Post-trauma Lipitor treatment prevents endothelial dysfunction, facilitates neuroprotection, and promotes locomotor recovery following spinal cord injury.
We have previously reported neuroprotection in spinal cord injury (SCI) by Lipitor [atorvastatin (AT)]-pre-treatment. Though informative, pre-treatment studies find only limited clinical application as trauma occurrence is unpredictable. Therefore, this study investigates the efficacy of AT treatment post-SCI. In a rat model of contusion-SCI resulting in complete hindlimb paralysis, AT treatment (5 mg/kg; gavage) was begun 2, 4, or 6 h post-SCI followed by a once daily dose thereafter for 6 weeks. While the placebo vehicle (VHC)-SCI rats showed substantial functional deficit, AT-SCI animals exhibited significant functional recovery. AT diminished injury-induced blood-spinal cord barrier (BSCB) dysfunction with significantly reduced infiltration and tumor necrosis factor-alpha/interleukin-1beta/inducible nitric oxide synthase expression at site of injury. BSCB protection in AT-SCI was attributable to attenuated matrix metalloproteinase-9 (MMP9) expression - a central player in BSCB disruption. Furthermore, endothelial MMP9 expression was found to be RhoA/ROCK pathway-mediated and regulated by AT through an isoprenoid-dependent mechanism. Attenuation of these early inflammatory events reduced secondary damage. Significant reduction in axonal degeneration, myelin degradation, gliosis, and neuronal apoptosis with resultant enhancement in tissue sparing was observed in AT-SCI compared with VHC-SCI. In summary, this novel report presenting the efficacy of post-injury AT treatment might be of critical therapeutic value as effective treatments are currently unavailable for SCI.
Pannu
Ravinder
R
Department of Pediatrics, Centre for Developmental Neurological Disorders: Charles P. Darby Children's Research Institute, Charleston, South Carolina 29425, USA.
Christie
Douglas K
DK
Barbosa
Ernest
E
Singh
Inderjit
I
Singh
Avtar K
AK
D000818:Animals; D000069059:Atorvastatin; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D020233:Gait Disorders, Neurologic / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D006538:Heptanoic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010243:Paralysis / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000098:blood supply / Q000187:drug effects* / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D013729:Terpenes / Q000378:metabolism; D016896:Treatment Outcome; D020742:rhoA GTP-Binding Protein / Q000187:drug effects / Q000378:metabolism
D016207:Cytokines; D006538:Heptanoic Acids; D061965:Matrix Metalloproteinase Inhibitors; D018696:Neuroprotective Agents; D011758:Pyrroles; D013729:Terpenes; D000069059:Atorvastatin; D020780:Matrix Metalloproteinase 9; D020742:rhoA GTP-Binding Protein