title: RNA-targeted suppression of stress-induced allostasis in primate spinal cord neurons.
abstract: Peripheral acetylcholine levels notably control the synthesis in macrophages of pro-inflammatory cytokines; however, it remains unclear whether this peripheral regulatory pathway affects central nervous system neurons. To explore the interrelationship between neuronal cholinergic homeostasis and peripheral inflammatory responses in primates, we used spinal cord sections from cynomolgus monkeys after 7 days oral or intravenous treatment with Monarsen oligonucleotide. Monarsen is an antisense oligonucleotide 3'-protected by 2'-oxymethylation, which was proved to induce selective destruction of the stress-induced acetylcholinesterase splice variant AChE-R mRNA. Handling stress predictably suppressed neuronal choline acetyl transferase (ChAT) and the vesicular acetylcholine transporter (VAChT) in all treated monkeys. In Monarsen-treated animals, we further observed suppression of stress-induced increases in plasma AChE activities. Corresponding decreases in AChE-R mRNA were seen in spinal cord neurons, associated with parallel decline patterns in the mRNA encoding for the splice factor SC35 (the levels of which co-increase with those of AChE-R) as well as in the neuronal pro-inflammatory interleukins IL-1beta and IL-6. The antisense effects showed direct dose dependence and were inversely associated with neuronal cell size. These findings suggest a causal association between neuronal cholinergic allostasis and inflammatory reactions in primates and support the peripheral use of RNA-targeted intervention with AChE-R accumulation for the management of both stress and inflammatory responses.
authors.affiliation: Department of Biological Chemistry, Institute of Life Sciences, and the Israel Center of Neuronal Computation, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Tama
authors.initials: T
authors.lastname: Evron
authors.forename: Liat Ben
authors.initials: LB
authors.lastname: Moyal-Segal
authors.forename: Noa
authors.initials: N
authors.lastname: Lamm
authors.forename: Adi
authors.initials: A
authors.lastname: Geffen
authors.forename: Hermona
authors.initials: H
authors.lastname: Soreq
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000096:biosynthesis / Q000235:genetics; D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics; D000818:Animals; D002795:Choline O-Acetyltransferase / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism; D008252:Macaca fascicularis; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism; D009187:Myelitis / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology* / Q000627:therapeutic use; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D013312:Stress, Physiological / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D016896:Treatment Outcome; D050494:Vesicular Acetylcholine Transport Proteins / Q000187:drug effects / Q000378:metabolism
chemical_list: D016376:Oligonucleotides, Antisense; D020033:Protein Isoforms; D012333:RNA, Messenger; C493459:SLC18A3 protein, human; D050494:Vesicular Acetylcholine Transport Proteins; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase; D000109:Acetylcholine