Effects of kynurenic acid and choline on lipopolysaccharide-induced cyclooxygenase pathway

Abstract

Objectives Inflammation can be endogenously modulated by the cholinergic anti-inflammatory pathway via calcium (Ca2+)-permeable alpha-7 nicotinic acetylcholine receptor (α7nAChR) ion channel expressed in immune cells. α7nAChR agonist choline and tryptophan metabolite kynurenic acid (KYNA) produces immunomodulatory effects. This study aimed to determine the effects of the choline and KYNA on the lipopolysaccharide (LPS)-induced cyclooxygenase (COX)-2 pathway. Methods In vitro inflammation model was produced via LPS administration in macrophage cells. To determine the effective concentrations, choline and KYNA were applied with increasing concentrations and LPS-induced inflammatory parameters investigated. The involvement of nAChR mediated effects was investigated with the use of non-selective nAChR and selective α7nAChR antagonists. The effects of choline and KYNA on COX-2 enzyme, PGE2, TNFα, NF-κB and intracellular Ca2+ levels were analyzed. Results LPS-induced COX-2 expression, PGE2 TNFα and NF-κB levels were decreased with choline treatment while intracellular calcium levels via α7nAChRs increased. KYNA also showed an anti-inflammatory effect on the same parameters. Additionally, KYNA administration increased the effectiveness of choline on these inflammatory mediators. Conclusions Our data suggest a possible interaction between the kynurenine pathway and the cholinergic system on the modulation of LPS-induced inflammatory response in macrophages.

Nicotinic acetylcholine receptor-mediated effects of varenicline on LPS-elevated prostaglandin and cyclooxygenase levels in RAW 264.7 macrophages

“…Therefore, in the first part of this study, RAW 264.7 macrophages, commonly used in LPS-induced inflammation models, were treated with increasing concentrations of LPS to determine optimal LPS concentration (1 μg/mL) to induce inflammation. The increase in the levels of PGs and COX that mediate inflammation confirms the development of inflammation, consistent with the earlier observations ( Gandhi et al, 2015 ; Baris et al, 2023a ). Varenicline, used as a reliable option for smoking cessation, exhibits strong agonistic activity on α7nAChRs ( Baris et al, 2021b ; Bigagli et al, 2021 ).…”

“…The distinction in PG's roles emphasizes the scope and direction of our study, while acknowledging the comprehensive landscape of prostaglandin function in various physiological and pathophysiological processes, including but not limited to inflammation, immune responses and homeostasis. Only a few studies reports its potential anti-inflammatory effects in different models ( Mihalak et al, 2006a ; Hays et al, 2008 ; Baris et al, 2023a ). Varenicline has been shown to decrease inflammation in lung tissue of animals with emphysema ( Hays et al, 2008 ) and reduce brain inflammation in animals with stroke ( Mihalak et al, 2006a ).…”

“…Varenicline has been shown to decrease inflammation in lung tissue of animals with emphysema ( Hays et al, 2008 ) and reduce brain inflammation in animals with stroke ( Mihalak et al, 2006a ). A clinical study has also demonstrated that varenicline significantly decreased eicosanoid-related inflammation and oxidative damage in patients during smoking cessation therapy ( Baris et al, 2023a ). Consistent with these, our previous study showed that varenicline decreased LPS-induced inflammatory cytokine levels in RAW 264.7 macrophage cells ( Baris et al, 2021b ).…”

“…Moreover, CAP-inducing agents; CDP-choline and choline, reduce the inflammation process through the COX pathway in LPS-induced endotoxemia in rats. Following LPS administration, COX-2 expressions and PG levels increased, both of which were significantly reduced by CDP-choline or choline treatment via α7nAChRs ( Baris et al, 2021a ; Baris et al, 2023a ), highlighting the potential of α7nAChRs to mediate modulation of the COX pathway.…”

“…Varenicline, which is widely used as an effective and safe therapeutic option for smoking cessation, is reported to have potent and full agonistic properties on α7nAChRs and partial agonistic effects on α4β2-nAChRs ( Baris et al, 2021b ; Bigagli et al, 2021 ). A recent clinical study showed that 12-week varenicline treatment modulated inflammation and oxidative damage ( Baris et al, 2023a ). Furthermore, immunohistochemical experiments showed that varenicline treatment suppressed inflammation and the number of immune system cells through α7nAChR activation in brain and lung tissues in an animal model of ischemia and emphysema ( Mihalak et al, 2006a ; Hays et al, 2008 ).…”