Search

It has recently been revealed that during the aorta-clamped period, D-Ala2, D-Leu5-Enkephalin (DADLE) infusion can protect the spinal cord against ischemia and reperfusion (I/R) injury. However, the protective effects of DADLE administration prior to ischemia or at the time of early reperfusion have not yet been investigated. Drug pre- or post-conditioning can serve as a more valuable clinical strategy. Therefore, the present study was designed to investigate the neuroprotective effect of DADLE infusion at different time intervals in order to determine the optimum time point for ischemic spinal cord protection. A total of 40 New Zealand white rabbits were randomly divided into 5 groups: Sham-operated (Sham), normal saline pre-conditioning (NS), DADLE per-conditioning (Dper), DADLE pre-conditioning (Dpre) and DADLE post-conditioning (Dpost). All animals were subjected to spinal cord ischemia for 30 min followed by 48 h reperfusion. Hind limb motor functions were assessed according to the Tarlov criterion when the animals regained consciousness, 6, 24 and 48 h after reperfusion. Histological analysis and the number of viable α-motor neurons were also used to assess the extent of spinal cord injury. Compared with the NS group, the Tarlov scores and the number of normal neurons were significantly higher in the Dper group (P<0.05), which were consistent with the results of a previous study. In addition, the paraplegia rate and loss of normal motor neurons were lower in the DADLE per- and post-conditioning groups compared with the DADLE pre-conditioning; however, these were not statistically significant. DADLE 0.05 mg/kg administration at three time points all mitigated normal motor neuron injury in the anterior horn and decreased the paraplegia rates in rabbits. The therapeutic benefits appeared best in the post-conditioning group with DADLE, and worst in the pre-conditioning group. [ABSTRACT FROM AUTHOR]

Background: Liver transplantation is the second most common transplant procedure in the United States. A leading cause of post-transplantation organ dysfunction is I/R injury. During I/R injury, the serine/threonine kinase Akt is activated, stimulating downstream mediators to promote cellular survival. Due to the cellular effects of Akt, therapeutic manipulation of the Akt pathway can help reduce cellular damage during hepatic I/R that occurs during liver transplantation. Objective: A full description of therapeutic options available that target Akt to reduce hepatic I/R injury has not been addressed within the literature. The purpose of this review is to illuminate advances in the manipulation of Akt that can be used to therapeutically target I/R injury in the liver. Methods: An in depth literature review was performed using the Scopus and PubMed databases. A total of 75 published articles were utilized for this manuscript. Terminology searched includes a combination of “hepatic ischemia/reperfusion injury”, “Akt/PKB”, “preconditioning” and “postconditioning.” Results: Four principal methods that reduce I/R injury include hepatic pre- and postconditioning, pharmacological intervention and future miRNA/gene therapy. Discussed therapies used serum alanine aminotransferase levels, liver histology and phosphorylation of downstream mediators to confirm the Akt protective effect. Conclusion: The activation of Akt from the reviewed therapies has resulted in predictable reduction in hepatocyte damage using the previously mentioned measurements. In a clinical setting, these therapies could potentially be used in combination to achieve better outcomes in hepatic transplant patients. Evidence supporting reduced I/R injury through Akt activation warrants further studies in human clinical trials.

Purpose: To determine and compare the effects of pre-conditioning and post-conditioning towards gamma radiation responses in human cancer cells and keratinocytes. Material and methods: The clonogenic survival of glioblastoma cells (T98G), keratinocytes (HaCaT), and colorectal carcinoma cells (HCT116 p53+/+ and p53−/−) was assessed following gamma ray exposure from a Cs-137 source. The priming dose preceded the challenge dose in pre-conditioning whereas the priming dose followed the challenge dose in post-conditioning. The priming dose was either 5 mGy or 0.1 Gy. The challenge dose was 0.5-5 Gy. Results: In both pre- and post-conditioning where the priming dose was 0.1 Gy and the challenge dose was 4 Gy, RAR developed in T98G but not in HaCaT cells. In HCT116 p53+/+, pre-conditioning had either no effect or a radiosensitizing effect and whereas post-conditioning induced either radiosensitizing or radioadaptive effect. The different observed outcomes were dependent on dose, the time interval between the priming and challenge dose, and the time before the first irradiation. Post-conditioning effects could occur with a priming dose as low as 5 mGy in HCT116 p53+/+ cells. When HCT116 cells had no p53 protein expression, the radiosensitizing or radioadaptive response by the conditioning effect was abolished. Conclusions: The results suggest that radiation conditioning responses are complex and depend on at least the following factors: the magnitude of priming/challenge dose, the time interval between priming and challenge dose, p53 status, cell seeding time prior to the first radiation treatment. This work is the first parallel comparison demonstrating the potential outcomes of pre- and post-conditioning in different human cell types using environmentally and medically relevant radiation doses. [ABSTRACT FROM AUTHOR]

