నానోమెడిసిన్ & నానోటెక్నాలజీ జర్నల్

నైరూప్య

Nanomedical Approach to Monitor the Central Role of NO/ONOOImbalance in Ischemic Stroke Brain Damage – The Effects of Statins and Heme Oxygenase-1

Heeba G, Corbalan JJ, Patton S, Burewicz A, Stys AT and Tadeusz Malinski

Background: There are conflicting reports concerning the role of nitric oxide (NO) and oxidative stress in brain ischemic damage. In the present study, a nanomedical approach was utilized to elucidate the role of NO and peroxynitrite (ONOO - ) imbalance in ischemic stroke. Methods: Nanosensors (diameter ~ 200 nm, detection limit of 10-9 molL-1, response time ~10 μs) were used to monitor in situ the concentration of NO and ONOO - . Adult male Sprague Dawley rats were given permanent middle cerebral artery occlusion (pMCAO) for 3 h, 12 h or 24 h. [NO]/[ONOO - ] was measured in striatum, along with, constitutive nitric oxide synthase (cNOS) enzymes and heme oxygenase-1 (HO-1) expression and infarct volume. The [NO]/[ONOO - ] was also monitored in pre-treated animals with simvastatin and atorvastatin in the presence of the cNOS inhibitor L-NAME. The effect of modulators of cNOS or NADPH oxidase (sepiapterin, PEG-SOD, VAS2870 and IN-7) on the [NO]/[ONOO - ] was elucidated. Results: After 3 h of ischemia, NO decreased from 400 ± 20 nmolL-1 to 217 ± 11 nmolL-1 and ONOO - increased from 150 ± 9 nmolL-1 to 244 ± 9 nmolL-1.The [NO]/[ONOO - ] balance shifted from 2.67 ± 0.06 to 0.89 ± 0.07 after 3 h of ischemia, indicating severe uncoupling of cNOS. The [NO]/[ONOO - ] imbalance shifted with time of ischemia and correlated directly with the increase in infarct volume and expression of cNOS and HO-1. Treatment with simvastatin or atorvastatin partially, but significantly, restored [NO]/[ONOO - ] balance and decreased infarct size in ischemic brain. Also, modulators of cNOS an NADPH restored [NO]/[ONOO - ]. Conclusions: The imbalance between cytoprotective NO and cytotoxic ONOO - directly correlates with brain damage in ischemic stroke. The [NO]/[ONOO - ] imbalance reflects on the level of uncoupled cNOS and the nitroxidative stress. [NO]/[ONOO - ] imbalance increases cNOS and HO-1, which contributes to or prevents further brain damage, respectively. Balancing [NO]/[ONOO - ] is the determinant in preventing or mollifying brain damage. Simvastatin or atorvastatin shifts favorably [NO]/[ONOO - ], and may provide prophylactic treatment strategy for ischemic stroke.