oxepins and myelin-oligodendrocyte-glycoprotein-(35-55)

We tested two novel bifunctional compounds: ibuprofen-N-octyl-pyridostigmine bromide (IBU-PO) and ibuprofen-N-decyl-pyridostigmine bromide (IBU-PD). They both contain a non-steroidal anti-inflammatory drug (NSAID), ibuprofen (IBU) and pyridostigmine (PO), a cholinesterase inhibitor that acts as a cholinergic up-regulator (CURE). The two moieties are conjugated by a hydrocarbon spacer consisting of 8 (octyl) and 10 (decyl) carbons, respectively. The compounds were tested for their efficiency in reducing the neurological symptoms observed in experimental autoimmune encephalomyelitis induced in mice by myelin oligodendrocyte glycoprotein (MOG). IBU-PO and IBU-PD significantly ameliorated the clinical score (a 40-50% reduction in disease severity) over a period of 30 days, following daily administration of 1 and 0.1mg/kg, i.p., respectively. Clinical improvement was accompanied by reduced responsiveness of MOG-specific T-cells. In addition, IBU-PO and IBU-PD down-regulated the production of nitric oxide (NO) and prostaglandin E2 (PGE2) in cultured astrocytes. To determine which moiety was responsible for these effects, we tested each of the two components, IBU and PO. Our findings indicate that combining NSAID with cholinergic intervention contributes an added therapeutic value for each distinct entity and that these bifunctional compounds act both on the peripheral immunological system and on the central nervous system (CNS) inflammatory pathways.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Astrocytes; Chemistry, Pharmaceutical; Cholinesterase Inhibitors; Dinoprostone; Drug Interactions; Encephalomyelitis, Autoimmune, Experimental; Glycoproteins; Ibuprofen; Lipopolysaccharides; Lymphocytes; Mice; Mice, Inbred C57BL; Myelin-Oligodendrocyte Glycoprotein; Naphthalenes; Nitric Oxide; Oxepins; Peptide Fragments; Pyridostigmine Bromide; Time Factors