Nitric Oxide in Brain Contusion

Trauma to the brain is a leading cause of death and disability. The primary injury initiates a cascade of biochemical reactions in the brain that causes further neuronal damage, a process referred to as secondary brain injury. The mechanisms for secondary brain injury are not fully understood and successful treatments for traumatic brain injury (TBI) still remain elusive. This study was undertaken to explore the pathophysiological role of nitric oxide (NO) in experimental and human brain contusion. The temporal pattern and cellular sources of the three nitric oxide synthase (NOS) isoforms were examined following experimental contusion. The immunoreactivities for the constitutive NOS isoforms: eNOS and nNOS were increased early during the first hours after the trauma in endothelial cells and neurons, respectively. The non-constitutive inducible NOS isoform, iNOS, was induced later mainly in inflammatory cells with a peak one day after the trauma. Brain biopsies from patients undergoing surgery for cerebral contusions were examined. We found that iNOS was induced following human contusions and with a temporal concordant pattern to our experimental findings. The cellular sources of iNOS differed at different times after trauma. The majority were inflammatory cells during the first twelve hours, while neurons dominated between one and three days after trauma. The trauma models were considered relevant for experimental studies and treatment trials, since the findings in humans and rodents were similar. Posttraumatic treatments with a non-selective NOS-inhibitor, a selective iNOSinhibitor, or a free radical scavenger were performed All drugs separately reduced histopathological damage at 24 hours and 6 days post trauma. Formation of the neurotoxic substance peroxynitrite, synthesized by NO and superoxide, was also reduced by the drugs. The combination of a non-selective NOS-inhibitor and a free radical scavenger did not show additive neuroprotection. The findings supported that NO produced during the first days were detrimental to the injured brain and that an important mediator of NO-mediated toxicity was the formation of peroxynitrite. Four drugs with different mechanism of action, directed against inflammatory-, free radicalor calcium-mediated toxicity were administrated and examined concerning histopathological damage and influence on iNOS. All four drugs showed some neuroprotective properties and all reduced iNOS induction. The present study supported the hypothesis that iNOS induction and NO played important roles in the development of secondary injury following TBI and that NO may be detrimental to the injured brain, due to formation of peroxynitrite. Posttraumatic pharmacological modulation of NOS may improve the outcome.