Application Of Ischemic Preconditioning Research Articles

Ischemic Preconditioning with High and Low Pressure Enhances Maximum Strength and Modulates Heart Rate Variability.

Background: The application of ischemic preconditioning (IPC) to resistance exercise has attracted some attention, owing to increases in muscle performance. However, there is still no consensus on the optimal occlusion pressure for this procedure. This study compared the acute effects of IPC with high and low pressure of occlusion on upper and lower limb maximal strength and heart rate variability in recreationally trained individuals. Methods: Sixteen recreationally trained men (25.3 ± 1.7 years; 78.4 ± 6.2 kg; 176.9 ± 5.4 cm; 25.1 ± 1.5 m2 kg−1) were thoroughly familiarized with one repetition maximum (1 RM) testing in the following exercises: bench press (BP), front latissimus pull-down (FLPD), and shoulder press (SP) for upper limbs, and leg press 45º (LP45), hack machine (HM), and Smith Squat (SS) for lower limbs. The 1 RM exercises were then randomly performed on three separate days: after a high pressure (220 mmHg, IPChigh) and a low pressure (20 mmHg, IPClow) IPC protocol and after no intervention (control, CON). Heart rate variability was also measured at rest, during and after the entire IPC protocol, and after the exercises. Results: Maximal strength was significantly (p < 0.05) higher in both IPChigh and IPClow compared with CON in all upper- and lower-limb exercises. There was no difference between the two experimental conditions. No significant differences were found in the comparison across the different experimental conditions for LFnu, HFnu, LF/HF ratio, and RMSSDms. Conclusions: IPC performed with both high and low pressures influenced heart rate variability, which may partly explain the maximal strength enhancement.

Beneficial postoperative micro-rheological effects of intraoperative administration of diclophenac or ischemic preconditioning in patients with lower extremity operations - Preliminary data.

Ischemia-reperfusion (I/R) may worsen blood rheology that has been demonstrated by clinical and experimental data. It is also known that anti-inflammatory agents and preconditioning methods may reduce I/R injury. We aimed to analyze hemorheological alterations in elective knee operations and the effects of intraoperative nonsteroidal anti-inflammatory drug (NSAID) administration and application of ischemic preconditioning. Hemorheological variables of 17 patients with total knee replacement or anterior crucial ligament replacement were analyzed. The ischemic (tourniquet) time was 92±15 minutes. Seven patients did not receive NSAID (Control group), 5 patients got i.v. sodium-diclophenac 10 minutes before and 6 hours after reperfusion. Five patients had ischemic preconditioning (3×15 minutes). Blood samples were collected before the ischemia, 10 minutes after reperfusion, on the 1st and 2nd p.o. day. Whole blood viscosity didn't show notable inter-group differences, except for a slight decrease in the preconditioning group. RBC deformability decreased, erythrocyte aggregation enhanced by the 1st and 2nd p.o. days in Control group. In NSAID and preconditioning groups the changes were moderate, aggregation values significantly lowered compared to the Control group. Intraoperatively administered diclophenac or ischemic preconditioning could moderate the deterioration in micro-rheological parameters caused by I/R in patients.

Effects of different ischemic preconditioning strategies on physiological and cellular mechanisms of intestinal ischemia/reperfusion injury: Implication from an isolated perfused rat small intestine model.

