GTS21 / CoMentis - LARVOL DELTA

α7 nicotinic acetylcholine receptor agonist attenuates lipopolysaccharide-induced acute kidney injury in mice by reducing CCL2 expression in macrophages. (PubMed, Sci Rep) - "In macrophages, the LPS-induced increase in TNF-α was suppressed by GTS-21 (50 μM) administration. Furthermore, CCL2 expression in macrophages might be involved in mediating these effects."

Journal • Preclinical • Acute Kidney Injury • Infectious Disease • Inflammation • Nephrology • Renal Disease • Septic Shock • CCL2 • TNFA

Alpha 7 nicotinic acetylcholine receptor contributes to long-term cognitive recovery following ischemic stroke. (PubMed, Exp Neurol) - "GTS-21 treatment improved cognition and reduced gliosis, supporting a protective role for α7nAChR activation. In conclusion, α7nAChR signaling supports reparative immune programs and promotes neurorepair after stroke, thereby enhancing long-term cognitive recovery."

Journal • Cardiovascular • Inflammation • Ischemic stroke • IL6 • SOCS3 • TNFA

Neuroimmune Regulation via the Cholinergic Anti-Inflammatory Pathway Mitigates Peritoneal Injury Induced by Inflammation and High-Salt Stress in Peritoneal Dialysis (KIDNEY WEEK 2025) - "CAP was activated via nicotine or GTS-21 (α7nAChR agonist)...Conclusion CAP activation preserves peritoneal function in PD by targeting both immune and structural cell compartments under infectious and salt-induced stress. These dual mechanisms highlight CAP as a promising therapeutic target for prolonging peritoneal membrane viability in long-term PD."

Fibrosis • Immunology • Inflammation • COL1A1 • IL1B • IL6 • NOS2 • TGFB1 • TNFA

Nociceptor α7nAChR activation blunts neuronal HMGB1 release and attenuates inflammation and nociceptive behavior. (PubMed, Mol Med) - "This study reveals a novel α7nAChR-dependent cholinergic mechanism that reduces nociceptive behavior and inflammation by retaining nuclear HMGB1 in nociceptors. Cholinergic agonists may serve as promising therapeutic agents to mitigate nociceptive behavior and inflammation by targeting α7nAChR in sensory neurons."

Journal • Inflammation • Pain • HMGB1 • IL6

Research progress on the potential mechanisms and effects of the cholinergic anti-inflammatory pathway in sepsis (PubMed, Zhonghua Wei Zhong Bing Ji Jiu Yi Xue) - "Potential applications of CAP in sepsis treatment include stimulating the vagus nerve (e.g., through pharmacological, electrical, or acupuncture stimulation), using α7nAChR agonists (e.g., nicotine, GTS-21, and PNU-282987), adrenergic receptor agonists (e.g., dexmedetomidine and salbutamol), or other drugs and bioactive substances (e.g., buprenorphine and traditional Chinese medicine components). These approaches aim to activate CAP, suppress inflammatory responses, and improve sepsis prognosis, providing a theoretical basis for treatment and promoting the development of related drugs."

Journal • Critical care • Infectious Disease • Inflammation • Septic Shock

GTS-21 alleviates sepsis-induced atrial fibrillation susceptibility by modulating macrophage polarization and Neuregulin-1 secretion. (PubMed, Int Immunopharmacol) - "GTS-21 mitigated atrial inflammation and reduced the incidence of AF in mice with sepsis by regulating macrophage polarization, reducing oxidative stress, and preserving mitochondrial and calcium dynamics in cardiomyocytes. These findings highlight the therapeutic potential of GTS-21 in treating sepsis-induced AF."

Journal • Atrial Fibrillation • Cardiovascular • Infectious Disease • Inflammation • Metabolic Disorders • Septic Shock • IL1B • NLRP3 • NRG1

Activated Microglia Mediate the Motor Neuron-, Synaptic Denervation- and Muscle Wasting-Changes in Burn Injured Mice. (PubMed, J Cachexia Sarcopenia Muscle) - "Microglia-mediated inflammatory responses play pivotal role in MNL as decrease of inflammatory responses improved MNL; α7AChR stimulation also mitigated synaptic denervation and MW changes of BI. α7AChRs have a role in spinal homeostasis even in uninjured state."

Journal • Preclinical • Anesthesia • Inflammation • CASP3 • CD86 • CHRNA7 • IL1B • NFKB1 • STAT3 • SYP • TNFA

Activation of α7nAch receptors ameliorates α-synuclein pathology in the brain and gut of a subacute MPTP mouse model of Parkinson's disease. (PubMed, Biomed Pharmacother) - "Pretreatment with MLA abolished the GTS-21-elicited behavioral recovery, α-syn clearance, and anti-inflammatory effects in the brain and gut. Therefore, α7nAchR activation may be a potential candidate strategy for the treatment of PD by altering α-syn aggregation in the brain and gut."

