Fenretinide Promotes Functional Recovery and Tissue Protection after Spinal Cord Contusion Injury in Mice

• Published in: The Journal of neuroscience 2010-03, Vol.30 (9), p.3220-3226
• Main Authors: Lopez-Vales, Ruben, Redensek, Adriana, Skinner, Thomas A. A, Rathore, Khizr I, Ghasemlou, Nader, Wojewodka, Gabriella, DeSanctis, Juan, Radzioch, Danuta, David, Samuel
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Anticarcinogenic Agents - pharmacology; Anticarcinogenic Agents - therapeutic use; Arachidonic Acid - antagonists & inhibitors; Arachidonic Acid - blood; Biomarkers - metabolism; Cytoprotection - drug effects; Cytoprotection - physiology; Disease Models, Animal; Docosahexaenoic Acids - agonists; Docosahexaenoic Acids - blood; Drug Administration Schedule; Fatty Acids, Unsaturated - metabolism; Female; Fenretinide - pharmacology; Fenretinide - therapeutic use; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Inflammation Mediators - antagonists & inhibitors; Inflammation Mediators - metabolism; Mice; Mice, Inbred BALB C; Microglia - drug effects; Microglia - metabolism; Nerve Degeneration - drug therapy; Nerve Degeneration - physiopathology; Nerve Degeneration - prevention & control; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Oxidative Stress - drug effects; Oxidative Stress - physiology; Recovery of Function - drug effects; Recovery of Function - physiology; Spinal Cord Injuries - drug therapy; Spinal Cord Injuries - metabolism; Spinal Cord Injuries - physiopathology; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.5770-09.2010

The inflammatory response is thought to contribute to secondary damage after spinal cord injury (SCI). Polyunsaturated fatty acids (PUFAs) play an important role in the onset and resolution of inflammation. Arachidonic acid (AA), an omega-6 PUFA, contributes to the initiation of inflammatory responses, whereas docosahexaenoic acid (DHA), an omega-3 PUFA, has antiinflammatory effects. Therefore, decreasing AA and increasing DHA levels after SCI might be expected to attenuate inflammation after SCI and promote tissue protection and functional recovery. We show here that daily oral administration of fenretinide after spinal cord contusion injury led to a significant decrease in AA and an increase in DHA levels in plasma and injured spinal cord tissue. This was accompanied by a significant reduction in tissue damage and improvement in locomotor recovery. Fenretinide also reduced the expression of proinflammatory genes and the levels of oxidative stress markers after SCI. In addition, in vitro studies demonstrated that fenretinide reduced TNF-alpha (tumor necrosis factor-alpha) expression by reactive microglia. These results demonstrate that fenretinide treatment after SCI can reduce inflammation and tissue damage in the spinal cord and improve locomotor recovery. These beneficial effects may be mediated via the ability of fenretinide to modulate PUFA homeostasis. Since fenretinide is currently in clinical trials for the treatment of cancers, this drug might be a good candidate for the treatment of acute SCI in humans.