Core and Penumbral Nitric Oxide Synthase Activity during Cerebral Ischemia and Reperfusion in the Rat Pup

Our studies examined the hypothesis that the distribution of cerebral injury after a focal ischemic insult in the immature rat pup is associated with the regional distribution of nitric oxide synthase (NOS) activity and that differences in the vulnerability to ischemia between pup and adult might be related to differences in cofactor availability. We measured NOS activity in well-defined regions prone to become either core or penumbra in controls and at different times (end of occlusion, 0.5 h, and 24 h reperfusion) after middle cerebral artery occlusion (MCAO) from the right and left hemispheres in a 14- to 18-day-old rat pup filament model. Three groups of corresponding isoflurane sham controls were also included. "Core" NOS activity for combined right and left hemispheres ranged from 113% to 217% more than "penumbral" regions in control and sham groups. In the three MCAO groups, marked decreases in ischemic core and penumbral NOS activity were seen; however, core NOS remained higher than penumbral regions bilaterally. The effects of cofactor addition (10 microM tetrahydrobiopterin, 3 microM flavin adenine dinucleotide, and 3 microM flavin mononucleotide) on NOS activity were similar in "core" and "penumbral" regions in control and sham groups. However, after 24 h MCAO, cofactor addition preferentially increased NOS activity in the ischemic hemisphere. Co-factor addition in the pup also had a greater effect on enhancing NOS activity in all regions compared with the adult. Greater NOS activity in core regions in the rat pup, as in the adult, could in part, explain the increased vulnerability of that region to ischemia. NOS activity also can be influenced by the availability of cofactors and this effect may be greater in the immature animal.