US EPA

3242752 

Journal Article 

Nitric oxide and its role in ischaemic brain injury 

Keynes, RG; Garthwaite, J 

2004 

Yes 

Current Molecular Medicine
ISSN: 1566-5240
EISSN: 1875-5666 

4 

2 

179-191 

WOS:000220637300008 

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.