title: A hydrogen sulfide-releasing cyclooxygenase inhibitor markedly accelerates recovery from experimental spinal cord injury.
abstract: Spinal cord trauma causes loss of motor function that is in part due to the ensuing inflammatory response. Hydrogen sulfide (H2S) is a potent, endogenous anti-inflammatory and neuroprotective substance that has been explored for use in the design of novel nonsteroidal anti-inflammatory drugs. In the current study, we evaluated the potential beneficial effects of ATB-346 [2-(6-methoxynapthalen- 2-yl)-propionic acid 4-thiocarbamoyl-phenyl ester], an H2S-releasing derivative of naproxen, in a murine model of spinal cord injury (SCI). SCI was induced in mice by spinal cord compression, produced through the application of vascular clips to the dura via a T5 to T8 laminectomy. ATB-346, naproxen (both at 30 μmol/kg), or vehicle was orally administered to the mice 1 and 6 h after SCI and once daily thereafter for 10 d. Motor function [Basso Mouse Scale (BMS) of locomotion] improved gradually in the mice treated with naproxen. However, those treated with ATB-346 exhibited a significantly more rapid and sustained recovery of motor function, achieving greater than double the increase in locomotion score of the naproxen group by the 10th day of treatment. ATB-346 also significantly reduced the severity of inflammation (proinflammatory cytokines, apoptosis of neural tissue, and nitrosative stress) that characterized the secondary effects of SCI. Again, the effects of ATB-346 were superior to those of naproxen for several parameters. These results showed marked beneficial effects of an H2S-releasing derivative of naproxen in an animal model of SCI, significantly enhancing recovery of motor function, possibly by reducing the secondary inflammation and tissue injury that characterizes this model. The combination of inhibition of cyclooxygenase and delivery of H2S may offer a promising alternative to existing therapies for traumatic injury.
authors.affiliation: 1Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, T2N 4N1, Canada. altapharm@hotmail.com.
authors.forename: Michela
authors.initials: M
authors.lastname: Campolo
authors.forename: Emanuela
authors.initials: E
authors.lastname: Esposito
authors.forename: Akbar
authors.initials: A
authors.lastname: Ahmad
authors.forename: Rosanna
authors.initials: R
authors.lastname: Di Paola
authors.forename: John L
authors.initials: JL
authors.lastname: Wallace
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
mesh_terms: D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D009288:Naproxen / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D020127:Recovery of Function; D013116:Spinal Cord / Q000378:metabolism / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000188:drug therapy*
chemical_list: C550692:2-(6-methoxy-napthalen-2-yl)-propionic acid 4-thiocarbamoyl-phenyl ester; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D009288:Naproxen; D006862:Hydrogen Sulfide
keywords: apoptosis; central nervous system; inflammation; motor recovery; nonsteroidal anti-inflammatory drug