Nanomedical Approach to Monitor the Central Role of NO/ONOOImbalance in Ischemic Stroke Brain Damage Ã¢ÂÂ The Effects of Statins and Heme Oxygenase-1
- *Corresponding Author:
- Tadeusz Malinski
Nanomedical Research Laboratories
Ohio University, 350 W. State Street Athens
OH 45701, USA
E-mail: [email protected]
Received Date: June 04, 2014; Accepted Date: July 25, 2014; Published Date: July 30, 2014
Citation: Heeba G, Corbalan JJ, Patton S, Burewicz A, Stys AT, et al. (2014) Nanomedical Approach to Monitor the Central Role of NO/ONOOImbalance in Ischemic Stroke Brain Damage – The Effects of Statins and Heme Oxygenase-1. J Nanomed Nanotechnol 5:215. doi:10.4172/2157-7439.1000215
Copyright: © 2014 Heeba G, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.