BackgroundIntestinal ischemia/reperfusion (I/R)-injury often results in sepsis and organ failure and is of major importance in the clinic. A potential strategy to reduce I/R-injury is the application of ischemic preconditioning (IPC) during which repeated, brief episodes of I/R are applied. The aim of this study was to evaluate physiological and cellular effects of intestinal I/R-injury and to compare the influence of in-vivo IPC (iIPC) with ex-vivo IPC (eIPC), in which blood derived factors and nerval regulations are excluded.MethodsUsing an established perfused rat intestine model, effects of iIPC and eIPC on physiological as well as cellular mechanisms of I/R-injury (60 min hypoxia, 30 min reperfusion) were investigated. iIPC was applied by three reversible occlusions of the mesenteric artery in-vivo for 5 min followed by 5 min of reperfusion before isolating the small intestine, eIPC was induced by stopping the vascular perfusion ex-vivo 3 times for 5 min followed by 5 min of reperfusion after isolation of the intestine. Study groups (each N = 8–9 animals) were: iIPC, eIPC, I/R (iIPC group), I/R (eIPC group), iIPC+I/R, eIPC+I/R, no intervention/control (iIPC group), no intervention/control (eIPC group). Tissue morphology/damage, metabolic functions, fluid shifts and barrier permeability were evaluated. Cellular mechanisms were investigated using signaling arrays.ResultsI/R-injury decreased intestinal galactose uptake (iIPC group: p<0.001), increased vascular perfusion pressure (iIPC group: p<0.001; eIPC group: p<0.01) and attenuated venous flow (iIPC group: p<0.05) while lactate-to-pyruvate ratio (iIPC group, eIPC group: p<0.001), luminal flow (iIPC group: p<0.001; eIPC group: p<0.05), goblet cell ratio (iIPC group, eIPC group: p<0.001) and apoptosis (iIPC group, eIPC group: p<0.05) were all increased. Application of iIPC prior to I/R increased vascular galactose uptake (P<0.05) while eIPC had no significant impact on parameters of I/R-injury. On cellular level, I/R-injury resulted in a reduction of the phosphorylation of several MAPK signaling molecules. Application of iIPC prior to I/R increased phosphorylation of JNK2 and p38δ while eIPC enhanced CREB and GSK-3α/β phosphorylation.ConclusionIntestinal I/R-injury is associated with major physiological and cellular changes. However, the overall influence of the two different IPC strategies on the acute phase of intestinal I/R-injury is rather limited.

Application of ischemic preconditioning in the rehabilitation of miners suffered from the vibration disease

Introduction. Vibration disease is characterized by the early development of sensory polyneuropathy. Sensitive disorders significantly worsen the quality of life and increase the duration of the unemployable period of miners, which requires the search for new modern methods of correction and rehabilitation. Ischemic preconditioning is a promising direction in the treatment of occupationally caused polyneuropathies. However, its potential neuroprotective effect has not been sufficiently studied. The aim of the study was to evaluate the effectiveness of ischemic preconditioning of the upper extremities for the correction of sensory polyneuropathy manifestations in miners with vibration disease. Material and methods. Seventy-eight persons with a proven diagnosis of vibration disease were examined. According to a specially elaborated technique, the ischemic preconditioning of the upper extremities was performed in 46 patients who were included in the leading group; 32 patients made up the control group. The clinical and electroneuromyographic examination was carried out before the ischemic preconditioning procedure and on the 5th day of the study. Results. The initial clinical and neurophysiological indices in both groups did not differ statistically significant and indicated sensory polyneuropathy. After ischemic preconditioning, the subjects of the leading group showed an improvement in clinical and functional indices (reduction of numbness and paresthesia, improvement of vibration sensitivity, an increase in the sensory conduction velocity of impulse and the amplitudes of sensory responses) of the peripheral nerves of the upper extremities. In contrast, in the control group, there was no statistically significant change in objective indices. Conclusion. Ischemic preconditioning of the upper extremities is effective in the rehabilitation of miners with vibration disease, helps to reduce the manifestations of sensory polyneuropathy, sensitive disorders and normalize neurophysiological indices.

Repeat Application of Ischemic Preconditioning Improves Maximal 1,000-m Kayak Ergometer Performance in a Simulated Competition Format.

