Bifunctional compounds eliciting both anti-inflammatory and cholinergic activity as potential drugs for neuroinflammatory impairments.
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.
Nizri
Eran
E
Laboratory of Neuroimmunology, Department of Neurology and the Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, P.O. Box 12000, Jerusalem 91120, Israel.
Adani
Rellie
R
Meshulam
Haim
H
Amitai
Gabi
G
Brenner
Talma
T
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000627:therapeutic use*; D001253:Astrocytes / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D015232:Dinoprostone / Q000378:metabolism; D004347:Drug Interactions; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy*; D006023:Glycoproteins; D007052:Ibuprofen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein; D009281:Naphthalenes; D009569:Nitric Oxide / Q000378:metabolism; D010082:Oxepins; D010446:Peptide Fragments; D011729:Pyridostigmine Bromide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use*; D013997:Time Factors
C461941:1-phenyl-1,4-epoxy-1H,4H-naphtho(1,8-de)(1,2)dioxepin; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002800:Cholinesterase Inhibitors; D006023:Glycoproteins; D008070:Lipopolysaccharides; D063308:Myelin-Oligodendrocyte Glycoprotein; D009281:Naphthalenes; D010082:Oxepins; D010446:Peptide Fragments; C501052:ibuprofen-N-decyl-pyridostigmine; C501051:ibuprofen-N-octyl-pyridostigmine; C445081:myelin oligodendrocyte glycoprotein (35-55); D009569:Nitric Oxide; D015232:Dinoprostone; D011729:Pyridostigmine Bromide; D007052:Ibuprofen