title: Peripheral hyperstimulation alters site of disease onset and course in SOD1 rats.
abstract: In amyotrophic lateral sclerosis (ALS), the exogenous temporal triggers that result in initial motor neuron death are not understood. Overactivation and consequent accelerated loss of vulnerable motor neurons is one theory of disease initiation. The vulnerability of motor neurons in response to chronic peripheral nerve hyperstimulation was tested in the SOD1(G93A) rat model of ALS. A novel in vivo technique for peripheral phrenic nerve stimulation was developed via intra-diaphragm muscle electrode implantation at the phrenic motor endpoint. Chronic bilateral phrenic nerve hyperstimulation in SOD1(G93A) rats accelerated disease progression, including shortened lifespan, hastened motor neuron loss and increased denervation at diaphragm neuromuscular junctions. Hyperstimulation also resulted in focal decline in adjacent forelimb function. These results show that peripheral phrenic nerve hyperstimulation accelerates cell death of vulnerable spinal motor neurons, modifies both temporal and anatomical onset of disease, and leads to involvement of disease in adjacent anatomical regions in this ALS model.
authors.affiliation: Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Angelo C
authors.initials: AC
authors.lastname: Lepore
authors.forename: Christopher
authors.initials: C
authors.lastname: Tolmie
authors.forename: John
authors.initials: J
authors.lastname: O'Donnell
authors.forename: Megan C
authors.initials: MC
authors.lastname: Wright
authors.forename: Christine
authors.initials: C
authors.lastname: Dejea
authors.forename: Britta
authors.initials: B
authors.lastname: Rauck
authors.forename: Ahmet
authors.initials: A
authors.lastname: Hoke
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Ignagni
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Onders
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Maragakis
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D000704:Analysis of Variance; D000818:Animals; D004558:Electric Stimulation; D004567:Electrodes, Implanted; D004576:Electromyography; D005260:Female; D018737:Hand Strength / Q000502:physiology*; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000503:physiopathology*; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010791:Phrenic Nerve / Q000378:metabolism / Q000503:physiopathology*; D051381:Rats; D055647:Rats, Transgenic; D013482:Superoxide Dismutase / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
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