title: IBU-octyl-cytisine, a novel bifunctional compound eliciting anti-inflammatory and cholinergic activity, ameliorates CNS inflammation by inhibition of T-cell activity.
abstract: Experimental autoimmune encephalomyelitis (EAE) is a central nervous system (CNS) inflammatory model in which MOG-specific T-cells initiate an autoimmune attack leading to demyelinization and consequently, neurological damage and morbidity. As EAE pathogenesis results from the involvement of immune cells, CNS resident-cells and inflammatory mediators, our treatment strategy was to use a bifunctional compound with dual anti-inflammatory properties: a non-steroidal anti-inflammatory moiety and a nicotinic agonist moiety, intended to interact with the alpha7 nicotinic receptor present on immune cells. We used IBU-Octyl-Cytisine, with an ibuprofen (IBU) moiety and Cytisine, as the nicotinic agonist. The two moieties are attached by an eight carbon (octyl) spacer. Treatment of EAE with IBU-Octyl-Cytisine (2.5 mg/kg/day, i.p.) reduced significantly (by 70%) disease severity and inflammatory infiltrates in the spinal cord. An equivalent dose of IBU was ineffective, whereas Cytisine was significantly toxic. Treatment with IBU-Octyl-Cytisine inhibited the T-cell response toward the encephalitogenic epitope of myelin oligodendrocyte glycoprotein (MOG). In addition, expression of CCR5 by CD4(+)T-cells was lower, indicating a reduced migratory capacity following treatment. IBU-Octyl-Cytisine reduced Th(1) but not Th(2) cytokine production. This reduction was accompanied by a drop in the level of T-bet mRNA, a transcription factor pivotal to Th(1) lineage differentiation. Thus, IBU-Octyl-Cytisine is an effective treatment for EAE, influencing T-cell responses in several stages of disease pathogenesis. This bifunctional compound was more efficient than IBU or Cytisine separately, as well as than both moieties unconjugated. Thus, it seems that this strategy may be applicable in wider context.
authors.affiliation: Laboratory of Neuroimmunology, Department of Neurology and the Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Nizri
authors.forename: Michal
authors.initials: M
authors.lastname: Irony-Tur-Sinai
authors.forename: Iris
authors.initials: I
authors.lastname: Lavon
authors.forename: Haim
authors.initials: H
authors.lastname: Meshulam
authors.forename: Gabi
authors.initials: G
authors.lastname: Amitai
authors.forename: Talma
authors.initials: T
authors.lastname: Brenner
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001392:Azocines / Q000494:pharmacology; D002478:Cells, Cultured; D018678:Cholinergic Agents / Q000494:pharmacology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D007052:Ibuprofen / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000187:drug effects; D011726:Pyridinium Compounds / Q000494:pharmacology*; D011807:Quinolizines / Q000494:pharmacology; D051381:Rats; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D000093843:Quinolizidine Alkaloids
chemical_list: D000470:Alkaloids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001392:Azocines; D018678:Cholinergic Agents; D007052:Ibuprofen; D011726:Pyridinium Compounds; D011807:Quinolizines; C500313:1-(8-(2-(4-isobutylphenyl)propionyl)octyl)-3-N,N-dimethylcarbamoyl pyridinium bromide; C004712:cytisine; D000093843:Quinolizidine Alkaloids