title: Preservation of neuromuscular function in symptomatic SOD1-G93A mice by peripheral infusion of methylene blue.
abstract: In mutant superoxide dismutase 1 (SOD1) mouse models of familial amyotrophic lateral sclerosis (fALS) some of the earliest signs of morphological and functional damage occur in the motor nerve terminals that innervate fast limb muscles. This study tested whether localized peripheral application of a protective drug could effectively preserve neuromuscular junctions in late-stage disease. Methylene blue (MB), which has mitochondria-protective properties, was infused via an osmotic pump into the anterior muscle compartment of one hind limb of late pre- symptomatic SOD1-G93A mice for ≥3weeks. When mice reached end-stage disease, peak twitch and tetanic contractions evoked by stimulation of the muscle nerve were measured in two anterior compartment muscles (tibialis anterior [TA] and extensor digitorum longus [EDL], both predominantly fast muscles). With 400μM MB in the infusion reservoir, muscles on the MB-infused side exhibited on average a ~100% increase in nerve-evoked contractile force compared to muscles on the contralateral non-infused side (p<0.01 for both twitch and tetanus in EDL and TA). Pairwise comparisons of endplate innervation also revealed a beneficial effect of MB infusion, with an average of 65% of endplates innervated in infused EDL, compared to only 35% on the non-infused side (p<0.01). Results suggested that MB's protective effects required an extracellular [MB] of ~1μM, were initiated peripherally (no evidence of retrograde transport into the spinal cord), and involved MB's reduced form. Thus peripherally-initiated actions of MB can help preserve neuromuscular structure and function in SOD1-G93A mice, even at late stages of disease.
authors: Department of Physiology and Biophysics, University of Miami Miller School of Medicine, P.O. Box 016430, Miami, FL 33101, USA.
authors: Janet D
authors: JD
authors: Talbot
authors: Department of Physiology and Biophysics, University of Miami Miller School of Medicine, P.O. Box 016430, Miami, FL 33101, USA; Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL, USA 33101.
authors: John N
authors: JN
authors: Barrett
authors: Department of Physiology and Biophysics, University of Miami Miller School of Medicine, P.O. Box 016430, Miami, FL 33101, USA.
authors: Doris
authors: D
authors: Nonner
authors: Department of Physiology and Biophysics, University of Miami Miller School of Medicine, P.O. Box 016430, Miami, FL 33101, USA.
authors: Zhongsheng
authors: Z
authors: Zhang
authors: Department of Physiology and Biophysics, University of Miami Miller School of Medicine, P.O. Box 016430, Miami, FL 33101, USA.
authors: Kyle
authors: K
authors: Wicomb
authors: Department of Physiology and Biophysics, University of Miami Miller School of Medicine, P.O. Box 016430, Miami, FL 33101, USA; Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL, USA 33101. Electronic address: ebarrett2@med.miami.edu.
authors: Ellen F
authors: EF
authors: Barrett
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000150:complications* / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D000818:Animals; D002038:Bungarotoxins / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D005455:Fluorescent Antibody Technique; D006801:Humans; D008751:Methylene Blue / Q000008:administration & dosage* / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D009045:Motor Endplate / Q000187:drug effects / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects; D020511:Neuromuscular Junction Diseases / Q000188:drug therapy* / Q000209:etiology*; D013482:Superoxide Dismutase / Q000235:genetics*
chemical_list: D002038:Bungarotoxins; D004791:Enzyme Inhibitors; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D008751:Methylene Blue
keywords: ALS; Amyotrophic lateral sclerosis; Methylene blue; Motor nerve terminal; Muscle contraction; Neuromuscular junction; SOD1-G93A; Skeletal muscle; Superoxide dismutase 1