Anti-inflammatory properties of cholinergic up-regulation: A new role for acetylcholinesterase inhibitors.
We investigated the anti-inflammatory effects of acetylcholinesterase inhibitors (AChEI) at the cellular and molecular levels. AChEI suppressed lymphocyte proliferation and pro-inflammatory cytokine production, as well as extracellular esterase activity. Anti-inflammatory activity was mediated by the alpha7 nicotinic acetylcholine receptor (neuronal); the muscarinic receptor had the opposite effect. Treatment of the central nervous system (CNS) inflammatory disease, experimental autoimmune encephalomyelitis (EAE), with EN101, an anti-sense oligodeoxynucleotide, targeted to AChE mRNA, reduced the clinical severity of the disease and CNS inflammation intensity. The results of our experiments suggest that AChEI increase the concentration of extracellular acetylcholine (ACh), rendering it available for interaction with a nicotinic receptor expressed on lymphocytes. Our findings point to a novel role for AChEI which may be relevant in CNS inflammatory diseases such as EAE and multiple sclerosis. They also emphasize the importance of cholinergic balance in neurological disorders, such as Alzheimer's disease and myasthenia gravis, in which these drugs are used.
Nizri
Eran
E
Laboratory of Neuroimmunology, Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, P.O. Box 12000, Jerusalem 91120, Israel.
Hamra-Amitay
Yasmine
Y
Sicsic
Camille
C
Lavon
Iris
I
Brenner
Talma
T
D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D004347:Drug Interactions; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010835:Phytohemagglutinins / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013116:Spinal Cord / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects*
D000893:Anti-Inflammatory Agents; D002800:Cholinesterase Inhibitors; D016207:Cytokines; C477243:EN101; D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense; D010835:Phytohemagglutinins; D012333:RNA, Messenger; D000110:Acetylcholinesterase