NO, Ischemia, and Brain Inflammation

The main focus of this article was to highlight the effect that NOS-2 plays in the role of stroke caused by cerebral ischemia and to look at experimental studies that examined the therapeutic utility of NO donors as well as NOS inhibitors.

Some of the main components of stroke include excitotoxicity, cell death, and compensatory neurogenesis often as a result of the activation of Nitric Oxide through Nitric Oxide Synthase. Nitric Oxide is a free radical and known vasodilator and is a crucial component of the activation of transcriptionally regulated genes, cell signaling proteins, and the initiation of apoptosis. There are also three different isoforms of the NOS enzyme including NOS-1 (neuronal NOS), NOS-2 (inducible NOS), and NOS-3 (endothelial NOS) with each enzyme being controlled by a single copy gene and different with the respect that each has a different binding domain to target different proteins.

Although it has been seen that all three isoforms of NOS are increased in response to ischemia, NOS-2 occurs later than the other isoforms and does not contribute to early injury related to strokes. This was supported with data that differences in infarct volume  were not seen between wildtype mice and mice lacking the NOS-2 gene after only 24 hours; however, after 48 hours, the NOS-2 deficient mice had a decreased infarct volume following cerebral ischemia. The infarct volume refers to the area of dead tissue from the failure of blod supply caused by the stroke. It was also noted that the NOS-2 deficient mice experienced less impairment related to motor performance following ischemia than the mice expressing the NOS-2 gene. Because NOS-2 is activated by transcription, it is assumed that the pro-inflammatory cytokines such as IL-1Beta and TNF-alpha trigger this activation and that the expression of NOS-2 increases with time when ischemia is present. It was also concluded that even though there is often an association with neutrophil action in response to NO from pro-inflammatory cytokines and adhesion molecules, no connection could be made between neutrophils and ischemia.

The therapeutic research that the article presented was related to both the inhibition of NOS as well as Nitric Oxide donors. It is suggested that the Nitric Oxide produced through NOS-1 and NOS-2 are detrimental, while the NO produced through NOS-3 is beneficial. It was found that in relation to NOS inhibitors, specific inhibitors were found to reduce infarct volume, however, when non-selective inhibitors were used, did not alter infarct volume. This was most likely due to the beneficial benefits of NOS-3 being inhibited as well. Similarly, NO donors  including L-arginine encountered the same problem as they could not differentiate between detrimental and beneficial routes. One postitive aspect of NO donors was that neurogenesis increased following ischemia and improved functional outcome. This was important because this neurogenic response was not seen in mice lacking NOS-2. Additionally it was concluded that the production of NO through NOS-3 has a protective effect through preconditioning. There was also evidence that supported the steroidal regulation of NOS-2 through items such as estrogen and progesterone, which actually blocks increased NOS-2 expression and reduces infarct volume.