Presymptomatic Treatment with Acetylcholinesterase Antisense Oligonucleotides Prolongs Survival in ALS (G93A-SOD1) Mice

Gotkine Marc,Rozenstein Leah,Rosenmann Hanna,Einstein Ofira,Argov Zohar,Abramsky Oded

doi:10.1155/2013/845345

Abstract

Objective. Previous research suggests that acetylcholinesterase (AChE) may be involved in ALS pathogenesis. AChE enzyme inhibitors can upregulate AChE transcription which in certain contexts can have deleterious (noncatalytic) effects, making them theoretically harmful in ALS, whilst AChE antisense-oligonucleotides (mEN101), which downregulate AChE may be beneficial. Our aim was to investigate whether downregulation of AChE using mEN101 is beneficial in an ALS mouse model. Methods. ALS (G93A-SOD1) mice received saline, mEN101, inverse-EN101, or neostigmine. Treatments were administered from 5 weeks. Disease-onset and survival were recorded. Additional mice were sacrificed for pathological analysis at 15 weeks of age. In a follow-up experiment treatment was started at the symptomatic stage at a higher dose. Results. mEN101 given at the presymptomatic (but not symptomatic) stage prolonged survival and attenuated motor-neuron loss in ALS mice. In contrast, neostigmine exacerbated the clinical parameters. Conclusions. These results suggest that AChE may be involved in ALS pathogenesis. The accelerated disease course with neostigmine suggests that any beneficial effects of mEN101 occur through a non-catalytic rather than cholinergic mechanism.

Highlights

IntroductionAcetylcholinesterase (AChE), an enzyme primarily functioning in cholinergic synapses both in the central and peripheral nervous system, has been linked to processes or events occurring in amyotrophic lateral sclerosis (ALS), namely, motor unit denervation [3] and excitatory amino acids (EAAs)-mediated neurotoxicity [2, 4]
The mechanisms leading to cell death in amyotrophic lateral sclerosis (ALS) are not fully understood; oxidative stress, excitatory amino acids (EAAs), and apoptosis have all been implicated [1, 2].Acetylcholinesterase (AChE), an enzyme primarily functioning in cholinergic synapses both in the central and peripheral nervous system, has been linked to processes or events occurring in ALS, namely, motor unit denervation [3] and EAA-mediated neurotoxicity [2, 4]
These results suggest that AChE may be involved in ALS pathogenesis

Summary

Introduction

Acetylcholinesterase (AChE), an enzyme primarily functioning in cholinergic synapses both in the central and peripheral nervous system, has been linked to processes or events occurring in ALS, namely, motor unit denervation [3] and EAA-mediated neurotoxicity [2, 4]. AChE has been shown to be present in tissues devoid of cholinergic synapses and to be involved in the process of apoptosis, a process involved in ALS pathogenesis, by playing a pivotal role in apoptosome formation [5]. To address the possibility that mEN101’s effect is mediated via a non-catalytic effect (i.e., reducing AChE levels) rather than via a decrease in catalytic activity, we compared mEN101 treatment to the AChE catalytic inhibitor Neo

Methods

Results

Conclusion