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  • ||||||||||  GTS21 / CoMentis
    Neuroimmune dysregulation in alcohol+nicotine co-use: A critical role for nicotinic ?7 receptors. (WCC Halls A-C) -  Nov 3, 2023 - Abstract #Neuroscience2023NEUROSCIENCE_12133;    
    Here, we demonstrate that increasing doses of GTS-21 decrease alcohol self-administration with a trend towards decreasing nicotine self-administration. These findings suggest the ?7 receptor may be an important target for future pharmacotherapies with the potential of treating both alcohol and nicotine dependence.
  • ||||||||||  GTS21 / CoMentis
    Regulation of neuronal HMGB1 release via an alpha7 nicotinic acetylcholine receptor-dependent mechanism (WCC Halls A-C) -  Nov 3, 2023 - Abstract #Neuroscience2023NEUROSCIENCE_7551;    
    Other cholinergic agonists, such as GTS-21 and carbachol, also suppress HMGB1 release by activated nociceptors...These results suggest that acetylcholine regulates HMGB1 release from nociceptors via alpha7nAChR-dependent cholinergic anti-inflammatory mechanism. (supported in part by grants from NIH, NIGMS, 1R35 GM118182 to KJT and R01GM132672 to SSC).
  • ||||||||||  GTS21 / CoMentis
    Journal:  Silent agonists for ?7 nicotinic acetylcholine receptors. (Pubmed Central) -  Apr 10, 2023   
    We discuss the strongly desensitizing partial agonist GTS-21 and its effectiveness in modulation of CAS...Most silent agonists bind to sites overlapping those for orthosteric agonists, but some appear to bind to allosteric sites. Finally, we discuss ?9 nAChRs and their potential role in CAS, and ligands that will be useful in defining and distinguishing the specific roles of ?7 and ?9 in CAS.
  • ||||||||||  GTS21 / CoMentis
    SYNERGISTIC ANTI-INFLAMMATORY AND RENAL PROTECTIVE MECHANISMS MEDIATED BY PARASYMPATHETIC AND SYMPATHETIC NERVOUS STIMULATION VIA IMMUNE SYSTEM () -  Mar 28, 2023 - Abstract #ISNWCN2023ISN_WCN_704;    
    Results Firstly, in vitro , administration of LPS and GTS-21 (?7 nicotinic acetylcholine receptor: ?7nAChR agonist) or salbutamol (?2 adrenergic receptor: ?2AR agonist) produced concentration-dependent anti-inflammatory effects in RAW 264 cells...However, no synergistic anti-inflammatory or renal protective effects were observed in vivo . To elucidate the mechanism in vivo , we are using macrophage-specific ?7nAChR and ?2AR knockout mice to determine the anti-inflammatory and renal protective effects, and to clarify the appropriate autonomic balance.
  • ||||||||||  GTS21 / CoMentis
    Journal:  Discovery of the Nicotinic Receptor Toxin Anabaseine in a Polystiliferan Nemertean. (Pubmed Central) -  Jan 21, 2023   
    Anabaseine has been a lead compound in the design of alpha7 nicotinic acetylcholine receptor agonists like GTS-21 (also called DMXBA) to treat disorders of cognition such as Alzheimer's disease and schizophrenia...A spectrophotometric assay for anabaseine, also based on its reaction with Ehrlich's reagent, revealed high concentrations of anabaseine in the body and proboscis. Apparently, the biosynthetic mechanism for producing anabaseine was acquired early in the evolution of the Hoplonemertea, before the monostiliferan-polystiliferan divergence.
  • ||||||||||  GTS21 / CoMentis
    Journal:  Outcomes of nicotinic modulation on markers of intestinal IgA antibody response. (Pubmed Central) -  Jan 17, 2023   
    Groups of mice were administered GTS-21 (an α7nAChR agonist) or mecamylamine (a non-selective nAChR antagonist) intraperitoneally for 7 days...These findings require further examination to address the impact of cholinergic modulation on IgA-transcytosis via pIgR. The present study may be an experimental reference for clinical trials that address the role of nicotinic system in intestinal dysfunctions as postoperative ileus.
  • ||||||||||  GTS21 / CoMentis
    Preclinical, Journal:  Nicotinic Stimulation of Splenic T Cells is Protective in ERCP-induced Acute Pancreatitis in Mice. (Pubmed Central) -  Oct 26, 2022   
    3-2,4-Dimethoxybenzylidene anabaseine (GTS-21), a specific partial agonist of the α7 nicotinic cholinergic receptor (α7nAChR), also protected the pancreas against ERCP-induced acute pancreatitis...When T cells were removed from the crude GTS-21-treated splenocyte preparation by immunomagnetic separation, the remaining non-T cell splenocytes did not protect against ERCP-induced acute pancreatitis. We conclude splenic T cells are required for nicotinic protection against ERCP-induced acute pancreatitis and that stimulation of α7 nicotinic cholinergic receptors may protect against ERCP-induced acute pancreatitis and also provide a novel approach to therapeutic reversal of ongoing acute pancreatitis.