Halley, SL, Peeling, P, Brown, H, Sim, M, Mallabone, J, Dawson, B, and Binnie, MJ. Repeat application of ischemic preconditioning improves maximal 1,000-m kayak ergometer performance in a simulated competition format. J Strength Cond Res XX(X): 000-000, 2020-This study examined the effects of ischemic preconditioning (IPC) on repeat 1,000-m kayak ergometer time-trial (TT) performance, completed in a simulated competition format. Eight well-trained male kayak athletes performed 3 experimental trials, each consisting of two 1,000-m TTs separated by 80 minutes (TT 1 and TT 2). Trials included; (a) IPC (4 × 5 minutes 220 mm Hg alternating bilateral leg occlusion) 40 minutes before TT 1 only (IPC1); (b) IPC 40 minutes before TT 1 and 20 minutes before TT 2 (IPC2); and (c) no IPC (CON). Time, power, stroke rate, and expired gas variables (V[Combining Dot Above]O2 and accumulated oxygen deficit) were measured throughout each TT; blood gas variables (blood lactate, partial pressure of oxygen and blood pH) and rating of perceived exertion were measured before and after each effort. Physiological, perceptual, and physical measures were analyzed via a repeated measures analysis of variance with the level of significance set at p ≤ 0.05. There were large improvements in completion time for TT 1 in IPC1 (d = 1.24 ± 0.68, p < 0.05) and IPC2 (d = 1.53 ± 0.99, p < 0.05) versus CON. There was also a large improvement in TT 2 completion time in IPC2 versus CON (d = 1.26 ± 1.13, p = 0.03) whereas, IPC1 and CON were indifferent (d = 0.3 ± 0.54, p = 0.23). This study showed that a repeat application of IPC in a simulated competition format may offer further benefit in comparison to a single pre-exercise application of IPC.

Ischemic preconditioning prevents impact of prolonged sitting on glucose tolerance and markers of cardiovascular health but not cerebrovascular responses.

Prolonged, uninterrupted sitting is demonstrated to acutely impair glucose homeostasis, but it also leads to detrimental cardiovascular health effects. We examined whether ischemic preconditioning (IPC) prevents the impact of prolonged sitting-induced glucose intolerance and measured related influencing factors such as (para)sympathetic nerve activity [assessed by heart rate variability (HRV)] and blood pressure during 2 h of prolonged sitting. In this randomized, controlled crossover study, 15 healthy participants (80% men) with a mean age of 21 ± 1 yr (means ± SD) and body mass index of 25.0 ± 2.4 kg/m2 performed IPC (IPC, 4 × 5-min 220-mmHg unilateral occlusion at the thigh muscle) or a sham intervention (sham, 4 × 5 min 20-mmHg), followed by 2 h of sitting. After IPC or sham intervention, fingertip blood glucose was measured before and after 30, 60, 90, and 120 min of 75 g of glucose ingestions. Blood glucose responses during an oral glucose tolerance test were significantly attenuated, resulting in a lower area under the curve when sitting was preceded by a bout of IPC than sham (P < 0.05). IPC increased high-frequency oscillations and decreased the ratio of low-frequency-to-high-frequency oscillations at 120 min in HRV (P < 0.05). Moreover, a lower blood pressure was observed with IPC compared with sham (P < 0.05). Prolonged sitting or IPC did not affect cerebrovascular responses (P > 0.05). Collectively, these results indicate that the application of IPC before prolonged, uninterrupted sitting bout was associated with a better glucose tolerance and prevented impairment in (para)sympathetic nerve activity and blood pressure in healthy young men and women.

Ischemic Preconditioning Of Thigh Muscles: Number Of Proper Repetitions And Effectiveness

Ischemic preconditioning (IPC) was introduced after it was demonstrated that repetitions of short-term ischemia and reperfusion of coronary arteries can reduce the myocardial damage following prolonged ischemia (direct IPC). It was later shown that the IPC of coronary arteries also protects remote cardiac tissue not directly exposed to IPC (remote IPC). Several studies suggested that the IPC of a limb may protect remote organs against an ischemic incident. Because of the intermittent nature of blood flow during intense muscle actions, it was proposed that IPC prior to exercise could increase muscular performance. Although most of the prior exercise studies used an IPC protocol involving four cycles of 5-min circulatory occlusion followed by a 5-min reperfusion period, the optimal number of repetitions of IPC has been unknown. PURPOSE: We examined the effects of direct IPC on thigh strength and sought to determine the optimal repetitions of IPC for successful results. METHODS: In a randomized cross-over study, 12 healthy young males (19.8 ± 2.1 yrs, body mass index: 22.1 ± 2.7 kg/m2) performed maximal knee extension (Biodex System 3; New York, USA) of the right leg preceded by direct IPC at four different repetitions (1, 2, 3, and 4 sets) and a control intervention. One IPC consisted of 5-min circulatory occlusion by 1.3-times systolic blood pressure and 5-min reperfusion. RESULTS: There was no significant difference in the maximal voluntary torque of knee extension between the control and any number of repetitions of the IPC, as shown below.MVT, maximal voluntary torque; Nm, newton meter. Data are mean ± SD (n=12). CONCLUSIONS: These data indicate that direct IPC for the thigh muscles could not improve maximal strength regardless of the number of repetitions. The application of pre-exercise IPC for improving performance should be further carefully examined concerning the optimal protocol and its indications, such as exercise types and target muscles.

