GTS21 / CoMentis - LARVOL DELTA

Neuromodulation via alpha7 nicotinic acetylcholine receptor signaling restrains alloimmunity and prolongs transplant survival (TTS 2026) - "These data support the therapeutic potential of neuro-immunomodulation in alloimmunity, prolonging transplant survival. Activation of the cholinergic anti-inflammatory pathway presents thus a novel approach for immune modulation in and beyond organ transplantation.Figure 1 (A) Graft survival probability of skin and heart transplants in animals treated with focused ultrasound vs. sham FUS or GTS-21 vs."

Immune Modulation • Immunology • Inflammation • Solid Organ Transplantation • Systemic Inflammatory Response Syndrome • Transplantation • CD4 • CD69 • CD8 • CD80 • CD86

Activation of lung megakaryocyte α7 nAChR exacerbates allergic airway inflammation via IL-33/p38 MAPK signaling. (PubMed, JCI Insight) - "In this study, allergen-challenged mouse models were used with conditional Mk-specific Chrna7 knockout, pharmacological activation (GTS-21), and Mk reconstitution...Mechanistically, α7 nAChR activation promoted Mk IL-33 synthesis and secretion through p38 MAPK signaling. Taken together, our results show that α7 nAChR on lung Mks plays a proinflammatory role in allergic airway inflammation, challenging its classical antiinflammatory paradigm and revealing pathogenic mechanisms."

Journal • Allergy • Asthma • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases • CHRNA7 • IL33

α7nAChR agonist GTS-21 ameliorates sepsis-induced acute kidney injury via MEF2/PGC-1α/HO-1 axis in mice. (PubMed, Clin Transl Med) - "These findings suggest that GTS-21 may represent a potential therapeutic strategy for sepsis-induced kidney injury."

Journal • Preclinical • Acute Kidney Injury • Infectious Disease • Inflammation • Metabolic Disorders • Nephrology • Renal Disease • Septic Shock • HMOX1

Splenic Focused Ultrasound Attenuates Alloimmune Response via the Cholinergic Anti-Inflammatory Pathway (ATC 2026) - "Studies utilizing a pharmacological agonist (GTS-21) as well as an antagonist (MLA) of the α7nAChR defined mechanistic components by confirming that immunomodulatory effects are mediated via α7nAChR-dependent pathways.* LPS-induced inflammation was significantly reduced, as evidenced by lower systemic IL-6 levels (p<0.01) and increased IL-10 levels (p<0.01)... This data demonstrates the therapeutic potential of neuro-immunomodulation in curbing alloimmunity. Activation of the cholinergic anti-inflammatory pathway presents a novel, non-invasive approach for immune modulation in and beyond organ transplantation."

Immune Modulation • Immunology • Inflammation • Solid Organ Transplantation • CD69 • CD8 • IL10 • IL6

THE ALPHA-7 NICOTINIC ACETYLCHOLINE RECEPTOR AGONISM AS A THERAPEUTIC TARGET IN AUTOIMMUNE AND NEUROINFLAMMATORY DISEASE (AUTO 2026) - "In one study, the selective α7nAChR agonist GTS-21 significantly reduced CD4+ T cells and inflammatory cytokines... These findings suggest α7nAChR as a prospective target for future therapies. Clinical trials are needed to explore the efficacy and safety of α7nAChR stimulation in these autoimmune and neurodegenerative diseases."

Alzheimer's Disease • CNS Disorders • Diabetes • Immunology • Inflammation • Inflammatory Arthritis • Metabolic Disorders • Rheumatoid Arthritis • Type 1 Diabetes Mellitus • CD4 • IFNG • TBX21

Alpha7 nicotinic acetylcholine receptor activation attenuates allergic airway inflammation and is associated with heme oxygenase-1 induction. (PubMed, Front Immunol) - "GTS-21 attenuated allergic airway inflammation and suppressed epithelial TSLP production in association with increased HO-1 expression. These findings suggest that cholinergic receptor-associated signaling may modulate epithelial inflammatory responses in allergic airway inflammation."

Journal • Inflammation • Respiratory Diseases • HMOX1 • TSLP

Nicotine Suppresses Human Memory Th Cell Subsets With Preferential Effects on Central Memory Th Cells in an α7 Nicotinic Acetylcholine Receptor-Dependent Manner. (PubMed, Eur J Immunol) - "Collectively, nicotine engages an α7nAChR-dependent checkpoint that preferentially regulates Tcm responses, while GTS-21 exerts broader suppressive effects not fully explained by α7nAChR loss. This cholinergic checkpoint in Tcm may limit Tfh-associated help and pathogenic recall responses in immune-mediated disease."

Journal • Inflammation • BCL6 • CCR7 • CD40LG • CHRNA7 • GATA3 • IFNG • IL17A • IL21 • IL4 • TBX21

RENOPROTECTIVE MECHANISMS VIA PARASYMPATHETIC NERVE STIMULATION IN CISPLATIN-INDUCED NEPHROPATHY (ISN-WCN 2026) - "In vitro, we administered cisplatin and GTS-21 (selective α7 nicotinic acetylcholine receptor agonist) to HK-2 (human proximal tubular epithelial cell line) cells, and evaluated the expression of tubular injury markers and inflammatory cytokines. It was suggested that parasympathetic nerve stimulation inhibited the activation of NF-κB pathway and provided an anti-inflammatory effect. We need further investigations to elucidate the mechanisms, which leads to the development of new treatments."

Acute Kidney Injury • Chronic Kidney Disease • Nephrology • Renal Disease

GTS-21 Alleviates Acute Lung Injury by Enhancing GLP-1 Secretion and Regulating Alveolar Surfactant Proteins via α7nAChR Activation. (PubMed, Inflammation) - No abstract available

Journal • Acute Lung Injury • Infectious Disease • Pneumonia • Respiratory Diseases

α7 Nicotinic acetylcholine receptor activation rescues mitochondrial dysfunction in gestational diabetes mellitus by competing with p66Shc for VDAC1 binding. (PubMed, Diabetologia) - "This study identifies a non-canonical role for α7nAChR in maintaining mitochondrial Ca2⁺ homeostasis by competitively regulating VDAC1-p66Shc interactions under hyperglycaemic conditions. The findings reveal a mechanistic link between α7nAChR dysfunction, mitochondrial Ca2⁺ overload and cellular senescence in GDM placentas. Targeting α7nAChR with pharmacological agents such as GTS-21 may offer a novel therapeutic approach to ameliorate mitochondrial dysfunction and placental pathology in GDM by restoring Ca2⁺ dynamics."

Journal • Diabetes • Gestational Diabetes • Metabolic Disorders • VDAC1

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