  • ||||||||||  GTS21 / CoMentis
    Cholinergic Signaling Increases Macrophage-Macrophage Interactions and Protects Sepsis-Induced AKI (Exhibit Hall, Orange County Convention Center, West Building) -  Oct 13, 2022 - Abstract #KIDNEYWEEK2022KIDNEY_WEEK_992;    
    Methods To confirm the importance of α7nAChR in macrophages in vivo , macrophage-specific α7nAChR knockout (KO) mice (LysM-Cre: Chrna7 flox/flox mice) were generated and tested whether GTS-21 (α7nAChR specific agonists) ameliorates lipopolysaccharide (LPS)-induced kidney injury...The anti-inflammatory and renal protective effects were canceled by splenectomy, suggesting that macrophage-macrophage cell interactions in the spleen are essential even in vivo . Conclusion Activation of cholinergic signaling via α7nAChR on macrophages increases macrophage-macrophage interactions in the spleen, resulting in anti-inflammatory and renoprotective effects in LPS-induced acute kidney injury.
  • ||||||||||  GTS21 / CoMentis
    Preclinical, Journal:  The alpha-7 nicotinic acetylcholine receptor agonist GTS-21 does not affect food intake in rats. (Pubmed Central) -  Sep 14, 2022   
    Our results showed that plasma levels of total GLP-1 in rats were not significantly altered by peripheral GTS-21 injection. These results represent an advance in understanding how α7nAChR activation impacts energy balance control in rodents and suggest that there may be important differences between rats and mice in the ability of GTS-21/α7nAChR activation to increase secretion of GLP-1.
  • ||||||||||  GTS21 / CoMentis
    Preclinical, Journal:  Nicotinic acetylcholine receptor agonist reduces acute lung injury after renal ischemia-reperfusion injury by acting on splenic macrophages in mice. (Pubmed Central) -  Apr 14, 2022   
    Treatment with GTS-21, an α7nAChR-selective agonist, significantly reduced the levels of circulating IL-6, a key proinflammatory cytokine, and lung chemokine (C-X-C motif) ligand (CXCL)1 and CXCL2 and neutrophil infiltration, and Evans blue dye (EBD) vascular leakage increased after renal IRI...In mice depleted of alveolar macrophages, GTS-21 treatment significantly reduced lung neutrophil infiltration, and Evans blue dye vascular leakage increased after renal IRI. Our findings show that nAChR agonist reduces circulating IL-6 levels and acute lung injury after renal IRI by acting on splenic macrophages.
  • ||||||||||  GTS21 / CoMentis
    Journal:  Role of Cholinergic Anti-Inflammatory Pathway in Protecting Sepsis-Induced Acute Lung Injury through Regulation of the Conventional Dendritic Cells. (Pubmed Central) -  Apr 1, 2022   
    The results of the present study revealed that GTS-21 treatment decreased the maturation of DCs and the production of DC-related proinflammatory cytokines in vitro and in sepsis-induced ALI mouse model; it reduced the quantity of CD11cMHCII conventional DCs and CD11cCD11b conventional DCs2 in vivo experiment. Cholinergic anti-inflammatory pathway contributes to the reduction in the inflammatory response in ALI by regulating maturation, phenotype, and quantity of DCs, conventional DCs, and conventional DCs2.
  • ||||||||||  GTS21 / CoMentis
    Journal:  α7 Nicotinic Acetylcholine Receptor Agonists Regulate Inflammation and Growth Hormone Resistance in Sepsis. (Pubmed Central) -  Mar 18, 2022   
    Capsaicin was used to perform SAV and GTS-21 (α7nAChR agonist) was used to activate the α7nAChR...Collectively these results confirm the protective effects of the anti-inflammatory CAP pathway and α7nAChR activation in sepsis. They also provide evidence the CAP and α7nAChR activation could be used to attenuate hepatic GH resistance and anabolic failure in sepsis.
  • ||||||||||  GTS21 / CoMentis
    α-7 Nicotinic Acetylcholine Receptor (α-7 nAChR) Agonists Are Efficacious in a Novel Ferret Model of AECOPD (Area F, Hall F (North Building, Exhibition Level), Moscone Center) -  Feb 19, 2022 - Abstract #ATS2022ATS_4933;    
    Smoke-exposed ferrets recapitulate antiviral immune defects present in COPD patients and present with rapidly deteriorating airway disease symptoms emblematic of viral exacerbations. Furthermore, administration of α-7 nAChR agonists improved lung function via beneficial effects on mucus clearance and inflammatory response without altering viral burden.
  • ||||||||||  GTS21 / CoMentis
    Journal:  Vagal-α7nAChR signaling is required for lung anti-inflammatory responses and arginase 1 expression during an influenza infection. (Pubmed Central) -  Jan 27, 2022   
    Mechanistically, the activation of α7nAChR by its agonist GTS-21 could enhance IL-4-induced Arg1 expression, reduced Nos2, and TNF-α expression in PR8-infected bone marrow-derived macrophages (BMDM)...Knockdown of Foxo1a reduced α7nAChR activation and IL-4 induced Arg1 expression in PR8-infected BMDM. Therefore, vagal-α7nAChR signaling is a novel therapeutic target for treating lung inflammatory responses during an influenza infection.