Journal • Preclinical • CNS Disorders • Developmental Disorders • Inflammation • Movement Disorders • Oncology • Parkinson's Disease • IL6 • TNFA

GTS-21 modulates rheumatoid arthritis Th17 and Th2 lymphocyte subset differentiation through the ɑ7nAch receptor. (PubMed, Clin Rheumatol) - "Key Points • GTS-21 suppressed RA Th17 differentiation and promoted Th2 differentiation via acting on ɑ7nAchR. • The protective effect of GTS-21 on RA may be related to its regulation of Th cell subsets."

Journal • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • CD4 • GATA3 • IL17A • IL4 • RORC

Early effects of α7nAChR regulation on maxillary expansion in mice : A study on osteogenesis and inflammatory factors. (PubMed, J Orofac Orthop) - "Using α7nAChR agonists and antagonists to regulate the cholinergic anti-inflammatory pathway, the secretion of inflammatory factors and osteoblast markers during maxillary expansion were altered, indicating the potential for clinical modulation of maxillary palatal suture expansion."

Journal • Preclinical • Oncology • BGLAP • IL1B • RUNX2 • TNFA

Anti-inflammatory Effects of Vagus Nerve Stimulation Are Mediated by the Notch Signaling Pathway during Sepsis-Associated AKI (KIDNEY WEEK 2024) - "Our findings suggest VNS protects the kidneys against sepsis-associated AKI via activation of the Notch2 signaling in MΦ."

Acute Kidney Injury • Infectious Disease • Inflammation • Nephrology • Renal Disease • Septic Shock • CCL2 • CSF1 • CX3CR1 • HES1 • NOTCH2

Examining the Anti-inflammatory and Renoprotective Effects Resulting from Parasympathetic Nerve Stimulation after Inflammation (KIDNEY WEEK 2024) - "Due to concerns about the highly invasive nature of direct vagus nerve stimulation, we chose to activate the parasympathetic nervous system by administering 3-(2,4-Dimethoxybenzylidene)-anabaseine dihydrochloride (GTS-21), a selective α7 nicotinic acetylcholine receptor agonist... Even after inflammation induction, stimulation of the parasympathetic nervous system yielded anti-inflammatory and renoprotective effects. This discovery holds significant promise for the development of novel treatments for sepsis and AKI."

Acute Kidney Injury • Infectious Disease • Inflammation • Nephrology • Renal Disease • Septic Shock • CCL2

Identification of O-arylated huperzinines as novel cholinergic anti-inflammatory pathway agonists against gout arthritis. (PubMed, Bioorg Chem) - "Compared with the clinical drugs hydrocortisone and indomethacin, as well as commercially available CAP agonists GTS-21 and pnu282987, 3k and 3q possessed greater potency against MSU-induced IL-1β production. Meanwhile, these molecules possessed less cytotoxicity against promonocytic THP-1 macrophages when compared with colchicine. This work reports a concise strategy for direct modification of 2-pyridone moiety from natural Lycodine alkaloids, and provides novel frameworks for discovering CAP activators and drugs for gout arthritis."

Journal • Gout • Immunology • Inflammatory Arthritis • Rheumatology • IL1B • NLRP3

Activation of the alpha 7 nicotinic acetylcholine receptor by GTS-21 mitigates contrast nephropathy in a rat model. (PubMed, Kidney Blood Press Res) - "GTS-21 significantly alleviated renal injury parameters through antioxidant, anti-inflammatory, and antiapoptotic mechanisms in the CN model."

Journal • Preclinical • Renal Disease • IL6 • TGFB1

Activation of the α7nAChR by GTS-21 mitigates septic tubular cell injury and modulates macrophage infiltration. (PubMed, Int Immunopharmacol) - "Its dual function of directly protecting renal tubular cells and regulating inflammatory responses represents a major advancement in the treatment of sepsis-induced AKI. This finding might pave the way for novel approaches to improving patient outcomes and reducing death rates in sepsis-related complications."

Journal • Acute Kidney Injury • Immunology • Infectious Disease • Inflammation • Nephrology • Renal Disease • Septic Shock • Systemic Inflammatory Response Syndrome • CCL20

α7 nicotinic acetylcholine receptor agonist attenuates allergen-induced immediate nasal response in murine model of allergic rhinitis. (PubMed, J Vet Med Sci) - "GTS-21 did not alter allergen-induced passive cutaneous anaphylaxis response in anti-dinitrophenyl IgE-sensitized mice. This evidence implies GTS-21's potential to alleviate allergic rhinitis without perturbing T cells or mast cells."