Ischemic preconditioning has no effect on maximal arm cycling exercise in women.

We investigated the effect of ischemic preconditioning (IPC) on performance of a 3min maximal effort arm ergometer test in young women. Twenty healthy women (23.1 (SD 3.3) years) performed a 3min maximal effort arm cycling exercise, preceded by IPC on both arms or SHAM in a counterbalanced randomized crossover design. Both blood flow (via high resolution ultrasound; n = 17) and muscle oxygenation/deoxygenation (via near infrared spectroscopy; n = 5) were measured throughout the IPC/SHAM. Performance and perceptual/physiological (i.e., heart rate, blood lactate, rating of perceived exertion, and triceps brachialis oxygenation) parameters were recorded during the exercise test. Occlusion during IPC completely blocked brachial artery blood flow, decreased oxygenated hemoglobin/myoglobin (Δ[oxy(Hb + Mb)]), and increased deoxygenated Hb/Mb (Δ[deoxy(Hb + Mb)]). There were no differences (P > 0.797) in performance (peak, mean, and end power output) or in any perceptual/physiological variables during the 3min all-out test between IPC/SHAM. During exercise, Δ[oxy(Hb + Mb)] initially decreased with no differences (P ≥ 0.296) between conditions and returned towards baseline by the completion of the test while Δ[deoxy(Hb + Mb)] increased with no differences between conditions and remained elevated until completion of the test (P ≥ 0.755). We verified the successful application of IPC via blood flow and NIRS measures but found no effects on performance of a 3min maximal effort arm cranking test in young women.

Lower limb ischemic preconditioning combined with dietary nitrate supplementation does not influence time-trial performance in well-trained cyclists

ObjectivesDietary nitrate (NO3−) supplementation and ischaemic preconditioning (IPC) can independently improve exercise performance. The purpose of this study was to explore whether NO3− supplementation, ingested prior to an IPC protocol, could synergistically enhance parameters of exercise. DesignDouble-blind randomized crossover trial. MethodsTen competitive male cyclists (age 34±6years, body mass 78.9±4.9kg, V⋅O2peak 55±4 mLkgmin−1) completed an incremental exercise test followed by three cycling trials comprising a square-wave submaximal component and a 16.1km time-trial. Oxygen uptake (V⋅O2) and muscle oxygenation kinetics were measured throughout. The baseline (BASE) trial was conducted without any dietary intervention or IPC. In the remaining two trials, participants received 3×5min bouts of lower limb bilateral IPC prior to exercise. Participants ingested NO3−-rich gel (NIT+IPC) 90min prior to testing in one trial and a low NO3− placebo in the other (PLA+IPC). Plasma NO3− and nitrite (NO2−) were measured immediately before and after application of IPC. ResultsPlasma [NO3−] and [NO2−] were higher before and after IPC in NIT+IPC compared to BASE (P<0.001) but did not differ between BASE and PLA+IPC. There were no differences in V⋅O2 kinetics or muscle oxygenation parameters between trials (all P>0.4). Performance in the time-trial was similar between trials (BASE 1343±72s, PLA+IPC 1350±75s, NIT+IPC 1346±83s, P=0.98). ConclusionsPre-exercise IPC did not improve sub-maximal exercise or performance measures, either alone or in combination with dietary NO3− supplementation.

Prevention of contrast induced nephropathy by ischemic preconditioning in patients undergoing percutaneous coronary angiography.

