title: Systemic bisperoxovanadium activates Akt/mTOR, reduces autophagy, and enhances recovery following cervical spinal cord injury.
abstract: Secondary damage following primary spinal cord injury extends pathology beyond the site of initial trauma, and effective management is imperative for maximizing anatomical and functional recovery. Bisperoxovanadium compounds have proven neuroprotective effects in several central nervous system injury/disease models, however, no mechanism has been linked to such neuroprotection from bisperoxovanadium treatment following spinal trauma. The goal of this study was to assess acute bisperoxovanadium treatment effects on neuroprotection and functional recovery following cervical unilateral contusive spinal cord injury, and investigate a potential mechanism of the compound's action. Two experimental groups of rats were established to 1) assess twice-daily 7 day treatment of the compound, potassium bisperoxo (picolinato) vanadium, on long-term recovery of skilled forelimb activity using a novel food manipulation test, and neuroprotection 6 weeks following injury and 2) elucidate an acute mechanistic link for the action of the drug post-injury. Immunofluorescence and Western blotting were performed to assess cellular signaling 1 day following SCI, and histochemistry and forelimb functional analysis were utilized to assess neuroprotection and recovery 6 weeks after injury. Bisperoxovanadium promoted significant neuroprotection through reduced motorneuron death, increased tissue sparing, and minimized cavity formation in rats. Enhanced forelimb functional ability during a treat-eating assessment was also observed. Additionally, bisperoxovanadium significantly enhanced downstream Akt and mammalian target of rapamycin signaling and reduced autophagic activity, suggesting inhibition of the phosphatase and tensin homologue deleted on chromosome ten as a potential mechanism of bisperoxovanadium action following traumatic spinal cord injury. Overall, this study demonstrates the efficacy of a clinically applicable pharmacological therapy for rapid initiation of neuroprotection post-spinal cord injury, and sheds light on the signaling involved in its action.
authors.affiliation: Department of Anatomy and Cell Biology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Chandler L
authors.initials: CL
authors.lastname: Walker
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Walker
authors.forename: Nai-Kui
authors.initials: NK
authors.lastname: Liu
authors.forename: Emelie C
authors.initials: EC
authors.lastname: Risberg
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: Jinhui
authors.initials: J
authors.lastname: Chen
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Xu
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002574:Cervical Vertebrae / Q000098:blood supply / Q000187:drug effects / Q000473:pathology*; D003288:Contusions / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005552:Forelimb / Q000187:drug effects / Q000503:physiopathology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008954:Models, Biological; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D017968:Vanadium Compounds / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; D051059:PTEN Phosphohydrolase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D017968:Vanadium Compounds; C526109:Anxa3 protein, rat; C472777:bisperoxovanadium