Nitric oxide in acute ischaemic stroke: a target for neuroprotection

Endothelial and neuronal nitric oxide synthase isoforms in cerebral ischaemia NOS isoform Cell source Physiological function Role in acute cerebral ischaemia9 Time to protein, catalytic upregulation and peak Pharmacological antagonist Effect of NOS antagonist on acute cerebral ischaemia Effects of cerebral ischaemia on gene knockout mice Endothelial (eNOS) Vascular Regulation of tissue perfusion Neuroprotective 1 hour, 24 hours - L-nitroarginine, Increased cerebral Increased cerebral Endothelium - Nitro-L-arginine infarct volume9 infarct volume 10 Mono-methyl Ester (L-NAME) Neuronal (nNOS) Neurons Mediation of synaptic plasticity and neuronal signalling Neurodestructive 10 minutes, 3 hours 7-nitroindazole Decreased cerebral infarct volume 12 Decreased cerebral infarct volume 11 Immunological or inducible (iNOS) Macrophages Oxidative free radical destruction of infectious agents Neurodestructive 12 hours, 48 hours Aminoguanidine Decreased cerebral Decreased cerebral Microglia infarct volume 13 21-23 infarct volume 14 Neutrophils By contrast with the neuroprotective effect of enhanced endothelial nitric oxide, neuronal release of nitric oxide plays a major part in ischaemic neurotoxicity. In rodents, the neuroprotective effect of L-arginine and nitric oxide donor drugs is lost about 2 hours after onset of cerebral ischaemia.\n 16 Cerebral infarcts after permanent MCAO are 28% smaller and motor deficits significantly less in iNOS gene knockout mice compared with wild-type mice. 14 Furthermore, aminoguanidine, a relatively selective iNOS inhibitor, shows time and dose dependent neuroprotective effects-that is, the earlier the drug is given and the higher the dose, the greater the reduction of infarct volume.