An overview of protective strategies against ischemia/reperfusion injury: The role of hyperbaric oxygen preconditioning.

Introduction: Ischemia/reperfusion (I/R) injury, such as myocardial infarction, stroke, and peripheral vascular disease, has been recognized as the most frequent causes of devastating disorders and death currently. Protective effect of various preconditioning stimuli, including hyperbaric oxygen (HBO), has been proposed in the management of I/R. Methods: In this study, we searched and reviewed up-to-date published papers to explore the pathophysiology of I/R injury and to understand the mechanisms underlying the protective effect of HBO as conditioning strategy. Results: Animal study and clinic observation support the notion that HBO therapy and conditioning provide beneficial effect against the deleterious effects of postischemic reperfusion. Several explanations have been proposed. The first likely mechanism may be that HBO counteracts hypoxia and reduces I/R injury by improving oxygen delivery to an area with diminished blood flow. Secondly, by reducing hypoxia-ischemia, HBO reduces all the pathological events as a consequence of hypoxia, including tissue edema, increased affective area permeability, postischemia derangement of tissue metabolism, and inflammation. Thirdly, HBO may directly affect cell apoptosis, signal transduction, and gene expression in those that are sensitive to oxygen or hypoxia. HBO provides a reservoir of oxygen at cellular level not only carried by blood, but also by diffusion from the interstitial tissue where it reaches high concentration that may last for several hours, improves endothelial function and rheology, and decreases local inflammation and edema. Conclusion: Evidence suggests the benefits of HBO when used as a preconditioning stimulus in the setting of I/R injury. Translating the beneficial effects of HBO into current practice requires, as for the "conditioning strategies", a thorough consideration of risk factors, comorbidities, and comedications that could interfere with HBO-related protection.

[Influence of electroacupuncture on spinal TNF-alpha and IL-6 contents in spinal cord ischemia-reperfusion injury rabbits].

OBJECTIVE: To observe the effect of electroacupuncture (EA) of "Zusanli" (ST 36)-"Quchi" (LI 11) on behavior changes and spinal inflammatory reactions in spinal ischemia-reperfusion injury (SI/RI) rabbits, so as to assess its protective effect on SI/RI. METHODS: Thirty New Zealand rabbits were randomly divided into sham-operation (sham), SI/RI model (model) and EA groups. SI/RI model was established by occlusion of the abdominal aorta for 45 min. EA (2 Hz, 1 mA) was applied to bilateral "Zusanli" (ST 36)-"Quchi" (LI 11) for 30 min after modeling, 4 times (0 h, 12 h, 24 h and 36 h after modeling) altogether. The animals' motor function score of the hindlimb was assessed according to Tarlov's method. The contents of tumor necrosis factor-alpha (TNF-alpha) and Interleukin-6 (IL-6) of the lumbar spinal cord tissue were assayed by ELISA 48 h after modeling. RESULTS: Compared with the sham group, the animals' motor scores at 24 h and 48 h after modeling were decreased, and spinal TNF-alpha and IL-6 contents were increased significantly (all P < 0.05) in the model group. In comparison with the model group, the animals' motor scores at both 24 h and 48 h were up-regulated considerably in the EA group (P < 0.05), suggesting an improvement of the neuronal function after EA intervention. The spinal TNF-alpha and IL-6 contents were obviously lower in the EA group than in the model group (P < 0.05). CONCLUSION: Electroacupuncture has a protective effect on the spinal cord ischemia- reperfusion injury of rabbits probably by reducing the local inflammatory reactions.

Aged garlic extract attenuates cerebral damage and cyclooxygenase-2 induction after ischemia and reperfusion in rats.

Different garlic products reduce the cerebral ischemic damage due to their antioxidant properties. In this work, we investigated the effect of aged garlic extract (AGE) on cyclooxygenase-2 (COX-2) protein levels and activity, and its role as a possible mechanism of neuroprotection in a cerebral ischemia model. Animals were subjected to 1 h of ischemia plus 24 h of reperfusion. AGE (1.2 ml/kg weight, i.p.) was administered at onset of reperfusion. To evaluate the damage induced by cerebral ischemia, the neurological deficit, the infarct area, and the histological alterations were measured. As an oxidative stress marker to deoxyribonucleic acid, 8-hydroxy-2-deoxyguanosine (8-OHdG) levels were determined. Finally, as inflammatory markers, TNFα levels and COX-2 protein levels and activity were measured. AGE treatment diminished the neurological alterations (61.6%), the infarct area (54.8%) and the histological damage (37.7%) induced by cerebral ischemia. AGE administration attenuated the increase in 8-OHdG levels (77.8%), in TNFα levels (76.6%), and in COX-2 protein levels (73.6%) and activity (30.7%) induced after 1 h of ischemia plus 24 h of reperfusion. These data suggest that the neuroprotective effect of AGE is associated not only to its antioxidant properties, but also with its capacity to diminish the increase in TNFα levels and COX-2 protein expression and activity. AGE may have the potential to attenuate the cerebral ischemia-induced inflammation.