Pharmacologically-induced pre- and post-conditioning represent attractive therapeutic strategies to reduce ischaemia/reperfusion injury during cardiac surgery and following myocardial infarction. We have previously reported that transglutaminase 2 (TG2) activity is modulated by the A 1 adenosine receptor and β 2 -adrenoceptor in H9c2 cardiomyoblasts. The primary aim of this study was to determine the role of TG2 in A 1 adenosine receptor and β 2 -adrenoceptor-induced pharmacological pre- and post-conditioning in the H9c2 cells. H9c2 cells were exposed to 8 h hypoxia (1% O 2 ) followed by 18 h reoxygenation, after which cell viability was assessed by monitoring mitochondrial reduction of MTT, lactate dehydrogenase release and caspase-3 activation. N 6 -cyclopentyladenosine (CPA; A 1 adenosine receptor agonist), formoterol (β 2 -adrenoceptor agonist) or isoprenaline (non-selective β-adrenoceptor agonist) were added before hypoxia/reoxygenation (pre-conditioning) or at the start of reoxygenation following hypoxia (post-conditioning). Pharmacological pre- and post-conditioning with CPA and isoprenaline significantly reduced hypoxia/reoxygenation-induced cell death. In contrast, formoterol did not elicit protection. Pre-treatment with pertussis toxin (G i/o -protein inhibitor), DPCPX (A 1 adenosine receptor antagonist) or TG2 inhibitors (Z-DON and R283) attenuated the A 1 adenosine receptor-induced pharmacological pre- and post-conditioning. Similarly, pertussis toxin, ICI 118,551 (β 2 -adrenoceptor antagonist) or TG2 inhibition attenuated the isoprenaline-induced cell survival. Knockdown of TG2 using small interfering RNA (siRNA) attenuated CPA and isoprenaline-induced pharmacological pre- and post-conditioning. Finally, proteomic analysis following isoprenaline treatment identified known (e.g. protein S100-A6) and novel (e.g. adenine phosphoribosyltransferase) protein substrates for TG2. These results have shown that A 1 adenosine receptor and β 2 -adrenoceptor-induced protection against simulated hypoxia/reoxygenation occurs in a TG2 and G i/o -protein dependent manner in H9c2 cardiomyoblasts. [ABSTRACT FROM AUTHOR]

Helium has been classified as a kind of inert gas that is not effortless to spark chemical reactions with other substances in the past decades. Nevertheless, the cognition of scientists has gradually changed accompanied with a variety of studies revealing the potential molecular mechanism underlying organ-protection induced by helium. Especially, as a non-anesthetic gas which is deficient of relevant cardiopulmonary side effects, helium conditioning is recognized as an emerging and promising approach to exert favorable effects by mimicking the cardioprotection of anesthetic gases or xenon. In this review we will summarize advances in the underlying biological mechanisms and clinical applicability with regards to the cardioprotective effects of helium. [ABSTRACT FROM AUTHOR]

Aim The isolated, retrogradely perfused heart (modified Langendorff model) is a widely used method in experimental heart research. The presence of an intraventricular balloon is necessary to get functional measurements. We have previously shown that the balloon induces phosphorylation of some suggested cardioprotective mitogen-activated protein kinases ( MAPK): P38- MAPK, ERK 1/2 and JNK. We hypothesized that the balloon could influence cardioprotection, protect against ischaemia reperfusion injury and interfere with coronary flow. Methods and Results Isolated mouse hearts were perfused for 5, 10, 20, 40 and 60 min with a balloon in the left ventricle. We found a wavelike phosphorylation of all MAPK while AKT displayed a gradual dephosphorylation when compared to non-perfused hearts. Hearts were subjected to 20 min of stabilization with or without the balloon, followed by 35 min of ischaemia and 120 min of reperfusion. Although the MAPK were phosphorylated, the infarcts were larger in the balloon group. When the balloon was present during the entire protocol, compared to removal at the end of ischaemia, the infarct size was also larger, especially in the endocardial layer. The balloon reduced post-ischaemic endocardial coronary flow, despite a higher average flow, indicating a hyperperfused epicard. Blocking the balloon-induced ERK 1/2 phosphorylation during stabilization did not affect infarct size. The effect of post-conditioning was influenced by the balloon, showing reduced infarct size when the balloon was present. Conclusion The balloon used for pressure measurements may contributes to cell death possibly by reducing endocardial coronary flow. [ABSTRACT FROM AUTHOR]

