title: N-acetylcysteine amide preserves mitochondrial bioenergetics and improves functional recovery following spinal trauma.
abstract: Mitochondrial dysfunction is becoming a pivotal target for neuroprotective strategies following contusion spinal cord injury (SCI) and the pharmacological compounds that maintain mitochondrial function confer neuroprotection and improve long-term hindlimb function after injury. In the current study we evaluated the efficacy of cell-permeating thiol, N-acetylcysteine amide (NACA), a precursor of endogenous antioxidant glutathione (GSH), on mitochondrial function acutely, and long-term tissue sparing and hindlimb locomotor recovery following upper lumbar contusion SCI. Some designated injured adult female Sprague-Dawley rats (n=120) received either vehicle or NACA (75, 150, 300 or 600mg/kg) at 15min and 6h post-injury. After 24h the total, synaptic, and non-synaptic mitochondrial populations were isolated from a single 1.5cm spinal cord segment (centered at injury site) and assessed for mitochondrial bioenergetics. Results showed compromised total mitochondrial bioenergetics following acute SCI that was significantly improved with NACA treatment in a dose-dependent manner, with maximum effects at 300mg/kg (n=4/group). For synaptic and non-synaptic mitochondria, only 300mg/kg NACA dosage showed efficacy. Similar dosage (300mg/kg) also maintained mitochondrial GSH near normal levels. Other designated injured rats (n=21) received continuous NACA (150 or 300mg/kg/day) treatment starting at 15min post-injury for one week to assess long-term functional recovery over 6weeks post-injury. Locomotor testing and novel gait analyses showed significantly improved hindlimb function with NACA that were associated with increased tissue sparing at the injury site. Overall, NACA treatment significantly maintained acute mitochondrial bioenergetics and normalized GSH levels following SCI, and prolonged delivery resulted in significant tissue sparing and improved recovery of hindlimb function.
authors.affiliation: Spinal Cord and Brain Injury Research Center, Department of Physiology, University of Kentucky, Lexington, KY 40536-0509, USA.
authors.forename: Samir P
authors.initials: SP
authors.lastname: Patel
authors.affiliation: Spinal Cord and Brain Injury Research Center, Department of Anatomy & Neurobiology, University of Kentucky, Lexington, KY 40536-0509, USA.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Sullivan
authors.affiliation: Spinal Cord and Brain Injury Research Center, Department of Anatomy & Neurobiology, University of Kentucky, Lexington, KY 40536-0509, USA.
authors.forename: Jignesh D
authors.initials: JD
authors.lastname: Pandya
authors.affiliation: Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden.
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Goldstein
authors.affiliation: Spinal Cord and Brain Injury Research Center, Department of Physiology, University of Kentucky, Lexington, KY 40536-0509, USA.
authors.forename: Jenna L
authors.initials: JL
authors.lastname: VanRooyen
authors.affiliation: Spinal Cord and Brain Injury Research Center, Department of Anatomy & Neurobiology, University of Kentucky, Lexington, KY 40536-0509, USA.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Yonutas
authors.affiliation: Spinal Cord and Brain Injury Research Center, Department of Physiology, University of Kentucky, Lexington, KY 40536-0509, USA.
authors.forename: Khalid C
authors.initials: KC
authors.lastname: Eldahan
authors.affiliation: Departments of Neurological Surgery, Anatomical Science, and Neurobiology, University of Louisville, Louisville, KY 40292, USA.
authors.forename: Johnny
authors.initials: J
authors.lastname: Morehouse
authors.affiliation: Departments of Neurological Surgery, Anatomical Science, and Neurobiology, University of Louisville, Louisville, KY 40292, USA.
authors.forename: David S K
authors.initials: DS
authors.lastname: Magnuson
authors.affiliation: Spinal Cord and Brain Injury Research Center, Department of Physiology, University of Kentucky, Lexington, KY 40536-0509, USA. Electronic address: agrab@uky.edu.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Rabchevsky
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D004311:Double-Blind Method; D016503:Drug Delivery Systems; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000473:pathology; D007794:Lameness, Animal / Q000188:drug therapy / Q000209:etiology; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D009043:Motor Activity / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects*; D013116:Spinal Cord / Q000473:pathology / Q000648:ultrastructure; D013119:Spinal Cord Injuries / Q000150:complications / Q000188:drug therapy*; D013569:Synapses / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D013997:Time Factors
chemical_list: D045222:Electron Transport Chain Complex Proteins; C487056:N-Acetylcysteinamide; D000111:Acetylcysteine
keywords: Contusion spinal cord injury; Gait analysis; N-acetylcysteine amide (NACA); Neuroprotective agent; Therapeutics