Effects of Nitric Oxide on Reactive Oxygen Species Production and Infarction Size after Brain Reperfusion Injury

OBJECTIVEDeleterious effects of strokes may be ameliorated when thrombolysis (i.e., with recombinant tissue plasminogen activator) restores circulation. However, reperfusion injury, mediated by oxygen free radicals (reactive oxygen species [ROS]), may limit the benefits of recombinant tissue plasminogen activator treatment. We hypothesized that, during reperfusion, exogenous nitric oxide (NO) would reduce stroke size by quenching ROS. METHODSTo investigate this hypothesis, we used two in vivo ischemia-reperfusion models, i.e., autologous cerebral embolism in rabbits and filament middle cerebral artery occlusion in rats. Using these models, we measured ROS levels (rabbit model) and stroke volumes (rat model) in response to transient ischemia, with and without intracarotid administration of ultrafast NO donor proline NO (proliNO). RESULTSIn the rabbit cerebral embolism model, intracarotid administration of proliNO (10−6 mol/L) (n = 6) during reperfusion decreased free radical levels from 538 ± 86 nmol/L in the vehicle-treated group (n = 7) to 186 ± 31 nmol/L (2,3′-dihydroxybenzoic acid;P < 0.001) and from 521 ± 86 nmol/L (n = 7) to 201 ± 39 nmol/L (2,5′-dihydroxybenzoic acid;P < 0.002). In the rat middle cerebral artery occlusion model, intracarotid administration of proliNO (10−5 mol/L) (n = 10) during reperfusion reduced the brain infarction volume from 256 ± 48 mm3 in the vehicle-treated group (n = 8) to 187 ± 41 mm3 (P < 0.005). In both experimental groups, intracarotid infusion of proliNO did not affect regional cerebral blood flow, mean arterial blood pressure, or brain and body temperatures. CONCLUSIONThe beneficial effects of early restoration of cerebral circulation after cerebral ischemia were enhanced by intracarotid infusion of proliNO, most likely because of ROS scavenging by NO. These findings suggest the possibility of preventive treatment of reperfusion injury using NO donors.

[1]  B. Siesjö,et al.  Pathophysiology and treatment of focal cerebral ischemia. Part I: Pathophysiology. , 1992, Journal of neurosurgery.

[2]  K. M. Davies,et al.  Localizing antithrombotic and vasodilatory activity with a novel, ultrafast nitric oxide donor. , 1996, Journal of medicinal chemistry.

[3]  K. M. Davies,et al.  "NONOates" (1-substituted diazen-1-ium-1,2-diolates) as nitric oxide donors: convenient nitric oxide dosage forms. , 1996, Methods in enzymology.

[4]  H. S. Mueller,et al.  The Thrombolysis in Myocardial Infarction (TIMI) trial. Phase I findings. , 1985, The New England journal of medicine.

[5]  H. Kontos George E. Brown memorial lecture. Oxygen radicals in cerebral vascular injury. , 1985, Circulation research.

[6]  E. Golanov,et al.  Inhibition of Nitric Oxide Synthesis Increases Focal Ischemic Infarction in Rat , 1992, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[7]  R. Busse,et al.  EDRF Increases Cyclic GMP in Platelets During Passage Through the Coronary Vascular Bed , 1989, Circulation research.

[8]  E. J. Green,et al.  Effects of combined postischemic hypothermia and delayed N-tert-butyl-a-pheylnitrone (PBN) administration on histopathological and behavioral deficits associated with transient global ischemia in rats , 1999, Brain Research.

[9]  P. Lyden,et al.  Tissue Plasminogen Activator: Reduction of Neurologic Damage After Experimental Embolic Stroke , 1988 .

[10]  M. Bednar,et al.  Activation of complement by tissue plasminogen activator, but not acute cerebral ischemia, in a rabbit model of thromboembolic stroke. , 1997, Journal of neurosurgery.

[11]  P. Weinstein,et al.  Reversible middle cerebral artery occlusion without craniectomy in rats. , 1989, Stroke.