Journal • Preclinical • Allergic Rhinitis • Immunology • Inflammation • Transplantation

New Pyridyl and Dihydroisoquinoline Alkaloids Isolated from the Chevron Nemertean Amphiporus angulatus. (PubMed, Mar Drugs) - "GTS-21, a drug candidate based on the anabaseine scaffold, has pro-cognitive and anti-inflammatory actions in animal models. One compound is an isomer of the tobacco alkaloid anatabine, another is a unique dihydroisoquinoline, and three are analogs of the tetrapyridyl nemertelline. The structural characteristics of these ten compounds suggest several possible pathways for their biosynthesis."

Journal

GTS-21 attenuates ACE/ACE2 ratio and glycocalyx shedding in lipopolysaccharide-induced acute lung injury by targeting macrophage polarization derived ADAM-17. (PubMed, Int Immunopharmacol) - "GTS-21 exerted a protective effect against LPS-induced ALI, which was reversed by recombinant ADAM-17. Collectively, GTS-21 alleviates LPS-induced ALI by attenuating AT2s ACE/ACE2 ratio and glycocalyx shedding through the inhibition of macrophage M1 polarization derived ADAM-17."

Journal • Acute Lung Injury • Critical care • Inflammation • Respiratory Diseases • EXT1 • SDC1

Anti-Inflammatory and Renal Protective Mechanisms by Controlling Parasympathetic and Sympathetic Balance (KIDNEY WEEK 2023) - "GTS-21 (α7nicotinic acetylcholine receptor: α7nAChR agonist) and salbutamol (β2 adrenergic receptor: β2AR agonist) were used... Simultaneous parasympathetic and sympathetic stimulation synergistically reduced inflammation in macrophages and tubular cell damages. However, in vivo experiments did not support this synergistic effect. Autonomic nerve stimulation appears to have indirect anti-inflammatory and renal protective effects mediated by the immune system, as well as direct protective effects on the kidney."

Acute Kidney Injury • Cardiovascular • Inflammation • Nephrology • Renal Disease • Reperfusion Injury

Neuroimmune dysregulation in alcohol+nicotine co-use: A critical role for nicotinic α7 receptors. (Neuroscience 2023) - "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 α7 receptor may be an important target for future pharmacotherapies with the potential of treating both alcohol and nicotine dependence."

Addiction (Opioid and Alcohol) • CNS Disorders • Nicotine Addiction • TLR3

Regulation of neuronal HMGB1 release via an alpha7 nicotinic acetylcholine receptor-dependent mechanism (Neuroscience 2023) - "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)."

CNS Disorders • HMGB1 • TRPV1

GTS-21 Enhances Regulatory T Cell Development from T Cell Receptor-Activated Human CD4 T Cells Exhibiting Varied Levels of CHRNA7 and CHRFAM7A Expression. (PubMed, Int J Mol Sci) - "GTS-21 did not alter CD4 T cell proliferation but significantly promoted Treg development. These results suggest the potential ex vivo utility of GTS-21 for preparing Tregs for adoptive immunotherapy, even with high expression of the dupα7 subunit."

IO biomarker • Journal • Inflammation • CD4 • CHRNA7

GTS-21 alleviates murine collagen-induced arthritis through inhibition of peripheral monocyte trafficking into the synovium. (PubMed, Int Immunopharmacol) - "Together, our data demonstrate that GTS-21 alleviates arthritis by inhibiting peripheral monocyte trafficking into the synovium. Our findings describe a novel mechanism through which the cholinergic signaling pathway can reduce synovial inflammation in RA patients."

Journal • Preclinical • Immunology • Inflammation • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • CCL2 • CCR2 • VCAM1

Alpha 7 nicotinic acetylcholine receptors signaling boosts cell-cell interactions in macrophages effecting anti-inflammatory and organ protection. (PubMed, Commun Biol) - "Using macrophage-derived cell lines, we demonstrated that GTS-21 increases cell contact, and that the contact between macrophages receiving α7nAChR signals leads to a reduction in TNF-α. Our results suggest that α7nAChR signaling increases macrophage-macrophage interactions in the spleen and has a protective effect on the kidneys."

Journal • Acute Kidney Injury • Nephrology • Renal Disease • TNFA

Activation of α7 nicotinic acetylcholine receptor promotes HIV-1 transcription. (PubMed, Cell Insight) - "In this study, we first found that activation of α7 nAChR by GTS-21 (an α7 nAChR agonist) can promote the transcription of HIV-1 proviral DNA...Taken together, activation of the α7 nAChR could trigger ROS/p-p38 MAPK/LMNB1/NFATC4 signaling pathway enhancing HIV-1 transcription. We have revealed an unrecognized mechanism of α7 nAChR-mediated neuroimmune regulation of HIV infection."

Journal • Human Immunodeficiency Virus • Infectious Disease • Inflammation • CD4 • DUSP1 • DUSP6 • MAPK14