BackgroundContrast-induced nephropathy (CIN) is the acute deterioration of renal function after parenteral administration of radio contrast media in the absence of other causes. The true incidence of CIN varies because of differences among the published studies in the definition of CIN, the proportion of high-risk patients, the types of contrast media, and the use of preventive measures. Remote ischemic preconditioning (IPC) may offer a non-pharmacological prevention strategy for lowering CIN in patients undergoing coronary procedures. The assumption that IPC produces protective effects on tissues or organs by multiple brief cycles of ischemia and reperfusion applied to another remote tissue or organ.AimTo investigate the effect of ischemic preconditioning in prevention of CIN in patients with renal impairment undergoing percutaneous coronary angiography.ResultsIn this study, 100 patients undergoing elective PCI with a base line creatinine clearance <60 ml/min were studied. Patients were divided into two equal groups (ischemic preconditioning group and control group). The incidence of CIN was markedly lower in ischemic preconditioning group 14% VS 38% in control group. The incidence of CIN difference as was found to be (24%). Amount of dye used, decreased LVEF and presence of a significant LAD lesion were significant risk factors for occurrence of CIN.ConclusionsThe current study showed that remote ischemic preconditioning plays an important role in prevention of CIN in patients undergoing PCI with renal impairment GFR < 60 ml/min. The amount of contrast, decreased LVEF, and presence of LAD significant lesion were significant risk factors for developing of CIN and these subgroups benefited from application of ischemic preconditioning.

Correction to: Neuroimmune Response in Ischemic Preconditioning.

Ischemic preconditioning (IPC) is a robust neuroprotective phenomenon in which a brief period of cerebral ischemia confers transient tolerance to subsequent ischemic challenge. Research on IPC has implicated cellular, molecular, and systemic elements of the immune response in this phenomenon. Potent molecular mediators of IPC include innate immune signaling pathways such as Toll-like receptors and type 1 interferons. Brain ischemia results in release of pro- and anti-inflammatory cytokines and chemokines that orchestrate the neuroinflammatory response, resolution of inflammation, and transition to neurological recovery and regeneration. Cellular mediators of IPC include microglia, the resident central nervous system immune cells, astrocytes, and neurons. All of these cell types engage in cross-talk with each other using a multitude of signaling pathways that modulate activation/suppression of each of the other cell types in response to ischemia. As the postischemic neuroimmune response evolves over time there is a shift in function toward provision of trophic support and neuroprotection. Peripheral immune cells infiltrate the central nervous system en masse after stroke and are largely detrimental, with a few subtypes having beneficial, protective effects, though the role of these immune cells in IPC is largely unknown. The role of neural progenitor cells in IPC-mediated neuroprotection is another active area of investigation as is the role of microglial proliferation in this setting. A mechanistic understanding of these molecular and cellular mediators of IPC may not only facilitate more effective direct application of IPC to specific clinical scenarios, but also, more broadly, reveal novel targets for therapeutic intervention in stroke.

Ischemic Preconditioning Produces Comparable Protection Against Hepatic Ischemia/Reperfusion Injury Under Isoflurane and Sevoflurane Anesthesia in Rats

BackgroundVarious volatile anesthetics and ischemic preconditioning (IP) have been demonstrated to exert protective effect against ischemia/reperfusion (I/R) injury in liver. We aimed to determine whether application of IP under isoflurane and sevoflurane anesthesia would confer protection against hepatic I/R injury in rats. MethodsThirty-eight rats weighing 270 to 300 grams were randomly divided into 2 groups: isoflurane (1.5%) and sevoflurane (2.5%) anesthesia groups. Each group was subdivided into sham (n = 3), non-IP (n = 8; 45 minutes of hepatic ischemia), and IP (n = 8, IP consisting of 10-minute ischemia plus 15-minute reperfusion before prolonged ischemia) groups. The degree of hepatic injury and expressions of B-cell lymphoma 2 (Bcl-2) and caspase 3 were compared at 2 hours after reperfusion. ResultsHepatic ischemia induced significant degree of I/R injuries in both isoflurane and sevoflurane non-IP groups. In both anesthetic groups, introduction of IP dramatically attenuated I/R injuries as marked by significantly lower aspartate aminotransferase and aminotransferase levels and better histologic grades compared with corresponding non-IP groups. There were 2.3- and 1.7-fold increases in Bcl-2 mRNA levels in isoflurane and sevoflurane IP groups, respectively, compared with corresponding non-IP groups (both P < .05). Caspase 3 level was significantly high in the isoflurane non-IP group compared with the sham group; however, there were no differences among the sevoflurane groups. ConclusionsThe degree of hepatic I/R injury was significantly high in both isoflurane and sevoflurane groups in rats. However, application of IP significantly protected against I/R injury in both volatile anesthetic groups to similar degrees, and upregulation of Bcl-2 might be an important mechanism.

