Trends in Neurosciences
Bright and dark sides of nitric oxide in ischemic brain injury
Section snippets
Focal cerebral ischemia: ischemic core and penumbra
Most of the results described here were obtained in rodent models of stroke in which the MCA was occluded (focal ischemia). Immediately after MCA occlusion cerebral blood flow decreases dramatically in the affected brain. In the center of the ischemic area (or ischemic core) the flow reduction is most pronounced (0–20% of control in rodents), and leads to rapid energy failure and cell death[7]. Towards the periphery of the ischemic region, the flow reduction becomes progressively less marked
Effect of cerebral ischemia on the NO biosynthetic pathway
Nitric oxide is synthesized from l-arginine by the enzyme NO synthase (NOS) (Appendix B). Cerebral ischemia has profound effects on the NO biosynthetic pathway, influencing both the synthesis of NO and the expression of the genes encoding NOS. After MCA occlusion, NO concentration in the ischemic area increases to micromolar levels within 20 min and then begins to decline, presumably, because substrate availability becomes rate limiting for NO synthesis[10]. The NO surge can be inhibited by
What is the role of NO in ischemic brain injury?
Although there is ample evidence that ischemia has profound effects on the l-arginine–NO biosynthetic pathway, the role that NO plays in the mechanisms of ischemic brain injury has been the source of much debate5, 6, 21. Part of the problem has been that the complex biological characteristics of NO suggest that this agent can be either detrimental or beneficial to the injured brain (Fig. 1Fig. 2). On the one hand, NO, a potent vasodilator and an inhibitor of platelet aggregation and leukocyte
A model of the role of NO in focal ischemic brain damage
The data reviewed in the previous sections suggest that the impact of NO on ischemic brain injury depends on the stage of evolution of the tissue damage. Studies using l-arginine and NO donors demonstrate clearly that, in the early stages following cerebral ischemia (<2 h) the vascular actions of NO are beneficial by promoting collateral circulation and microvascular flow. At the same time, glutamate-induced Ca2+ overload in ischemic neurons leads to a persistent activation of nNOS resulting in
NO-based strategies for neuroprotection
The evidence reviewed above suggests that NO contributes to the pathogenesis of ischemic brain injury and, consequently, manipulation of the NO system might be used to devise new strategies for stroke treatment. In patients who reach medical attention within the first few hours of onset of ischemia, NO donors might be useful, particularly when interventional approaches to restore flow are not feasible. Owing to the hypotension that they cause, however, the safest and most effective
Some unanswered questions
Although our understanding of the participation of NO in the mechanisms of ischemic brain injury has advanced considerably in recent years, several important issues remain to be resolved. First, the spatial and temporal pattern of the increase in NO production in the post-ischemic brain remains to be determined. In particular, it would be important to define the timecourse of NO production in the ischemic penumbra, the region that is salvageable after stroke. Second, the cellular localization
Concluding remarks
The evidence presented above indicates that NO plays a significant role in the mechanisms of cerebral ischemia. The data suggest that the effect of NO on the ischemic brain depends on the stage of evolution of the ischemic process and on the cell type producing NO. Immediately after induction of ischemia, endothelial NO limits the degree of flow reduction by promoting vasodilation and by inhibiting microvascular plugging by platelets and leukocytes. Later, when the vascular effects of NO are no
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