Nitric Oxide and its Role in Ischaemic Brain Injury

Abstract

The role of the neural messenger nitric oxide (NO) in cerebral ischaemia has been investigated extensively in the past decade. NO may play either a protective or destructive role in ischaemia and the literature is plagued with contradictory findings. Working with NO presents many unique difficulties and here we review the potential artifacts that may have contributed to discrepancies and cause future problems for the unwary investigator. Recent evidence challenges the idea that NO from neurones builds up to levels (micromolar) sufficient to directly elicit cell death during the post-ischaemic period. Concomitantly, the case is strengthened for a role of NO in delayed death mediated post-ischaemia by the inducible NO synthase. Mechanistically it seems unlikely that NO is released in high enough quantities to inhibit respiration in vivo; the formation of reactive nitrogen species, such as peroxynitrite, represents the more likely pathway to cell death. The protective and restorative properties of NO have become of increasing interest. NO from endothelial cells may, via stimulating cGMP production, protect the ischaemic brain by acutely augmenting blood flow, and by helping to form new blood vessels in the longer term (angiogenesis). Elevated cGMP production may also stop cells dying by inhibiting apoptosis and help repair damage by stimulating neurogenesis. In addition NO may act as a direct antioxidant and participate in the triggering of protective gene expression programmes that underlie cerebral ischaemic preconditioning. Better understanding of the molecular mechanisms by which NO is protective may ultimately identify new potential therapeutic targets.

NO synthase 2 ( NOS2 ) deletion promotes multiple pathologies in a mouse model of Alzheimer's disease

“…Low levels of NO (Ͻ100 nM) promote progrowth and antiapoptotic pathways (33). For example, activation of guanyl cyclase by NO and the subsequent phosphorylation of cGMP-dependent protein kinases such as Ras-Raf-extracellular regulated kinase and phosphatidylinositol 3-kinase-Akt (33, 34) play a critical role in neuronal survival (35,36). Neuronal survival is also mediated by NO's inhibition of executioner caspase-3 and caspase-6 (37) where NO can block the conversion of the proenzymes via Akt-mediated phosphorylation or chemically modify and decrease enzyme activity (38,39).…”

Association of a Functional Inducible Nitric Oxide Synthase Promoter Variant with Susceptibility to Infantile Cerebral Palsy

“…However, to our knowledge the role of NO in human infant cerebral palsy has not been studied. Some studies have described the role of NO as protective in various neuropathologies [29] although other authors consider said molecule as pathogenic [30]. Some studies have attributed the appearance of neuropathologies to an increased production of NO by NOS2A causing direct neurotoxicity or vasodilatation and increased cerebral pressure [31].…”

Neuroimaging in traumatic brain imaging

“…141 Other potential culprits include nitrous oxide, endogenous opioid peptides such as naloxone, catecholamines, acetylcholine, thyrotropin-releasing hormone (TRH), lactate, and adenosine. 142,143 Cytokines such as tumor necrosis factor (TNF) and interleukins 1,6, and 8, also have found to increase following TBI. 144,145 PET, functional MRI, MR spectroscopy, and SPECT, have been and will continue to be crucial in identifying the concentrations and locations of these various molecules in animal and human brains following injury.…”