  • ||||||||||  GTS21 / CoMentis
    Preclinical, Journal:  Activation of α7nAChR Protects Against Gastric Inflammation and Dysmotility in Parkinson's Disease Rats. (Pubmed Central) -  Dec 13, 2021   
    After treatment with PNU-282987 in vivo, the PD rats showed decreased NF-κB activation, inflammatory mediator production, and contractile protein expression and improved gastric motility. The present study reveals that α7nAChR is involved in the development of gastroparesis in PD rats and provides novel insight for the treatment of gastric dysmotility in PD patients.
  • ||||||||||  GTS21 / CoMentis
    Preclinical, Journal:  The Cholinergic Anti-Inflammatory Pathway Attenuates the Development of Atherosclerosis in Apoe Mice through Modulating Macrophage Functions. (Pubmed Central) -  Sep 29, 2021   
    Primary mouse bone marrow-derived macrophages (BMDM), peritoneal macrophages, and RAW264.7 cells were treated with CAP agonists acetylcholine (Ach) and GTS-21 to study their effects on macrophage functions...Moreover, the activation of CAP inhibited the formation of macrophage foam cells in the peritoneal cavity by regulating genes related to cholesterol metabolism. (4) This study provides novel evidence and mechanisms that the CAP plays an important role in the regulation of AS development by controlling macrophage functions, implying a potential use of CAP activation as a therapeutic strategy for AS treatment.
  • ||||||||||  GTS21 / CoMentis
    Review, Journal:  Therapeutic potential of α7 nicotinic acetylcholine receptor agonists to combat obesity, diabetes, and inflammation. (Pubmed Central) -  Sep 29, 2021   
    Of special note is the recent finding that α7nAChR agonist GTS-21 acts at L-cells of the distal intestine to stimulate the release of two glucoregulatory and anorexigenic hormones: glucagon-like peptide-1 (GLP-1) and peptide YY (PYY)...This review provides an overview of α7nAChR function as it pertains to CAIR, vagovagal reflexes, and metabolic homeostasis. We also consider the possible usefulness of α7nAChR agonists for treatment of obesity, diabetes, and inflammation.
  • ||||||||||  GTS21 / CoMentis
    Journal:  Antiproliferative effect of GTS-21 in glioblastoma cells. (Pubmed Central) -  Sep 21, 2021   
    Interestingly, treatment with α-BTX restored the proliferation of U87 cells, but not that of A172 and G28 cells. Collectively, the findings of the present study suggested that GTS-21 may inhibit the proliferation of GBM cells and may therefore serve as a novel therapeutic approach to the treatment of GBM, which warrants further investigation.
  • ||||||||||  GTS21 / CoMentis
    Preclinical, Journal:  GTS-21 ameliorates polymicrobial sepsis-induced hepatic injury by modulating autophagy through α7nAchRs in mice. (Pubmed Central) -  Aug 27, 2021   
    This suggests that the α7nAChR represents a potential pharmacological target for the treatment regimen of oxidative inflammatory lung injury in patients receiving oxygen therapy. Our findings suggested that α7nAchR is involved in diminishing hepatic damage by inhibiting inflammatory responses and improving autophagy in mice with polymicrobial sepsis.
  • ||||||||||  GTS21 / CoMentis
    Journal:  Exploring the Mechanism on the Medullary Visceral Zone Inhibiting the Cholinergic Anti-inflammatory Pathway Induced by Sepsis. (Pubmed Central) -  Aug 4, 2021   
    Our study demonstrates for the first time that cholinergic and catecholaminergic neurons in MVZ went through significant apoptosis and inactiveness in sepsis, which contributes to the inhibition of CAP and acceleration of the inflammation storm in early sepsis. Intervening with CAP has a significant effect on the activity and apoptosis of MVZ neurons while altering systemic inflammation and immunity; in addition, for the first time, we confirmed that some indicators of HRV such as SDNN, HF band, RMSSD, SD1, and SD2 can reflect the activity of CAP, but the CAP interference had little effect on these indicators.
  • ||||||||||  GTS21 / CoMentis
    Clinical, Journal:  Therapeutic efficacy of α7 ligands after acute ischemic stroke is linked to conductive states of α7 nAChRs. (Pubmed Central) -  Jul 7, 2021   
    Intervening with CAP has a significant effect on the activity and apoptosis of MVZ neurons while altering systemic inflammation and immunity; in addition, for the first time, we confirmed that some indicators of HRV such as SDNN, HF band, RMSSD, SD1, and SD2 can reflect the activity of CAP, but the CAP interference had little effect on these indicators. These results suggest that α7 ionotropic activity may be obligatory for therapeutic efficacy of α7 ligands after AIS yet, highlight the potential for selective application of α7 ligands to disease states based on their mode of receptor activation.