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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 ?-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.

SUBMITTER: Hanes WM

PROVIDER: S-EPMC4749496 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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

Hanes William M WM Olofsson Peder S PS Kwan Kevin K Hudson LaQueta K LK Chavan Sangeeta S SS Pavlov Valentin A VA Tracey Kevin J KJ

Molecular medicine (Cambridge, Mass.) 20150817 1

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. ...[more]

PMID: 26322849

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Project description:Background: Epigenetic alteration of the genome has been shown to provide palliative effects in mouse models of certain human autoimmune disorders. We have investigated whether chromatin remodeling could provide protection against autoimmune diabetes in nonobese diabetic (NOD) mice. Treatment of female mice during the transition from prediabetic to diabetic stage (18-24 weeks of age) with the well-characterized histone deacetylase inhibitor, Trichostatin A (TSA) effectively reduced the incidence of diabetes and abrogated the ability of splenocytes to adoptively transfer the disease into immunodeficient NOD.scid mice. Protection against diabetes was accompanied by histone hyperacetylation in pancreas and spleen, increased frequency of CD4+ CD62L+ cells in the spleen, reduction in cellular infiltration of islets, restoration of normoglycemia and glucose-induced insulin release by beta cells. In vitro activation of splenic T lymphocytes derived from protected mice resulted in enhanced expression of IFN-gamma mRNA and protein without altering the expression of Il4, Il17, Il18, Inos, and Tnfa genes nor the secretion of IL-2, IL-4, IL-17 and TNF-alpha proteins. Consistently, expression of the transcription factor involved in Ifng transcription, Tbet/Tbx21 but not Gata3 and Rorgt, respectively required for the transcription of Il4 and Il17, was upregulated in activated splenocytes of protected mice. These data indicate that abrogation of autoimmune diabetes is associated with the selective upregulation of certain inducible genes in T lymphocytes. Microarray analysis was performed to determine the changes in global gene expression underlying abrogation of autoimmune diabetes by TSA-mediated epigenetic modulation and identified a distinct group of genes down-regulated during this process. Female NOD mice were treated subcutaneously with TSA (500 µg/Kg body weight) during the transition from prediabetic to diabetic stage (18-24 weeks of age), at weekly intervals. Since we sought to determine the modulation of global gene expression associated with long-term protection against diabetes, TSA treated mice were killed between 32 and 36 weeks of age and total RNA was extracted from uninduced splenocytes. RNA was also extracted from splenocytes of untreated mice that became diabetic and those that did not develop diabetes till 36 weeks of age. Blood glucose levels were determined weekly to monitor the glycemic condition in untreated and TSA-treated mice. To minimize the variability in gene expression among individual mice, RNA was extracted from splenocytes of 3 to 5 mice per group and pooled. Each sample was hybridized to microchips in duplicate. Female NOD mice were treated with Trichostatin A (500 µg/Kg body weight) between 18-24 weeks of age or left untreated.

Dataset Information

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

Publications

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

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