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GTS-21 attenuates LPS-induced renal injury via the cholinergic anti-inflammatory pathway in mice.

ABSTRACT: This study aimed to investigate the role of GTS-21 in cholinergic anti-inflammatory pathway-mediated protection of LPS-induced septic renal injury in mice. C57BL/6 mice were used to construct septic injury models. The optimal duration of lipopolysaccharide (LPS) treatment was determined using HE staining and TUNEL assay. Mice injected with saline were used as blank control and with LPS (10 mg/kg) as model, which were further treated with ?-bungarotoxin (BT-LPS), GTS-21 (GTS-21-LPS) and BT and GTS-21 (BT-GTS-21-LPS). The pathological examinations were performed on HE stained renal tissues, apoptosis was determined using TUNEL assay, mRNA expression of NF-kB p65, Caspase-3, Caspase-8, Bcl-2, Bax, p53 and a7nACh was quantified using qRT-PCR, protein levels of IL-6, IL-1?, TNF-? and phosphorylated STAT3 (p-STAT3) were analyzed using Western blots. HE staining and TUNEL assays showed that the optimal LPS treatment time for renal injury induction was 16 h. Compared with the blank control, mice in LPS group had significantly higher levels of NF-Kb p65, Caspase-3, Caspase-8, Bax, p53, IL-6, IL-1?, TNF-? and p-STAT3, while ?7nAChR and Bcl-2 levels were decreased significantly (P < 0.01); GTS-21 and BT significantly increased the expression of NF-Kb p65, Caspase-3, Caspase-8, Bax, p53, IL-6, IL-1?, TNF-? and p-STAT3, while ?7nAChR and Bcl-2 levels were decreased significantly (P < 0.01). It is concluded that GTS-21 can effective alleviate the renal injury, while ?7nAChR-specific blocker BT is antagonistic against the anti-inflammatory effect of GTS-21 on sepsis in mice.

SUBMITTER: Gao Y

PROVIDER: S-EPMC5666073 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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GTS-21 attenuates LPS-induced renal injury via the cholinergic anti-inflammatory pathway in mice.

Gao Yang Y Kang Kai K Liu Haitao H Kong Weilan W Han Qiuyuan Q Zhang Xing X Huang Rui R Qu Jingdong J Wang Hongliang H Wang Sicong S Liu Ruijin R Liu Yansong Y Yu Kaijiang K

American journal of translational research 20171015 10

This study aimed to investigate the role of GTS-21 in cholinergic anti-inflammatory pathway-mediated protection of LPS-induced septic renal injury in mice. C57BL/6 mice were used to construct septic injury models. The optimal duration of lipopolysaccharide (LPS) treatment was determined using HE staining and TUNEL assay. Mice injected with saline were used as blank control and with LPS (10 mg/kg) as model, which were further treated with α-bungarotoxin (BT-LPS), GTS-21 (GTS-21-LPS) and BT and GT ...[more]

PMID: 29118926

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Project description:BackgroundRenal denervation (RDN) reduces sympathetic tone and may alter the sympathetic-parasympathetic balance. The autonomic nervous system is partly a regulator of innate immunity via the cholinergic anti-inflammatory pathway (CAP) which inhibits inflammation via the vagus nerve. Placental Growth Factor (PlGF) influences a neuro-immunological pathway in the spleen which may contribute to hypertension. The aim of this study was to investigate if modulation of renal sympathetic nerve activity affects CAP in terms of cytokine release as well as levels of PlGF.MethodsTen patients treated with RDN (Medtronic Inc), were analyzed for TNF, IL-1b and IL-10 and Lipopolysaccharide (LPS)-stimulated cytokine release before RDN, 1 day after and at 3- and 6-months follow-up. Four patients who underwent elective coronary angiography served as disease controls (DC).ResultsBaseline TNF was significantly lower 1 day after RDN (p = 0.03). LPS-stimulated (0, 10 and 100 ng/mL) TNF and IL-1b were significantly lower 1 day after RDN (TNF p = 0.0009, p = 0.0009 and p = 0.001, IL-1b; p = 0.0001, p = 0.002 and p = 0.005). IL-10 was significantly higher one day after RDN (p = ns, p = 0.02 and p = 0.01). These differences however declined during follow up. A more marked TNF reduction was achieved with a cholinergic analogue, GTS-21, in LPS-stimulated whole blood as compared with samples without GTS-21. Cytokine levels in controls did not differ before and 1 day after coronary angiography. PlGF was significantly higher in RDN patients and DC compared with healthy controls but did not change during follow-up.ConclusionRDN has an immediate effect on TNF in vivo and cytokine release ex vivo but seems to wane over time suggesting that current RDN techniques may not have long-lasting immunomodulatory effect. Repeated and extended stimulation of CAP in resistant hypertension by targeting neural circuits may be a potential therapeutic strategy for treatment of both hypertension and inflammation.

Project description:BackgroundBurn injury (BI) pain consists of inflammatory and neuropathic components and activates microglia. Nicotinic alpha 7 acetylcholine receptors (α7AChRs) expressed in microglia exhibit immunomodulatory activity during agonist stimulation. Efficacy of selective α7AChR agonist GTS-21 to mitigate BI pain and spinal pain-mediators was tested.MethodsAnesthetized rats after hind-paw BI received intraperitoneal GTS-21 or saline daily. Allodynia and hyperalgesia were tested on BI and contralateral paw for 21 days. Another group after BI receiving GTS-21 or saline had lumbar spinal cord segments harvested (day 7 or 14) to quantify spinal inflammatory-pain transducers or microglia activation using fluorescent marker, ionized calcium-binding adaptor protein (Iba1).ResultsBI significantly decreased allodynia withdrawal threshold from baseline of ~9-10 to ~0.5-1 g, and hyperalgesia latency from ~16-17 to ~5-6 seconds by day 1. Both doses of GTS-21 (4 or 8 mg/kg) mitigated burn-induced allodynia from ~0.5-1 to ~2-3 g threshold (P = .089 and P = .010), and hyperalgesia from ~5-6 to 8-9 seconds (P < .001 and P < .001) by day 1. The GTS-21 group recovered to baseline pain threshold by day 15-17 compared to saline-treated, where the exaggerated nociception persisted beyond 15-17 days. BI significantly (P < .01) increased spinal cord microgliosis (identified by fluorescent Iba1 staining), microglia activation (evidenced by the increased inflammatory cytokine), and pain-transducer (protein and/or messenger RNA [mRNA]) expression (tumor necrosis factor-α [TNF-α], interleukin-1β [IL-1β], nuclear factor-kappa B [NF-κB], interleukin-6 [IL-6], Janus-associated kinase signal transducer and activator of transcription 3 [JAK-STAT3], and/or N-methyl-D-aspartate receptor [NMDAR]). GTS-21 mitigated pain-transducer changes. The α7AChR antagonist methyllycaconitine nullified the beneficial effects of GTS-21 on both increased nociception and pain-biomarker expression.ConclusionsNonopioid, α7AChR agonist GTS-21 elicits antinociceptive effects at least in part by decreased activation spinal-cord pain-inducers. The α7AChR agonist GTS-21 holds promise as potential therapeutic adjunct to decrease BI pain by attenuating both microglia changes and expression of exaggerated pain transducers.

Dataset Information

GTS-21 attenuates LPS-induced renal injury via the cholinergic anti-inflammatory pathway in mice.

Publications

GTS-21 attenuates LPS-induced renal injury via the cholinergic anti-inflammatory pathway in mice.

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