[12]  R. Bullock,et al.  Increased free radical production due to subdural hematoma in the rat: effect of increased inspired oxygen fraction. , 1998, Journal of neurotrauma.

[13]  M. Moskowitz,et al.  The NOS Inhibitor, 7-Nitroindazole, Decreases Focal Infarct Volume but Not the Response to Topical Acetylcholine in Pial Vessels , 1994, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[14]  T. Obata,et al.  Intracranial microdialysis of salicyclic acid to detect hydroxyl radical generation by monoamine oxidase inhibitor in the rat , 1995, Neuroscience Letters.

[15]  M. Moskowitz,et al.  Nitric Oxide Synthase Inhibition and Cerebrovascular Regulation , 1994, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[16]  M Fisher,et al.  Medical therapy for ischemic stroke. , 1996, Clinical neuropharmacology.

[17]  A. Buisson,et al.  The neuroprotective effect of a nitric oxide inhibitor in a rat model of focal cerebral ischaemia , 1992, British journal of pharmacology.

[18]  B. Lin,et al.  Detection of Free Radical Activity During Transient Global Ischemia and Recirculation: Effects of Intraischemic Brain Temperature Modulation , 1995, Journal of neurochemistry.

[19]  J. Beckman The double-edged role of nitric oxide in brain function and superoxide-mediated injury. , 1991, Journal of developmental physiology.

[20]  K. Takakura,et al.  Effects of a hydroxyl radical scavenger on delayed ischemic neurological deficits following aneurysmal subarachnoid hemorrhage: results of a multicenter, placebo-controlled double-blind trial. , 1996, Journal of neurosurgery.

[21]  A. Shuaib,et al.  Neuroprotection by 2-h Postischemia Administration of Two Free Radical Scavengers, α-phenyl-n-tert-butyl-nitrone (PBN) and N-tert-butyl-(2-sulfophenyl)-nitrone (S-PBN), in Rats Subjected to Focal Embolic Cerebral Ischemia , 2000, Experimental Neurology.

[22]  H. Kontos Oxygen Radicals in Cerebral Vascular Injury , 1985 .

[23]  N. Tamaki,et al.  Reactive oxygen species in reoxygenation injury of rat brain capillary endothelial cells. , 1998, Neurosurgery.

[24]  M. Stratford,et al.  Ischemia reperfusion injury in tumors: the role of oxygen radicals and nitric oxide. , 1995, Cancer research.

[25]  L. Sekhar,et al.  Persistent trigeminal artery: an anatomic study. , 1998, Neurosurgery.

[26]  Joseph Loscalzo,et al.  A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds , 1993, Nature.

[27]  S. Snyder,et al.  Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[28]  James B. Mitchell,et al.  Nitric oxide (NO) protects against cellular damage by reactive oxygen species. , 1995, Toxicology letters.

[29]  G. D. del Zoppo Thrombolytic therapy in the treatment of stroke. , 1997, Drugs.

[30]  C. Colton,et al.  Hypoxia modulates nitric oxide-induced regulation of NMDA receptor currents and neuronal cell death. , 1999, American journal of physiology. Cell physiology.

[31]  L. Ignarro Biosynthesis and metabolism of endothelium-derived nitric oxide. , 1990, Annual review of pharmacology and toxicology.

[32]  W J Quinones-Baldrich,et al.  Reperfusion injury. , 1991, Critical care nursing clinics of North America.

[33]  U. Tuor,et al.  DNA fragmentation indicative of apoptosis following unilateral cerebral hypoxia-ischemia in the neonatal rat , 1995, Brain Research.

[34]  M. Weisfeldt,et al.  Reperfusion injury. , 1988, Free radical biology & medicine.

[35]  C. Iadecola,et al.  Nitric Oxide Donors Increase Blood Flow and Reduce Brain Damage in Focal Ischemia: Evidence That Nitric Oxide is Beneficial in the Early Stages of Cerebral Ischemia , 1994, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[36]  R. Koehler,et al.  Nitric Oxide Synthase Inhibition Reduces Caudate Injury Following Transient Focal Ischemia in Cats , 1994, Stroke.

