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-1β 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.

Hydrolytic and Nonenzymatic Functions of Acetylcholinesterase Comodulate Hemopoietic Stress Responses

“…The specificity of ARP 26 is supported by the finding that ASP 40 , the C-terminal peptide of AChE-S, failed to induce such effects. Thus, extended granulocytosis reflects cellular consequences unique to the AChE-R variant, compatible with recent reports that AChE-R suppression reduces the levels of proinflammatory cytokines in both rats (45) and Cynomolgus monkeys (46) and not as previously related exclusively to the sympathetic pathways (47).…”

Termination and beyond: acetylcholinesterase as a modulator of synaptic transmission

“…Three identified AChE polymorphisms have been shown to have biological implications and clinical relevance: a polymorphism in the distal promoter of AChE affecting interaction with a glucocorticoid response element (GRE; Shapira et al 2000), a 4-bp deletion in a hepatocyte nuclear factor 3 (HNF3)-binding site also located at the promoter region (Shapira et al 2000), and a single nucleotide polymorphism (SNP) producing the His322 Asn substitution, which is responsible for the YT-2 blood group phenotype (Bartels et al 1993;Ehrlich et al 1994). Specific but rare polymorphisms at the ACHE/paraoxonase (PON1) locus have further been found to be correlated with hypersensitivity to AChE inhibitors (Shapira et al 2000), insecticide-induced Parkinson's disease (PD; Benmoyal-Segal et al 2005), and trait anxiety . Individuals carrying the rare GRE and the HNF3-binding-site polymorphisms show increased constitutive AChE expression and hypersensitivity to AChE inhibitors (Shapira et al 2000).…”

Oxygen Toxicity Is Reduced by Acetylcholinesterase Inhibition in the Developing Rat Brain

“…Stimulation of the vagus nerve or administration of nicotinic ACh receptor agonists reduces the production of proinflammatory cytokines and an increase in the activity of the ‘inflammatory reflex' and the anti-inflammatory pathway normalize innate immune responses without causing immunosuppression [5]. Antisense suppression of AChE production reduces the level of proinflammatory cytokines in spinal cord neurons of primates [12]. AChE inhibitors increase the availability of ACh in central cholinergic synapses and are the most promising currently available drugs for the treatment of Alzheimer's disease (AD) [13].…”