Antisense oligodeoxynucleotide to inducible nitric oxide synthase protectsagainst transient focal cerebral ischemia-induced brain injury

Nitric oxide (NO) has been suspected to mediate brain damage during ischemi a. Here the authors studied the effects of an antisense oligodeoxynucleotid e (ODN) directed against the inducible isoform of NO synthase (iNOS) in a m odel of transient focal cerebral ischemia in rats. Treatment consisted of s even intracerebroventricular injections of a phosphodiester/phosphorothioat e chimera ODN (3 nmol each) at 12-hour intervals, and was initiated 12 hour s before a 2-hour occlusion of the left middle cerebral artery and common c arotid artery. Outcomes were measured three days after ischemia. When compa red with animals treated with vehicle or an appropriate random non-sense co ntrol ODN sequence, the anti-sense treatment reduced the lesion volume by 3 0% and significantly improved recovery of sensorimotor functions, as assess ed on a neuroscore. This effect was associated with a decrease in iNOS expr ession, as assessed by Western blot, a 39% reduction in iNOS enzymatic acti vity evaluated as Ca2+-independent NOS activity, and a 37% reduction in nit rotyrosine formation, reflecting protein nitration by NO-derived peroxynitr ite. These findings provide new evidence that inhibition of iNOS may be of interest for the treatment of stroke.