title: N-acetylcysteine amide confers neuroprotection, improves bioenergetics and behavioral outcome following TBI.
abstract: Traumatic brain injury (TBI) has become a growing epidemic but no approved pharmacological treatment has been identified. Our previous work indicates that mitochondrial oxidative stress/damage and loss of bioenergetics play a pivotal role in neuronal cell death and behavioral outcome following experimental TBI. One tactic that has had some experimental success is to target glutathione using its precursor N-acetylcysteine (NAC). However, this approach has been hindered by the low CNS bioavailability of NAC. The current study evaluated a novel, cell permeant amide form of N-acetylcysteine (NACA), which has high permeability through cellular and mitochondrial membranes resulting in increased CNS bioavailability. Cortical tissue sparing, cognitive function and oxidative stress markers were assessed in rats treated with NACA, NAC, or vehicle following a TBI. At 15days post-injury, animals treated with NACA demonstrated significant improvements in cognitive function and cortical tissue sparing compared to NAC or vehicle treated animals. NACA treatment also was shown to reduce oxidative damage (HNE levels) at 7days post-injury. Mechanistically, post-injury NACA administration was demonstrated to maintain levels of mitochondrial glutathione and mitochondrial bioenergetics comparable to sham animals. Collectively these data provide a basic platform to consider NACA as a novel therapeutic agent for treatment of TBI.
authors.affiliation: Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536; Department of Anatomy and Neurobiology, University of Kentucky, Lexington, KY 40536.
authors.forename: Jignesh D
authors.initials: JD
authors.lastname: Pandya
authors.affiliation: Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536; Department of Anatomy and Neurobiology, University of Kentucky, Lexington, KY 40536.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Readnower
authors.affiliation: Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536; Department of Physiology, University of Kentucky, Lexington, KY 40536.
authors.forename: Samir P
authors.initials: SP
authors.lastname: Patel
authors.affiliation: Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536; Department of Anatomy and Neurobiology, University of Kentucky, Lexington, KY 40536.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Yonutas
authors.affiliation: Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536; Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY 40536.
authors.forename: James R
authors.initials: JR
authors.lastname: Pauly
authors.affiliation: Pediatric Endocrinology Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Goldstein
authors.affiliation: Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536; Department of Physiology, University of Kentucky, Lexington, KY 40536.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Rabchevsky
authors.affiliation: Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536; Department of Anatomy and Neurobiology, University of Kentucky, Lexington, KY 40536. Electronic address: Patsull@uky.edu.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Sullivan
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D001930:Brain Injuries / Q000150:complications* / Q000188:drug therapy*; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D004311:Double-Blind Method; D004734:Energy Metabolism / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000447:Aldehydes; D018696:Neuroprotective Agents; C046538:4-hydroxy-2-octenal; C002744:3-nitrotyrosine; D014443:Tyrosine; C487056:N-Acetylcysteinamide; D005978:Glutathione; D000111:Acetylcysteine