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The pivotal role of nitric oxide (NO) in cerebral ischaemia has been elegantly highlighted in the recent editorial by O'Mahony and Kendall.1 Although studies of neuroprotective agents have been largely disappointing, pharmacological manipulation of NO may represent a novel means of protecting the brain from ischaemic insult. One area not discussed in this editorial is the neuroprotective effect of 3-hydroxy-3methylglutaryl coenzyme A reductase inhibitors or “statins” in cerebral ischaemia. Preliminary studies have shown that statins modulate brain nitric oxide synthase (NOS) isoform activity in a neuroprotective manner. Data from a murine model of ischaemic stroke demonstrate that prophylactic statin therapy reduces infarct size by about 30%, and improves neurological outcome in normocholesterolaemic animals.2 In this investigation, statin therapy directly up regulated endothelial NOS in the brain without altering expression of neuronal NOS. Recent findings also suggest that statin therapy influences the activity of inducible NOS. Lovastatin has been shown to inhibit cytokine mediated upregulation of inducible NOS and production of NO in rat astrocytes and macrophages,3 and this inhibition may represent a novel means of suppressing inflammatory responses that accompany ischaemia. Most interestingly, these preliminary findings suggest that statin therapy may modify the friendly and unfriendly faces of brain NO in a synergistically neuroprotective manner. These and other vascular effects4 of statins in cerebral ischaemia are potentially of great importance in human neuroprotection and ongoing studies such as the The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) study5 will help clarify their role in human cerebrovascular disease.
The comments of Vaughan and Delanty draw attention to the evidence that statin therapy up regulates endothelial NOS without affecting neuronal NOS. Their contention is that statin therapy may be neuroprotective. Statins may indeed prevent strokes and reduce infarct size when given as prophylactic therapy in at risk persons. However, our editorial article was not intended to discuss the wide variety of pharmacological agents that may have favourable effects on endothelial NOS as stroke preventive therapy. Rather, it is focused on the possible ways of inhibiting neuronal NOS and inducible NOS mediated nitric oxide release after the event of acute stroke. At present, there is no information indicating that acute administration of statins in animal models of ischaemic stroke is neuroprotective. Their point about statins and endothelial NOS is interesting, but not relevant to neuroprotective therapy in acute stroke.