title: Pioglitazone treatment following spinal cord injury maintains acute mitochondrial integrity and increases chronic tissue sparing and functional recovery.
abstract: Pioglitazone is an FDA-approved PPAR-γ agonist drug used to treat diabetes, and it has demonstrated neuroprotective effects in multiple models of central nervous system (CNS) injury. Acute treatment after spinal cord injury (SCI) in rats is reported to suppress neuroinflammation, rescue injured tissues, and improve locomotor recovery. In the current study, we additionally assessed the protective efficacy of pioglitazone treatment on acute mitochondrial respiration, as well as functional and anatomical recovery after contusion SCI in adult male C57BL/6 mice. Mice received either vehicle or pioglitazone (10mg/kg) at either 15min or 3h after injury (75kdyn at T9) followed by a booster at 24h post-injury. At 25h, mitochondria were isolated from spinal cord segments centered on the injury epicenters and assessed for their respiratory capacity. Results showed significantly compromised mitochondrial respiration 25h following SCI, but pioglitazone treatment that was initiated either at 15min or 3h post-injury significantly maintained mitochondrial respiration rates near sham levels. A second cohort of injured mice received pioglitazone at 15min post injury, then once a day for 5days post-injury to assess locomotor recovery and tissue sparing over 4weeks. Compared to vehicle, pioglitazone treatment resulted in significantly greater recovery of hind-limb function over time, as determined by serial locomotor BMS assessments and both terminal BMS subscores and gridwalk performance. Such improvements correlated with significantly increased grey and white matter tissue sparing, although pioglitazone treatment did not abrogate long-term injury-induced inflammatory microglia/macrophage responses. In sum, pioglitazone significantly increased functional neuroprotection that was associated with remarkable maintenance of acute mitochondrial bioenergetics after traumatic SCI. This sets the stage for dose-response and delayed administration studies to maximize pioglitazone's efficacy for SCI while elucidating the precise role that mitochondria play in governing its neuroprotection; the ultimate goal to develop novel therapeutics that specifically target mitochondrial dysfunction.
authors.affiliation: Spinal Cord and Brain Injury Research Center, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA; Department of Physiology, College of Medicine, 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, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Cox
authors.affiliation: Spinal Cord and Brain Injury Research Center, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA; Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA.
authors.forename: Jenna L
authors.initials: JL
authors.lastname: Gollihue
authors.affiliation: Spinal Cord and Brain Injury Research Center, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Bailey
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV 26506, USA.
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Geldenhuys
authors.affiliation: Spinal Cord and Brain Injury Research Center, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA; Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Gensel
authors.affiliation: Spinal Cord and Brain Injury Research Center, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA; Department of Neuroscience, College of Medicine, 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, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA; Department of Physiology, College of Medicine, 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: D000704:Analysis of Variance; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D009097:Multienzyme Complexes / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D000077205:Pioglitazone; D020127:Recovery of Function / Q000187:drug effects*; D013119:Spinal Cord Injuries / Q000188:drug therapy*; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D007004:Hypoglycemic Agents; D008840:Microfilament Proteins; D009097:Multienzyme Complexes; D045162:Thiazolidinediones; D000077205:Pioglitazone
keywords: Bioenergetics; Locomotor recovery; Neuroprotection; PPAR; mitoNEET