Background:Liver transplantation is the second most common transplant procedure in the United States. A leading cause of post-transplantation organ dysfunction is I/R injury. During I/R injury, the serine/threonine kinase Akt is activated, stimulating downstream mediators to promote cellular survival. Due to the cellular effects of Akt, therapeutic manipulation of the Akt pathway can help reduce cellular damage during hepatic I/R that occurs during liver transplantation.Objective:A full description of therapeutic options available that target Akt to reduce hepatic I/R injury has not been addressed within the literature. The purpose of this review is to illuminate advances in the manipulation of Akt that can be used to therapeutically target I/R injury in the liver.Methods:An in depth literature review was performed using the Scopus and PubMed databases. A total of 75 published articles were utilized for this manuscript. Terminology searched includes a combination of “hepatic ischemia/reperfusion injury”, “Akt/PKB”, “preconditioning” and “postconditioning.”Results:Four principal methods that reduce I/R injury include hepatic pre- and postconditioning, pharmacological intervention and future miRNA/gene therapy. Discussed therapies used serum alanine aminotransferase levels, liver histology and phosphorylation of downstream mediators to confirm the Akt protective effect.Conclusion:The activation of Akt from the reviewed therapies has resulted in predictable reduction in hepatocyte damage using the previously mentioned measurements. In a clinical setting, these therapies could potentially be used in combination to achieve better outcomes in hepatic transplant patients. Evidence supporting reduced I/R injury through Akt activation warrants further studies in human clinical trials. [ABSTRACT FROM AUTHOR]

Isoflurane, a volatile and inhalational anesthetic, has been extensively used in perioperative period for several decades. A large amount of experimental studies have indicated that isoflurane exhibits neuroprotective properties when it is administrated before or after (preconditioning and post-conditioning) neurodegenerative diseases (e.g., hypoxic ischemia, stroke and trauma). Multiple mechanisms are involved in isoflurane induced neuroprotection, including activation of glycine and γ-aminobutyric acid receptors, antagonism of ionic channels and alteration of the function and activity of other cellular proteins. Although neuroprotection provided by isoflurane is observed in many animal studies, convincing evidence is lacking in human trials. Therefore, there is still a long way to go before translating its neuroprotective properties into clinical practice. [ABSTRACT FROM AUTHOR]

Acute brain injury is a critical and emergent condition in clinical settings, which needs to be addressed urgently. Commonly acute brain injuries include traumatic brain injury, ischemic and hemorrhagic strokes. Oxidative stress is a key contributor to the subsequent injuries and impedes the reparative process after acute brain injury; therefore, facilitating an anti-oxidative approach is important in the care of those diseases. Readiness to deliver and permeability to blood brain barrier are essential for the use of this purpose. Inhaled anesthetic gases are a group of such agents. In this article, we discuss the anti-oxidative roles of anesthetic gases against acute brain injury. [ABSTRACT FROM AUTHOR]

Ischemic heart disease is a common cause of patients' death worldwide. Recently, cardiac pre- and post-conditioning (IPC, IPoC) were indentified to reduce infarct size. Nevertheless, not only infarct size but also post-infarct remodelling is critical for the long-term enhancing effect. Calcium-sensing receptors (CaSRs) signalling was shown to be involved in IPC and IPoC in the heart. This study aims to clarify CaSRs expression after ischemia-reperfusion injury (I/R), IPC and IPoC. Experiments were performed on adult Wistar rats with left anterior descending coronary artery (LAD) occlusion. Troponin I (TnI) levels were measured in plasma of all animals to quantify the infarct size. Sham-operated animals, rats with I/R, IPC, and IPoC were compared. Left and right ventricular tissue samples from these groups were collected for qRT-PCR analysis. CaSR expression was enhanced in rats with I/R and IPC. Its increase after IPoC was not pronounced. In contrast, left ventricles (LV) showed decreased CaSR expression in rat hearts after I/R, IPC, and IPoC. Data suggest differences in CaSR regulation between LV and RV. Enhanced CaSR expression in RV was observed in tissue with small infarct size. [ABSTRACT FROM AUTHOR]