Inhibition of gp91(phox) contributes towards normobaric hyperoxia afforded neuroprotection in focal cerebral ischemia.

Oxygen therapy is a promising treatment strategy for ischemic stroke. One potential safety concern with oxygen therapy, however, is the possibility of increased generation of reactive oxygen species (ROS), which could exacerbate ischemic brain injury. Our previous study indicated that normobaric hyperoxia (NBO, 95% O(2) with 5% CO(2)) treatment during ischemia salvaged ischemic brain tissue and significantly reduced ROS generation in transient experimental stroke. In this follow-up study, we tested the hypothesis that suppression of NADPH oxidase is an important mechanism for NBO-induced reduction of ROS generation in focal cerebral ischemia. Male Sprague-Dawley rats were given NBO (95% O(2)) or normoxia (21% O(2)) during 90-min filament occlusion of the middle cerebral artery, followed by 22.5-hour reperfusion. NBO treatment increased the tissue oxygen partial pressure (pO(2)) level in the ischemic penumbra close to the pre-ischemic value, as measured by electronic paramagnetic resonance (EPR), and led to a 30.2% reduction in magnetic resonance imaging (MRI) apparent diffusion coefficients (ADC) lesion volume. Real time PCR and western blot analyses showed that the mRNA and protein expression of NADPH oxidase catalytic subunit gp91(phox) were upregulated in the ischemic brain, which was significantly inhibited by NBO. As a consequence of gp91(phox) inhibition, NBO treatment reduced NADPH oxidase activity in the ischemic brain. Our results suggest that NBO treatment given during ischemia reduces ROS generation via inhibiting NADPH oxidase, which may serve as an important mechanism underlying NBO's neuroprotection in acute ischemic stroke.

Unilateral renal ischemia reperfusion in the rat: effect of blood volume trapped in the kidney, sucrose infusion, and antioxidant treatments.

This study was carried out in order to examine whether the severity of acute renal failure observed during the four hours following a 45 min period of unilateral occlusion of the renal pedicle could be reduced by various treatments. These include intrarenal flush with saline immediately before the occlusion, by sucrose infusion immediately before reperfusion, or by injection of NAO (natural antioxidant) and vitamin E before the occlusion. After renal pedicle occlusion, creatinine levels increased to 165% of their pre-ischemic values. Urine flow, GFR, renal cortex blood flow and NADH decreased by 99%, 99%, 50% and 36%, respectively. A decrease in the Na and K reabsorption (15% and 32%, respectively) was also observed. Partial protection of renal function against ischemic damage was observed when kidney tissue remained blood-free, by exposing it to saline throughout the period of ischemia. Significant protection was observed after treatment with sucrose, vitamin E and NAO. This study demonstrates that it is possible to attenuate the injury to the ischemic kidney by inducing ischemia in a bloodless kidney, by inducing diuresis in the first phase of reperfusion, or by antioxidant treatment, such as vitamin E or NAO.

Electron microscopic and 31-P NMR studies of ischemic injured rat livers during preservation and reflow.

Ischemic injury induced during preservation and reperfusion contributes to post-operative failure in liver transplantation. Hepatic injury and recovery from preservation was studied in an isolated rat liver model reperfused with oxygenated erythrocytes. In order to correlate morphological and functional findings, 31-P nuclear magnetic resonance spectroscopy and electron microscopy were used to investigate metabolic and ultrastructural changes during 6 hours of reperfusion. Following cold preservation, EM's showed a primary sinusoidal cell injury, whereas the hepatocytes were well maintained. During reperfusion, hepatocytes displayed further damage. The simultaneous presence of vacuolarly degenerated mitochondria and mitochondria of increased activity was noted. 31-P NMP spectra demonstrated initially a partial ATP-recovery. The maximum level of 60% of the control ATP-value could not be further increased. EM and 31-P NMR indicate that the progressive injury to the liver is due to microcirculatory malfunction induced by an endothelial cell damage, followed by injured hepatocytes themselves, and the consequent intracellular energy crisis that is produced.