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1.
Neuromolecular Med ; 16(2): 292-307, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24272426

ABSTRACT

Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system (CNS) involving demyelinating and neurodegenerative processes. Several of the major pathological CNS alterations and behavioral deficits of MS are recapitulated in the experimental autoimmune encephalitis (EAE) mouse model in which the disease process is induced by administration of myelin peptides. Development of EAE requires infiltration of inflammatory cytokine-generating monocytes and macrophages, and auto-reactive T cells, into the CNS. Very late antigen-4 (VLA-4, α4ß1) is an integrin molecule that plays a role in inflammatory responses by facilitating the migration of leukocytes across the blood-brain barrier during inflammatory disease, and antibodies against VLA-4 exhibit therapeutic efficacy in mouse and monkey MS models. Here, we report that the tellurium compound AS101 (ammonium trichloro (dioxoethylene-o,o') tellurate) ameliorates EAE by inhibiting monocyte and T cell infiltration into the CNS. CD49d is an alpha subunit of the VLA-4 (α4ß1) integrin. During the peak stage of EAE, AS101 treatment effectively ameliorated the disease process by reducing the number of CD49d(+) inflammatory monocyte/macrophage cells in the spinal cord. AS101 treatment markedly reduced the pro-inflammatory cytokine levels, while increasing anti-inflammatory cytokine levels. In contrast, AS101 treatment did not affect the peripheral populations of CD11b(+) monocytes and macrophages. AS101 treatment reduced the infiltration of CD4(+) and CD49(+)/VLA4 T cells. In addition, treatment of T cells from MS patients with AS101 resulted in apoptosis, while such treatment did not affect T cells from healthy donors. These results suggest that AS101 reduces accumulation of leukocytes in the CNS by inhibiting the activity of the VLA-4 integrin and provide a rationale for the potential use of Tellurium IV compounds for the treatment of MS.


Subject(s)
Cell Movement/drug effects , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Ethylenes/therapeutic use , Immunologic Factors/therapeutic use , Integrin alpha4beta1/antagonists & inhibitors , Monocytes/drug effects , Spinal Cord/immunology , T-Lymphocyte Subsets/drug effects , Animals , Apoptosis/drug effects , Blood-Brain Barrier/immunology , Brain/immunology , Brain/pathology , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , Chemotaxis, Leukocyte/drug effects , Cytokines/biosynthesis , Cytokines/genetics , Encephalomyelitis, Autoimmune, Experimental/immunology , Ethylenes/pharmacology , Female , Humans , Immunologic Factors/pharmacology , Membrane Potential, Mitochondrial/drug effects , Mice , Mice, Inbred C57BL , Monocytes/immunology , Multiple Sclerosis/immunology , Multiple Sclerosis/pathology , Spinal Cord/metabolism , Spinal Cord/pathology , Spleen/metabolism , T-Lymphocyte Subsets/immunology
2.
Aging (Albany NY) ; 4(6): 436-47, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22761194

ABSTRACT

The histone deacetylase, SIRT1, plays a major role in glucose regulation and lipid metabolism. Ammonium Trichloro (dioxoethylene-o,o') Tellurate, AS101, is a potent in vitro and in vivo immunomodulator, with several potential therapeutic applications. AS101 administration resulted in upregulation of SIRT1 protein expression and activity. These effects were associated with decreased levels of serum insulin like growth factor-1 (IGF-1) and of insulin. The properties of AS101 prompted us to investigate its potential therapeutic role in rats with type 2 diabetes (T2D). T2D was induced by a high fat diet combined with a low dose of Streptozotocin (STZ). Treatment with AS101 before manifestation of hyperglycemia, resulted in increased insulin sensitivity, and decreased blood glucose levels, and prevented symptoms of diabetes including defective glucose clearance, fatty liver, and abnormal distribution of insulin-producing beta cells in the pancreas. Treatment after disease emergence resulted in partial restoration of normal glucose homeostasis. Diabetic rats showed a reduction in liver SIRT1 levels. In both treatment regimens the reduction in SIRT1 levels in the liver were blocked by AS101 consumption. Together, these findings demonstrate the therapeutic potential of AS101 for treating T2D, and for reversing impaired fat and glucose metabolism.


Subject(s)
Diabetes Mellitus, Type 2/prevention & control , Ethylenes/pharmacology , Sirtuin 1/metabolism , Animals , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/metabolism , Disease Models, Animal , Ethylenes/therapeutic use , Insulin Resistance , Insulin-Like Growth Factor I/physiology , Rats , Tellurium/pharmacology , Tellurium/therapeutic use
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