ABSTRACT
Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system (CNS) affecting more than 2.5 million individuals worldwide. In the present study, myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) mice were treated with adenosine receptor A2A antagonist SCH58261 at different periods of EAE development. The administration of SCH58261 at 11-28 days post-immunization (d.p.i.) with MOG improved the neurological deficits. This time window corresponds to the therapeutic time window for MS treatment. SCH58261 significantly reduced the CNS neuroinflammation including reduced local infiltration of inflammatory cells, demyelination, and the numbers of macrophage/microglia in the spinal cord. Importantly, SCH58261 ameliorated the EAE-induced neurobehavioral deficits. By contrast, the SCH58261 treatment was ineffective when administered at the beginning of the onset of EAE (i.e., 1-10â¯d.p.i). The identification of the effective therapeutic window of A2A receptor antagonist provide insight into the role of A2A receptor signaling in EAE, and support SCH58261 as a candidate for the treatment of MS in human.
Subject(s)
Adenosine A2 Receptor Antagonists/therapeutic use , Encephalomyelitis, Autoimmune, Experimental/prevention & control , Macrophage Activation/drug effects , Microglia/drug effects , Neuroprotective Agents/therapeutic use , Pyrimidines/therapeutic use , Receptors, Adrenergic, alpha-2/physiology , Triazoles/therapeutic use , Adenosine A2 Receptor Antagonists/administration & dosage , Adenosine A2 Receptor Antagonists/pharmacology , Animals , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Down-Regulation/drug effects , Drug Administration Schedule , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Encephalomyelitis, Autoimmune, Experimental/etiology , Encephalomyelitis, Autoimmune, Experimental/pathology , Female , Interferon-gamma/biosynthesis , Interferon-gamma/genetics , Mice , Mice, Inbred C57BL , Microglia/physiology , Myelin Sheath/pathology , Myelin-Oligodendrocyte Glycoprotein/immunology , Myelin-Oligodendrocyte Glycoprotein/toxicity , Neuroprotective Agents/administration & dosage , Neuroprotective Agents/pharmacology , Nitric Oxide Synthase Type II/biosynthesis , Nitric Oxide Synthase Type II/genetics , Peptide Fragments/immunology , Peptide Fragments/toxicity , Pyrimidines/administration & dosage , Pyrimidines/pharmacology , Quadriplegia/etiology , Receptors, Adrenergic, alpha-2/drug effects , Spinal Cord/drug effects , Spinal Cord/pathology , Triazoles/administration & dosage , Triazoles/pharmacologyABSTRACT
Our previous studies showed that ligands to type 2 imidazoline receptors (I2R), including 2-(2-Benzofuranyl)-2-imidazoline (2-BFI) and Idazoxan, were effective in reducing spinal cord inflammation caused by experimental autoimmune encephalomyelitis (EAE). In the present study, we determined the effective therapeutic time window of 2-BFI and found that administration of 2-BFI in mice before the appearance of ascending flaccid paralysis (1-10 days post immunization), but not during the period when neurological deficits occurred (11-20 days post immunization), significantly ameliorated EAE-induced neurobehavioral deficits, reduced the infiltration of inflammatory cells into the spinal cord, and reduced the level of demyelination. More interestingly, giving 2-BFI during 1-10 days post immunization selectively suppressed IL-17 levels in the peripheral blood, which strongly suggests that IL-17 may be a good early marker to indicate EAE progression and that 2-BFI may target CD4⺠T lymphocytes, especially Th17 cells to reduce IL-17 expression. Collectively, these studies led us to envisage that 2-BFI can be a useful drug to treat multiple sclerosis (MS) when used in combination with an early indicator of MS progression, such as IL-17.