Nitric oxide in the injured spinal cord:: Synthases cross-talk, oxidative stress and inflammation

Nitric oxide (NO) is a unique informational molecule involved in a variety of physiological processes in the central nervous system (CNS). It has been demonstrated that it can exert both protective and detrimental effects in several disease states of the CNS, including spinal cord injury (SCI). The effects of NO on the spinal cord depend on several factors such as: concentration of produced NO, activity of different synthase isoforrns, cellular source of production and time of release. Basically, it has been shown that low NO concentrations may play a role in physiologic processes, whereas large amounts of NO may be detrimental by increasing oxidative stress. However, this does not explain all the discrepancies evidenced studying the effects of NO in SCI models. The analysis of the different synthase isoforms, of their temporal profile of activation and cellular source has shed light on this topic. Two post-injury time intervals can be defined with reference to the NO production: immediately after injury and several hours-to-days later. The initial immediate peak of NO production after injury is due to the up-regulation of the neuronal NO synthase (nNOS) in resident spinal cord cells. The late peak is due primarily to the activity of inducible NOS (iNOS) produced by inflammatory infiltrating cells. High NO levels produced by up-regulated nNOS and NOS are neurotoxic; the down-regulation of nNOS corresponds temporally to the expression of NOS. On the bases of those evidence, therapeutic approaches should be aimed: (1) to reduce the NO-elicited damage by inhibition of specific synthases according to the temporal profile of activation; (2) by maintaining physiologic amount of NO to keep the induction of iNOS expression suppressed and avoiding ischemia/reperfusion injuries; (3) by using scavengers of oxygen and nitrogen reactive species or using inhibitors of the specific kinases. (C) 2007 Elsevier B.V. All rights reserved.