title: Simvastatin ameliorates cauda equina compression injury in a rat model of lumbar spinal stenosis.
abstract: Lumbar spinal stenosis (LSS) is the leading cause of morbidity and mortality worldwide. LSS pathology is associated with secondary injury caused by inflammation, oxidative damage and cell death. Apart from laminectomy, pharmacological therapy targeting secondary injury is limited. Statins are FDA-approved cholesterol-lowering drug. They also show pleiotropic anti-inflammatory, antioxidant and neuroprotective effects. To investigate the therapeutic efficacy of simvastatin in restoring normal locomotor function after cauda equina compression (CEC) in a rat model of LSS, CEC injury was induced in rats by implanting silicone gels into the epidural spaces of L4 and L6. Experimental group was treated with simvastatin (5 mg/kg body weight), while the injured (vehicle) and sham operated (sham) groups received vehicle solution. Locomotor function in terms of latency on rotarod was measured for 49 days and the threshold of pain was determined for 14 days. Rats were sacrificed on day 3 and 14 and the spinal cord and cauda equina fibers were extracted and studied by histology, immunofluorescence, electron microscopy (EM) and TUNEL assay. Simvastatin aided locomotor functional recovery and enhanced the threshold of pain after the CEC. Cellular Infiltration and demyelination decreased in the spinal cord from the simvastatin group. EM revealed enhanced myelination of cauda equina in the simvastatin group. TUNEL assay showed significantly decreased number of apoptotic neurons in spinal cord from the simvastatin group compared to the vehicle group. Simvastatin hastens the locomotor functional recovery and reduces pain after CEC. These outcomes are mediated through the neuroprotective and anti-inflammatory properties of simvastatin. The data indicate that simvastatin may be a promising drug candidate for LSS treatment in humans.
authors.affiliation: Department of Pediatrics, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA.
authors.forename: Anandakumar
authors.initials: A
authors.lastname: Shunmugavel
authors.forename: Marcus M
authors.initials: MM
authors.lastname: Martin
authors.forename: Mushfiquddin
authors.initials: M
authors.lastname: Khan
authors.forename: Anne G
authors.initials: AG
authors.lastname: Copay
authors.forename: Brian R
authors.initials: BR
authors.lastname: Subach
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Schuler
authors.forename: Inderjit
authors.initials: I
authors.lastname: Singh
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002420:Cauda Equina / Q000473:pathology*; D005260:Female; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006930:Hyperalgesia / Q000517:prevention & control; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008124:Locomotion / Q000502:physiology; D008279:Magnetic Resonance Imaging; D046529:Microscopy, Electron, Transmission; D018696:Neuroprotective Agents / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D010812:Physical Stimulation; D004856:Postural Balance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology*; D013117:Spinal Cord Compression / Q000188:drug therapy* / Q000473:pathology*; D013130:Spinal Stenosis / Q000188:drug therapy* / Q000473:pathology*
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018696:Neuroprotective Agents; D019821:Simvastatin