[37]  R. Koehler,et al.  Oxygen radical mechanisms of brain injury following ischemia and reperfusion. , 1991, Journal of applied physiology.

[38]  E. Oldfield,et al.  Reversal and prevention of cerebral vasospasm by intracarotid infusions of nitric oxide donors in a primate model of subarachnoid hemorrhage. , 1997, Journal of neurosurgery.

[39]  C. Iadecola,et al.  Time Dependence of Effect of Nitric Oxide Synthase Inhibition on Cerebral Ischemic Damage , 1995, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[40]  M. Chopp,et al.  ARL 17477, a Potent and Selective Neuronal NOS Inhibitor Decreases Infarct Volume after Transient Middle Cerebral Artery Occlusion in Rats , 1996, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[41]  I. Hanbauer,et al.  Nitric Oxide Protects against the Cytotoxic Effects of Reactive Oxygen Species , 1994, Annals of the New York Academy of Sciences.

[42]  G. Bernardi,et al.  Nitric oxide inhibition aggravates ischemic damage of hippocampal but not of NADPH neurons in gerbils. , 1994, Stroke.

[43]  M. Bednar,et al.  Delayed tissue-plasminogen activator therapy in a rabbit model of thromboembolic stroke. , 1995, Neurosurgery.

[44]  D. Graham,et al.  Inhibition of nitric oxide synthesis does not reduce infarct volume in a rat model of focal cerebral ischaemia , 1992, Neuroscience Letters.

[45]  J. Hibbs,et al.  Nitric oxide: a cytotoxic activated macrophage effector molecule. , 1988, Biochemical and biophysical research communications.

[46]  D. Murphy,et al.  Intracranial microdialysis of salicylic acid to detect hydroxyl radical generation through dopamine autooxidation in the caudate nucleus: effects of MPP+. , 1992, Free radical biology & medicine.

[47]  F. Berthou,et al.  Involvement of cytochromes P-450 2E1 and 3A4 in the 5-hydroxylation of salicylate in humans. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[48]  S. Moncada,et al.  Nitric oxide: physiology, pathophysiology, and pharmacology. , 1991, Pharmacological reviews.

[49]  O. Paulson Regional cerebral blood flow in apoplexy due to occlusion of the middle cerebral artery , 1970, Neurology.

[50]  D. Lefer,et al.  Antineutrophil and Myocardial Protecting Actions of a Novel Nitric Oxide Donor After Acute Myocardial Ischemia and Reperfusion in Dogs , 1993, Circulation.

[51]  J. Hallenbeck,et al.  Background review and current concepts of reperfusion injury. , 1990, Archives of neurology.

[52]  M. Ingelman-Sundberg,et al.  Hydroxylation of salicylate as an assay for hydroxyl radicals: a cautionary note. , 1991, Free radical biology & medicine.

[53]  E. Oldfield,et al.  Production of reactive oxygen species after reperfusion in vitro and in vivo: protective effect of nitric oxide. , 2000, Journal of neurosurgery.

[54]  Joseph P. Broderick,et al.  Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. , 1995 .

[55]  James B. Mitchell,et al.  Nitric oxide protects against cellular damage and cytotoxicity from reactive oxygen species. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[56]  M. Chopp,et al.  Nitric Oxide Measured by a Porphyrinic Micro Sensor in Rat Brain after Transient Middle Cerebral Artery Occlusion , 1993, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[57]  James B. Mitchell,et al.  Neuroprotection by the stable nitroxide Tempol during reperfusion in a rat model of transient focal ischemia. , 2000, Journal of neurosurgery.

[58]  B. Thompson,et al.  Effect of intracarotid nitric oxide on primate cerebral vasospasm after subarachnoid hemorrhage. , 1995, Journal of neurosurgery.

[59]  J. Kucharczyk,et al.  NG-nitro-L-arginine delays the development of brain injury during focal ischemia in rats. , 1995, Stroke.

[60]  Christian M. Kerskens,et al.  Reperfusion after Thrombolytic Therapy of Embolic Stroke in the Rat: Magnetic Resonance and Biochemical Imaging , 1998, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.