The expression of endothelial and inducible nitric oxide synthase and apoptosis in intestinal ischemia and reperfusion injury under the action of ischemic preconditioning and pentoxifylline.

To investigate the expression of nitric oxide synthase (NOS) and apoptosis associated with ischemic preconditioning (IPC) and pentoxifylline (PTX) in intestinal ischemia (I) and reperfusion (R) injury. Thirty male rats were assigned to 5 groups: (CG), no clamping of the superior mesenteric artery (90 minutes); (IR-SS) saline + ischemia (30 minutes) + reperfusion (60 minutes); (IR-PTX) PTX + ischemia (30 minutes) + reperfusion (60 minutes); (IPC-IR-SS) 5 minutes of ischemia + 5 minutes of reperfusion (IPC) + saline + I(30 minutes)+R(60 minutes); and (IPC-IR-PTX) IPC + PTX + I(30 minutes)+ R(60 minutes). The application of IPC and PTX showed a significantly lower immunohistochemistry reaction for active caspase-3 (P<0.05) compared to IR+SS. The number of cells immunoreactive to BCL-2 was higher in the IR-PTX group (P>0.05). The NOS-2 expression (qRTPCR) in the IR-PTX group (P<0.05) was higher than the values for the IPC+IR-SS and IPC-IR-PTX groups. The NOS-3 expression was significantly upper in the IPC-IR-PTX group than in the CG (P<0.05), the IR-SS (P<0.05) and the IR-PTX (P<0.05) groups. The BCL-2 and active caspase-3 showed beneficial effects on PTX and IPC. The expression of NOS-2 and NOS-3 in the IPC and IPC-PTX groups showed no synergistic effect.

Ischemic Tolerance of the Brain and Spinal Cord: A Review.

Ischemic tolerance is an endogenous neuroprotective phenomenon induced by sublethal ischemia. Ischemic preconditioning (IPC), the first discovered form of ischemic tolerance, is widely seen in many species and in various organs including the brain and the spinal cord. Ischemic tolerance of the spinal cord is less familiar among neurosurgeons, although it has been reported from the viewpoint of preventing ischemic spinal cord injury during aortic surgery. It is important for neurosurgeons to have opportunities to see patients with spinal cord ischemia, and to understand ischemic tolerance of the spinal cord as well as the brain. IPC has a strong neuroprotective effect in animal models of ischemia; however, clinical application of IPC for ischemic brain and spinal diseases is difficult because they cannot be predicted. In addition, one drawback of preconditioning stimuli is that they are also capable of producing injury with only minor changes to their intensity or duration. Numerous methods to induce ischemic tolerance have been discovered that vary in their timing and the site at which short-term ischemia occurs. These methods include ischemic postconditioning (IPoC), remote ischemic preconditioning (RIPC), remote ischemic perconditioning (RIPerC) and remote ischemic postconditioning (RIPoC), which has had a great impact on clinical approaches to treatment of ischemic brain and spinal cord injury. Especially RIPerC and RIPoC to induce spinal cord tolerance are considered clinically useful, however the evidence supporting these methods is currently insufficient; further experimental or clinical research in this area is thus necessary.

Neuroimmune Response in Ischemic Preconditioning.

