Cortical spreading depression (CSD) is associated with various short- and long-term physiological and neurochemical changes and has been shown to confer an increased susceptibility to accompanying ischemic injury or provide protection against a subsequent experimental ischemia. Nitric oxide is involved in the processes of ischemic injury and under certain conditions mediates cellular protection. To investigate the possibility that CSD-induced alterations in nitric oxide synthase (NOS) expression and activity occur and might be associated with the time-dependent enhancement or prevention by CSD of ischemic damage, this study examined the spatiotemporal changes in nNOS expression and activity in cerebral cortex following CSD. Anesthetized rats had unilateral CSD induced by a 10-min topical application of KCl and were killed at various times thereafter. CSD increased both nNOS mRNA and protein levels throughout layers II–III of cortex. nNOS mRNA in the affected neocortex was significantly increased by 30–90% at 2, 7, and 14 days ( P ≤ 0.05) compared with contralateral levels, but was not significantly above control values at 1–6 h, 1 day, and 28 days after CSD induction. Levels of ( 3 H)- l - N G -nitroarginine binding to NOS were increased by 40–170% 7, 14, and 28 days ( P ≤ 0.01) after CSD in a similar, but delayed, profile to nNOS mRNA. Levels of nNOS-immunoreactivity were also increased in both neurons and astrocytes of ipsilateral cortex 7 and 14 days after CSD—confirmed by double-immunofluorescence localization. Ex vivo NOS activity in layers I–III of ipsilateral cortex was also increased by 30–50% ( P ≤ 0.01) at 7 and 14 days after CSD, times coincident with reported maximal ischemic protection. These results demonstrate that nNOS is up-regulated by cellular depolarization/depression occurring during CSD, or by resultant stimuli and suggest that “CSD-conditioned” cortex may be capable of producing appropriate levels of NO to mediate or contribute to protective/adaptive responses to subsequent physical ischemic injury.
Experimental Neurology – Elsevier
Published: Dec 1, 1999
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