate gene expression of many members of the TLR down-stream pathways, including CD14 [13], MyD88 [158, 159], IRAK1 and TRAF6 [160] and MMP-2 activation [153]. Whether the novel mechanism postulated here has a role in other conditions remain to be determined.…”

Section: Resultsmentioning

confidence: 99%

Telmisartan Protects a Microglia Cell Line from LPS Injury Beyond AT1 Receptor Blockade or PPARγ Activation

et al. 2018

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The Angiotensin II Receptor Blocker (ARB) Telmisartan reduces inflammation through Angiotensin II AT1 receptor blockade and peroxisome proliferator-activated receptor gamma (PPARγ) activation. However, in a mouse microglia-like BV2 cell line, imitating primary microglia responses with high fidelity and devoid of AT1 receptor gene expression or PPARγ activation, Telmisartan reduced gene expression of pro-injury factors, enhanced that of anti-inflammatory genes, and prevented LPS-induced increase in inflammatory markers. Using global gene expression profiling and pathways analysis, we revealed that Telmisartan normalized the expression of hundreds of genes upregulated by LPS and linked with inflammation, apoptosis and neurodegenerative disorders, while downregulating the expression of genes associated with oncological, neurodegenerative and viral diseases. The PPARγ full agonist Pioglitazone had no neuroprotective effects. Surprisingly, the PPARγ antagonists GW9662 and T0070907 were neuroprotective and enhanced Telmisartan effects. GW9226 alone significantly reduced LPS toxic effects and enhanced Telmisartan neuroprotection, including downregulation of pro-inflammatory TLR2 gene expression. Telmisartan and GW9662 effects on LPS injury negatively correlated with pro-inflammatory factors and upstream regulators, including TLR2, and positively with known neuroprotective factors and upstream regulators. Gene Set Enrichment Analysis (GSEA) of the Telmisartan and GW9662 data revealed negative correlations with sets of genes associated with neurodegenerative and metabolic disorders and toxic treatments in cultured systems, while demonstrating positive correlations with gene sets associated with neuroprotection and kinase inhibition. Our results strongly suggest that novel neuroprotective effects of Telmisartan and GW9662, beyond AT1 receptor blockade or PPARγ activation, include downregulation of the TLR2 signaling pathway, findings that may have translational relevance.

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Section: Resultsmentioning

confidence: 99%

Telmisartan Protects a Microglia Cell Line from LPS Injury Beyond AT1 Receptor Blockade or PPARγ Activation

et al. 2018

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“…These results suggest that CSA and 5c is relying on resisting the LPS-induced decrease of PPARγ through improving its expression to enhance its activity. In summary, the anti-inflammatory mechanism of CSA and its derivatives is to suppress the activation of NF-κB and MAPK pathways by resisting the LPS-induced decrease of PPARγ, an identified negative regulatory factor of inflammation with the inhibitory effect on the activation of NF-κB and MAPK pathways, − through improving its expression.…”

Section: Results and Discussionmentioning

confidence: 99%

Anti-Inflammatory Effects of Cajaninstilbene Acid and Its Derivatives

Huang

Lin

et al. 2016

J. Agric. Food Chem.

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Cajaninstilbene acid (CSA) is one of the active components isolated from pigeon pea leaves. In this study, anti-inflammatory effects of CSA and its synthesized derivatives were fully valued with regard to their activities on the production of nitric oxide (NO) and pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in vitro cell model, as well as their impacts on the migration of neutrophils and macrophages in fluorescent protein labeled zebrafish larvae model by live image analysis. Furthermore, the anti-inflammatory mechanism of this type of compounds was clarified by western-blot and reverse transcription-polymerase chain reaction (RT-PCR). The results showed that CSA, as well as its synthesized derivatives 5c, 5e and 5h, exhibited strong inhibition activity on the release of NO and inflammatory factor TNF-α and IL-6 in lipopolysaccharides (LPS)-stimulated murine macrophages. CSA and 5c greatly inhibited the migration of neutrophils and macrophages in injury zebrafish larvae. CSA and 5c treatment greatly inhibited the phosphorylation of proteins involved in nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. Moreover, we found that peroxisome proliferator-activated receptor gamma (PPARγ) inhibitor GW9662 could reverse partly the roles of CSA and 5c, and CSA and 5c treatment greatly resist the decrease of PPARγ mRNA and protein induced by LPS stimulation. Our results identified the promising anti-inflammatory effects of CSA and its derivatives, which may serve as valuable anti-inflammatory lead compound. Additionally, the mechanism studies demonstrated that the anti-inflammatory activity of CSA and its derivative is associated with the inhibition of NF-κB and MAPK pathways, relying partly on resisting the LPS-induced decrease of PPARγ through improving its expression.

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“…This may explain the upregulation of SARM1 in Fmr1 KO mice. For LPS-induced autism mice, it has been reported that the expression level of SARM1 is upregulated in cultured neuronal cells treated with LPS [ 27 ]. Thus, it is plausible that SARM1 can be upregulated in the brains of offspring mice exposed to LPS.…”

Section: Discussionmentioning

confidence: 99%

SARM1 deletion in parvalbumin neurons is associated with autism-like behaviors in mice

et al. 2022

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Autism spectrum disorder (ASD), a group of neurodevelopmental disorder diseases, is characterized by social deficits, communication difficulties, and repetitive behaviors. Sterile alpha and TIR motif-containing 1 protein (SARM1) is known as an autism-associated protein and is enriched in brain tissue. Moreover, SARM1 knockdown mice exhibit autism-like behaviors. However, its specific mechanism in ASD pathogenesis remains unclear. Here we generated parvalbumin-positive interneurons (PVI)-specific conditional SARM1 knockout (SARM1PV-CKO) mice. SARM1PV-CKO male mice showed autism-like behaviors, such as mild social interaction deficits and repetitive behaviors. Moreover, we found that the expression level of parvalbumin was reduced in SARM1PV-CKO male mice, together with upregulated apoptosis-related proteins and more cleaved-caspase-3-positive PVIs, suggesting that knocking out SARM1 may cause a reduction in the number of PVIs due to apoptosis. Furthermore, the expression of c-fos was shown to increase in SARM1PV-CKO male mice, in combination with upregulation of excitatory postsynaptic proteins such as PSD-95 or neuroligin-1, indicating enhanced excitatory synaptic input in mutant mice. This notion was further supported by the partial rescue of autism-like behavior deficits by the administration of GABA receptor agonists in SARM1PV-CKO male mice. In conclusion, our findings suggest that SARM1 deficiency in PVIs may be involved in the pathogenesis of ASD.

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

Cited by 19 publications

References 41 publications

Telmisartan Protects a Microglia Cell Line from LPS Injury Beyond AT1 Receptor Blockade or PPARγ Activation

Telmisartan Protects a Microglia Cell Line from LPS Injury Beyond AT1 Receptor Blockade or PPARγ Activation

Anti-Inflammatory Effects of Cajaninstilbene Acid and Its Derivatives

SARM1 deletion in parvalbumin neurons is associated with autism-like behaviors in mice

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