Bifunctional compounds eliciting both anti-inflammatory and cholinergic activity as potential drugs for neuroinflammatory impairments

Eran Nizri, Rellie Adani, Haim Meshulam, Gabi Amitai, Talma Brenner*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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 0.1 mg/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 (PGE 2) 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.

Original languageEnglish
Pages (from-to)46-50
Number of pages5
JournalNeuroscience Letters
Volume376
Issue number1
DOIs
StatePublished - 7 Mar 2005
Externally publishedYes

Keywords

  • AChE inhibitors
  • Bifunctional molecules
  • Central nervous system inflammation
  • Experimental autoimmune encephalomyelitis
  • Multiple sclerosis
  • Non-steroidal anti-inflammatory drugs

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