Galantamine Attenuates Type 1 Diabetes and Inhibits Anti-Insulin Antibodies in Nonobese Diabetic Mice

Abstract

Type 1 diabetes in mice is characterized by autoimmune destruction of insulin-producing pancreatic β-cells. Disease pathogenesis involves invasion of pancreatic islets by immune cells, including macrophages and T cells, and production of antibodies to self-antigens, including insulin. Activation of the inflammatory reflex, the neural circuit that inhibits inflammation, culminates on cholinergic receptor signals on immune cells to attenuate cytokine release and inhibit B-cell antibody production. Here, we show that galantamine, a centrally acting acetylcholinesterase inhibitor and an activator of the inflammatory reflex, attenuates murine experimental type 1 diabetes. Administration of galantamine to animals immunized with keyhole limpet hemocyanin (KLH) significantly suppressed splenocyte release of immunoglobulin G (IgG) and interleukin (IL)-4 and IL-6 during KLH challenge ex vivo. Administration of galantamine beginning at 1 month of age in nonobese diabetic (NOD) mice significantly delayed the onset of hyperglycemia, attenuated immune cell infiltration in pancreatic islets and decreased anti-insulin antibodies in serum. These observations indicate that galantamine attenuates experimental type 1 diabetes in mice and suggest that activation of the inflammatory reflex should be further studied as a potential therapeutic approach.

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

“…Of note, adoptive transfer of vagally activated CD4+ T cells to nude mice (that are devoid of T cells) led to reduced endotoxin-induced TNF responses in these animals (Rosas-Ballina et al, 2011). In terms of the translational implications of these findings, recent work indicates that galantamine, an allosteric potentiating ligand of the α7 nicotinic acetylcholine receptor, can reduce the expression of diabetes through suppression of inflammatory cytokine responses (Hanes et al, 2015), and afferent stimulation of the vagus nerve reduces the inflammatory cytokine response to endotoxin (Borovikova et al, 2000). Clinical trials are currently underway to test whether afferent vagal nerve electrostimulation (in contrast to the efferent nerve stimulation currently used in depression) can treat inflammatory disorders including Crohn's disease (NCT01569503).…”

Mechanisms and Therapeutic Relevance of Neuro-immune Communication

“…In addition to vagus nerve stimulation, several lines of pharmacological modalities, including α7nAChR agonists, centrally-acting acetylcholinesterase inhibitors and mAChR agonists, and β2 adrenoreceptor agonists have been explored in preclinical settings of inflammatory and autoimmune disorders (van Westerloo et al, 2006; Parrish et al, 2008; Pavlov et al, 2007; Hanes et al, 2015; Rosas-Ballina et al, 2015; Yeboah et al, 2008; Terrando et al, 2014; Pavlov et al, 2009; Marino and Cosentino, 2013; Ji et al, 2013; Munyaka et al, 2014). Pharmacological approaches that target the inflammatory reflex have been currently studied in subjects with obesity-driven disorders.…”

Neuro–Immune Cell Units: A New Paradigm in Physiology

“…The main neuroimmune pathways that were therapeutically explored comprise the modulation of the inflammatory reflex through electrical vagus nerve stimulation. Pharmacological approaches, including α 7 nAChR agonists, acetylcholinesterase inhibitors, muscarinic acetylcholine receptor agonists, and β 2 -adrenoreceptor agonists, are also being explored (198)(199)(200)(201)(202)(203)(204)(205)(206)(207)(208). Galantamine, an acetylcholinesterase inhibitor acting on the CNS, and in clinical use to treat Alzheimer disease, is currently being tested in a clinical trial, as a pharmacological approach for neuronal modulation of inflammation, in patients with metabolic syndrome (200,207,209).…”