title: A selective phosphodiesterase-4 inhibitor reduces leukocyte infiltration, oxidative processes, and tissue damage after spinal cord injury.
abstract: We tested the hypothesis that a selective phosphodiesterase type 4 inhibitor (PDE4-I; IC486051) would attenuate early inflammatory and oxidative processes following spinal cord injury (SCI) when delivered during the first 3 days after injury. Rats receiving a moderately severe thoracic-clip-compression SCI were treated with the PDE4-I (0.5, 1.0, and 3.0 mg/kg IV) in bolus doses from 2-60 h post-injury. Doses at 0.5 mg/kg and 1.0 mg/kg significantly decreased myeloperoxidase (MPO) enzymatic activity (neutrophils), expression of a neutrophil-associated protein and of ED-1 (macrophages), and estimates of lipid peroxidation in cord lesion homogenates at 24 h and 72 h post-injury by 25-40%. The 3.0 mg/kg dose had small or no effects on these measures. The PDE4-I treatment (0.5 or 1.0 mg/kg) reduced expression of the oxidative enzymes gp91(phox), inducible nitric oxide synthase, and cyclooxygenase-2, and diminished free radical generation by up to 40%. Treatment with 0.5 mg/kg PDE4-I improved motor function (as assessed by the Basso-Beattie-Bresnahan scale) significantly from 4-8 weeks after SCI (average difference 1.3 points). Mechanical allodynia elicited from the hindpaw decreased by up to 25%. The PDE4-I treatment also increased white matter volume near the lesion at 8 weeks after SCI. In conclusion, the PDE4-I reduced key markers of oxidative stress and leukocyte infiltration, producing cellular protection, locomotor improvements, and a reduction in neuropathic pain. Early inhibition of PDE4 is neuroprotective after SCI when given acutely and briefly at sufficient doses.
authors.affiliation: Spinal Cord Injury Team, Robarts Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada. fbao@uwo.ca
authors.forename: Feng
authors.initials: F
authors.lastname: Bao
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Fleming
authors.forename: Roozbeh
authors.initials: R
authors.lastname: Golshani
authors.forename: Damien D
authors.initials: DD
authors.lastname: Pearse
authors.forename: Levent
authors.initials: L
authors.lastname: Kasabov
authors.forename: Arthur
authors.initials: A
authors.lastname: Brown
authors.forename: Lynne C
authors.initials: LC
authors.lastname: Weaver
mesh_terms: D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000187:drug effects* / Q000502:physiology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D009187:Myelitis / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D009410:Nerve Degeneration / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology
chemical_list: D018696:Neuroprotective Agents; D058988:Phosphodiesterase 4 Inhibitors; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4