Inflammatory mechanisms in experimental CNS trauma

Abstract: Traumatic brain and spinal cord injuries are important causes of premature death and permanentdisability. To improve the treatment of CNS-injured patients increased knowledge about thepathophysiological events that mediate death or dysfunction of nervous tissue is urgently needed.This thesis focuses on the expression and potential pathogenetic role of endothelial adhesionmolecules that promote vascular adhesion and extravasation of leukocytes, in these wayscontrolling the inflammatory response.Immunohistochemical investigations showed microvascular up-regulation of the adhesionmolecule ICAM-1 during the first few days after experimental brain injury of the rat. Thepathophysiologic role of ICAM-1 was also evaluated by systemic treatment of rats with ICAM-l-antibodies following severe brain injury. Neither cognitive outcome, assessed by the Morris-Water maze paradigm, nor histopathologic sequele were influenced by anti-ICAM-l-treatment.One to two days after compression of the rat spinal cord, immunohistochemistry showed anincreased expression of ICAM-1, chiefly in endothelial cells. Immunostaining of CD11b, thecounter-receptor of ICAM-1, was detected in leukocytes that adhered to vessel walls or infiltrated the traumatized spinal cord. Moreover, CD11b-immunohistochemistry revealed a rapidly induced and prolonged microglial activation.The pathogenetic role of the adhesion molecules ICAM-1 and P-selectin in spinal cordcompression was evaluated by studying post-injury histopathologic and functional end-points in wild type mice and mice lacking ICAM- l/P-selectin or ICAM- 1. Compared to injured wild types, ICAM-l/P-selectin-deficient mice had a better motor function in the early post-injury phase and significant sparing of white matter 14 days after trauma. Genetic deficiency of ICAM-1 alone, however, did not affect the outcome after spinal cord injury. In another study, mice deficient in the NO-secreting enzyme iNOS had significantly better functional outcome than wild type controls on day 14 after spinal cord injury.In conclusion, microvascular up-regulation of ICAM-1 occurs after experimental CNS trauma. ICAM-1 and P-selection in combination seem to have a destructive role after experimental spinal trauma. The same holds true for iNOS. However, the present investigations do not support the idea that ICAM-1 alone mediates secondary injury after trauma to the brain and spinal cord.