SB203580, a p38 mitogen-activated protein kinase inhibitor, fails to improve functional outcome following a moderate spinal cord injury in rat

• Published in: Neuroscience Vol. 155; no. 1; pp. 128 - 137
• Main Authors: Stirling, D.P, Liu, J, Plunet, W, Steeves, J.D, Tetzlaff, W
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 31.07.2008; Elsevier
• Subjects: Activating Transcription Factor 2 - metabolism; Analysis of Variance; Animals; Behavior, Animal - drug effects; Biological and medical sciences; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors - therapeutic use; Fundamental and applied biological sciences. Psychology; Imidazoles - therapeutic use; macrophages; Male; microglia; Motor Activity - drug effects; Neurology; neuroprotection; p38 MAPK; p38 Mitogen-Activated Protein Kinases - metabolism; Pyridines - therapeutic use; Rats; Rats, Wistar; SB203580; Spinal Cord Injuries - drug therapy; Spinal Cord Injuries - metabolism; Spinal Cord Injuries - pathology; Spinal Cord Injuries - physiopathology; spinal cord injury; Time Factors; Vertebrates: nervous system and sense organs; spinal cord injury; PBS; NO; nitric oxide; BBB; Basso, Beattie, Bresnahan; phosphate-buffered saline; SB203580; MAPK; p38 MAPK; eriochrome cyanine; mitogen-activated protein kinase; BSA; macrophages; Tris-buffered saline/0.1% Tween 20; neuroprotection; TTBS; SCI; microglia; bovine serum albumin; EC; Neuroprotection; Spinal cord; Rat; Neuroglia; Rodentia; Central nervous system; Microglia; Vertebrata; Mammalia; Animal; p38 Mitogen activated protein kinase; Lesion; Macrophage
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2008.05.007

Abstract We examined the spatial and temporal expression patterns of active p38 mitogen-activated protein kinase (MAPK), an important regulator of immune cell function, following spinal cord injury (SCI). We further assessed whether administration of SB203580, an inhibitor of p38 MAPK activity, would reduce inflammation, improve tissue sparing, and improve functional outcome after SCI. Adult Wistar rats were subjected to a T9/10 SCI contusion of moderate severity and killed at several time points after injury, whereas sham-injured (control) animals only received a laminectomy. In control animals, active p38 MAPK expression was primarily localized to resting microglia within the spinal cord. Over the first 24 h after SCI, a continuing increase in active p38 MAPK expression was evident in neutrophils and activated microglia (OX42+) surrounding the spinal lesion site. At 15 days post-injury, active p38 MAPK was localized to macrophages (ED1+) that now dominated the lesion site. In addition, active p38 MAPK was localized to macrophages within white matter fiber tracts undergoing degeneration, several segments rostral and caudal to the injury site, which persisted for at least 6 weeks. Overall, our results demonstrate that active p38 MAPK is increased within resident and invading immune cells after SCI contusion injury and, therefore, may be an important target to regulate the inflammatory cascade after SCI. However, intrathecal application of SB203580 failed to improve functional outcome after a moderate SCI contusion.