Ischemic preconditioning (IPC) is a robust neuroprotective phenomenon in which a brief period of cerebral ischemia confers transient tolerance to subsequent ischemic challenge. Research on IPC has implicated cellular, molecular, and systemic elements of the immune response in this phenomenon. Potent molecular mediators of IPC include innate immune signaling pathways such as Toll-like receptors and type 1 interferons. Brain ischemia results in release of pro- and anti-inflammatory cytokines and chemokines that orchestrate the neuroinflammtory response, resolution of inflammation, and transition to neurological recovery and regeneration. Cellular mediators of IPC include microglia, the resident central nervous system immune cells, astrocytes, and neurons. All of these cell types engage in cross-talk with each other using a multitude of signaling pathways that modulate activation/suppression of each of the other cell types in response to ischemia. As the postischemic neuroimmune response evolves over time there is a shift in function toward provision of trophic support and neuroprotection. Peripheral immune cells infiltrate the central nervous system en masse after stroke and are largely detrimental, with a few subtypes having beneficial, protective effects, though the role of these immune cells in IPC is largely unknown. The role of neural progenitor cells in IPC-mediated neuroprotection is another active area of investigation as is the role of microglial proliferation in this setting. A mechanistic understanding of these molecular and cellular mediators of IPC may not only facilitate more effective direct application of IPC to specific clinical scenarios, but also, more broadly, reveal novel targets for therapeutic intervention in stroke.

Ameliorative Effect of Recombinant Human Erythropoietin and Ischemic Preconditioning on Renal Ischemia Reperfusion Injury in Rats.

Background:Ischemia-reperfusion (IR) injury is one of the most common causes of renal dysfunction. There is increasing evidence about the role of the reactive oxygen species (ROS) in these injuries and endogenous antioxidants seem to have an important role in decreasing the renal tissue injury.Objectives:The aim of this study was to compare the effect of recombinant human erythropoietin (EPO) and ischemic preconditioning (IPC) on renal IR injury.Materials and Methods:Twenty four male Wistar rats were allocated into four experimental groups: sham-operated, IR, EPO + IR, and IPC + IR. Rats were underwent 50 minutes bilateral ischemia followed by 24 hours reperfusion. Erythropoietin (5000 IU/kg, i.p) was administered 30 minutes before onset of ischemia. Ischemic preconditioning was performed by three cycles of 3 minutes ischemia followed by 3 minutes reperfusion. Plasma concentrations of urea and creatinine were measured. Kidney samples were taken for reactive oxidative species (ROS) measurement including superoxide dismutase (SOD) activity, glutathione (GSH) contents, and malondialdehyde (MDA) levels.Results:Compared to the sham group, IR led to renal dysfunction as evidenced by significantly higher plasma urea and creatinine. Treatment with EPO or IPC decreased urea, creatinine, and renal MDA levels and increased SOD activity and GSH contents in the kidney.Conclusions:Pretreatment with EPO and application of IPC significantly ameliorated the renal injury induced by bilateral renal IR. However, both treatments attenuated renal dysfunction and oxidative stress in kidney tissues. There were no significant differences between pretreatment with EPO or application of IPC.

Identical MicroRNAs Regulate Liver Protection during Anaesthetic and Ischemic Preconditioning in Rats: An animal study.

Anaesthetic preconditioning (APC) and ischemic preconditioning (IPC) ameliorate liver ischemia–reperfusion (I/R) injury and are important for regulating hepatic I/R injury. MicroRNAs (miRNAs) are short, noncoding RNA molecules of 21–23 nucleotides in length, and are currently under intensive investigation regarding their ability to regulate gene expression in a wide range of species. miRNA activity is involved in controlling a wide range of biological functions and processes. We evaluated whether APC and IPC are mediated by the same miRNAs by performing comprehensive miRNA screening experiments in a rat model of hepatic I/R injury. Twenty-one rats were randomly divided into three groups (n = 7/group): control (mock preconditioning), APC, and IPC. Control rats were subjected to 60 min of hepatic ischemia followed by 4 h of reperfusion, whereas the APC and IPC groups were preconditioned with 2% sevoflurane and hepatic ischemia for 10 min prior to ischemia-reperfusion, respectively. Liver samples were collected to measure miRNA levels after 3 h of reperfusion, and gene networks and canonical pathways were identified using Ingenuity Pathway Analysis (IPA). Blood samples were collected to measure the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Although haemodynamic parameters did not vary among the groups, AST and ALT levels were significantly higher in the control group than in the APC and IPC groups. Comprehensive miRNA screening experiments revealed that most miRNAs altered in the APC group were common to those in the IPC group. IPA identified five miRNAs related to the Akt–glycogen synthase kinase-3β (GSK-3β)–cyclin D1 pathway that were significantly affected by both preconditioning strategies. The application of either APC or IPC to ameliorate hepatic I/R injury results in expression of several common miRNAs that are related to the Akt–GSK–cyclin D1 pathway.

