Nitric Oxide in Brain Ischemia: basis for new therapeutical strategies

Stroke represents one of the major causes of death or invalidity in developed countries. In most case, stroke results from the obstruction of blood flow in a major cerebral vessel. Understanding biochemical mechanisms involved in brain damage subsequent to ischemic injury is crucial for developing new therapies. Evidence suggests a dual role for nitric oxide (NO): in fact, it can exert either detrimental and beneficial effects depending on several factors such as the isoform of nitric oxide synthetase (NOS) involved, the amount of NO released, the time and the site of NO production. To this regard, NO produced by endothelial NOS (eNOS) immediately after ischemic attack, promoting vasodilatation, may play a protective role. Later, when over-activation of neuronal NOS (nNOS) and de novo expression of inducible NOS (iNOS) occur, the contribution of NO to brain damage becomes relevant. An increasing number of reports in the literature indicate that endogenously produced inhibitors of NOS, particularly asymmetric dimethylarginine (ADMA), regulate NO generation and then may be implicated in the pathophysiology of several disorders. The major pathways for ADMA elimination are via renal clearance and via metabolism to L-citrulline by the intracellular enzymes dimethylarginine dimethylaminohydrolase (DDAH 1 and DDAH 2) and it is increasingly apparent that metabolism of ADMA is highly regulated. Thus, regulation of DDAHs might represent a novel mechanism by which ADMA levels can be modulated to regulate NO generation and to evaluate possible therapeutical options.