Ischemic brain extract increases SDF-1 expression in astrocytes through the CXCR2/miR-223/miR-27b pathway

Ischemic cerebral stroke is one of the leading global causes of mortality and morbidity. Ischemic preconditioning (IPC) refers to a sublethal ischemia and resulting in tolerance to subsequent severe ischemic injury. Although several pathways are reportedly involved in IPC-mediated neuroprotection, the functional role of astrocytes is not fully understood. Stromal cell-derived factor-1 (SDF-1), a CXC chemokine produced mainly in astrocytes, is a ligand for chemokine receptor CXCR4. SDF-1 is reported to play a critical role in neuroprotection after stroke by mediating the migration of neuronal progenitor cells. We hypothesized that stimuli derived from ischemic brain were involved in the protective effects of IPC. To investigate this hypothesis, the mechanism in which ischemic brain extract (IBE) induced SDF-1 expression was investigated in C6 astrocytoma cells. IBE treatment of C6 cells increased SDF-1 expression compared to that in untreated or normal brain extract (NBE)-treated cells by downregulating SDF-1 targeting miRNA, miR-27b. MiR-223 was inversely upregulated in IBE-treated cells; overexpression of miR-223 decreased the expression of miR-27b by suppressing IKKα expression. Analysis of cytokine array data revealed an IBE associated enhanced expression of CINC-1 (CXCL1) and LIX1 (CXCL5). Knockdown or inhibition of their receptor, CXCR2, abolished IBE-mediated increased expression of SDF-1. These results were confirmed in primary cultured astrocytes. Taken together, the data demonstrate that IBE-elicited signals increase SDF-1 expression through the CXCR2/miR-223/miR-27b pathway in C6 astrocytoma cells and primary astrocytes, supporting the view that increased expression of SDF-1 by ischemic insults is a possible mechanism underlying therapeutic application of IPC.

Renoprotective mechanisms of ischemic postconditioning in ischemia-reperfusion injury: improved mitochondrial function and integrity

Renoprotective mechanisms of ischemic postconditioning in ischemia-reperfusion injury: improved mitochondrial function and integrity

Aging attenuates the protective effect of ischemic preconditioning against endothelial ischemia-reperfusion injury in humans

Reperfusion is mandatory after ischemia but also triggers ischemia-reperfusion (I/R) injury. Ischemic preconditioning (IPC) can limit endothelial I/R injury. Nonetheless, translation of IPC to the clinical arena is often disappointing. Since application of IPC typically relates to older patients, efficacy of IPC may be attenuated with aging. Our objective was to examine the impact of advanced age on the ability of IPC to protect against endothelial dysfunction due to I/R injury. We included 15 healthy young (20-25 yr) and 15 older (68-77 yr) men. We examined brachial artery endothelial function using flow-mediated dilation (FMD) before and after arm I/R (induced by inflation of an upper-arm blood pressure cuff for 20 min and 15 min of reperfusion). In a randomized order, I/R was preceded by IPC or a control intervention consisting of three cycles of 5 min upper-arm cuff inflation to 220 or 20 mmHg, respectively. As a result, in young men, FMD decreased significantly after I/R (6.4 ± 2.7 to 4.4 ± 2.5%). This decrease was not present when I/R was preceded by IPC (5.9 ± 2.3 to 5.6 ± 2.5%). IPC-induced protection appeared to be significantly reduced in the elderly patients (P = 0.04). Although FMD decreased after I/R in older men (3.5 ± 1.7 to 2.5 ± 1.0%), IPC could not prevent this (3.7 ± 2.1 to 2.2 ± 1.1%). In conclusion, this study is the first to observe in humans in vivo that older age is associated with an abolished effect of IPC to protect against endothelial dysfunction after I/R in the brachial artery. This provides a possible explanation for the problematic translation of strategies that reduce I/R injury from preclinical work to the clinical arena.