Aim To investigate the impact of ischaemic pre-conditioning ( Ipre) and post-conditioning ( Ipost) on expression of nuclear factor erythroid 2-related factor 2 ( Nrf2) gene and its dependent genes, haem oxygenase-1 ( HO-1) and NADPH-quinone oxidoreductase-1 ( NQO-1); inflammatory cytokines TNF-α, IL1β and ICAM-1; and apoptotic markers such as caspase-3 in renal ischaemia/reperfusion ( I/ R) injury. Methods One hundred and fifty male Sprague Dawley rats were classified into five groups (each consisted of 30 rats): sham, control ( I/ R), Ipre + I/ R, Ipre without I/ R and Ipost + I/ R. Serum creatinine and blood urea nitrogen ( BUN) were measured at 2, 24 and 48 h after ischaemia. In kidney tissues, m RNA of Nrf2, HO-1, NQO-1, TNF-α, IL-1β and ICAM-1 and immunohistochemical expression of Nrf2 and caspase-3 were assessed. Results Serum creatinine and BUN improved significantly in Pre + I/ R group; however, they did not show any significant improvement in Post + I/ R group. Also, Ipre- I/ R group showed non-significant change in serum creatinine and BUN. The expression of Nrf2, HO-1 and NQO-1 is increased significantly in Pre + I/ R and Pre − I/ R groups, while the enhancement in Post + I/ R group was non-significant. Moreover, the expression of proinflammatory cytokines ( TNF-α, IL-1 and ICAM-1) and apoptotic (caspase-3) markers showed high significant attenuation in Pre + I/ R group, but slight significant attenuation in Pre + I/ R group. Conclusion The renoprotective action of Ipre might include early activation and enhanced expression of Nrf2 gene and its dependent antioxidant genes, HO-1 and NOQ1, as endogenous adaptive renoprotective genes, as well as reduction in TNF-α, IL-1β, ICAM-1 and caspase-3. [ABSTRACT FROM AUTHOR]

Acute myocardial infarction (AMI) with subsequent left ventricular dysfunction and heart failure continues to be a major cause of morbidity and mortality in the Western world. Rapid advances in the treatment of AMI, mainly through timely reperfusion, have substantially improved outcomes in patients presenting with acute coronary syndrome and particularly ST-segment elevation myocardial infarction. A vast amount of research, both translational and clinical, has been published on various pharmacological and interventional techniques to prevent myocardial cell death during the time of ischemia and subsequent reperfusion. Several methods of cardioprotection have shown the ability to limit myocardial infarction size in clinical trials. Examples of interventional techniques that have proven beneficial are ischemic post-conditioning and remote ischemic per-conditioning, both of which can reduce infarction size. Lowering core body temperature with cold saline infusion and cooling catheters have also been shown to be effective in certain circumstances. The most promising pharmaceutical cardioprotective agents at this time appear to be adenosine, atrial natriuretic peptide, and cyclosporine, with other potentially effective medications in the pipeline. Additional pre-clinical and clinical research is needed to further investigate newer cardioprotective strategies to continue the current trend of improving outcomes following AMI. [ABSTRACT FROM AUTHOR]

Abstract: Ischemic conditioning has long held promise for preventing ischemic–reperfusion (I–R) injury. Although a number of studies have evaluated the effects of brief repeated episodes of ischemia before a prolonged ischemic episode on the cardiovascular system using clinical endpoints, more sensitive techniques by which to measure its effects are lacking. Since endothelial function is sensitive to I–R injury, flow mediated dilation of the brachial artery has been proposed for this purpose, but has significant limitations. Hyperemia normally decreases carotid to radial pulse wave velocity (PWV). Accordingly, we sought to determine the effects of I–R injury and ischemic conditioning on the hyperemic change (Δ) in PWV. We induced hyperemia by release of arterial cuff occlusion before and after ipsilateral arm I–R injury (7.5min occlusion) in 25 healthy males, age 29±6 years. The protocol was repeated on 2 occasions in combination with either pre- or post- conditioning stimuli (3× 30s contralateral arm occlusions). Hyperemia resulted in a significant decrease (−13.7%, p <.001) before but not after prolonged ischemia (−0.88%, p =0.40). I–R along with either pre- or post-ischemic conditioning restored the PWV decline (pre: −11.0%, p <0.001; post: −9.9%, p <0.001). In conclusion, 7.5min ischemia blunts the normal PWV decline produced by hyperemia. Remote pre- and post-conditioning restores this response. This technique may be useful for the assessment of novel treatment strategies and mechanisms underlying remote pre- and post-ischemic conditioning in protecting the cardiovascular system. [Copyright &y& Elsevier]

Abstract: Ischemic pre-conditioning (IPC) provides neuroprotection in the rat retina from the damaging effects of severe ischemia. Recently, neuroprotection by retinal ischemic post-conditioning (Post-C), i.e., transient ischemia after more lengthy, damaging ischemia, was described, but its mechanisms are not yet known. One possible explanation of the effectiveness of Post-C is that it augments intrinsic neuroprotective mechanisms initiated during ischemia. Increasing duration of the damaging ischemic insult may therefore impact the effectiveness of Post-C. IPC, in contrast, sets in motion a series of neuroprotective events prior to the onset of ischemia. Thus, IPC and Post-C may operate by differing mechanisms. Accordingly, we examined the effect of retinal ischemic duration on post-ischemic outcome in vivo in rats after adding Post-C, and the impact of combining pre- and post-conditioning. Recovery after ischemia performed 24 h after IPC, or after Post-C performed 5 min after ischemia ended, was assessed functionally (electroretinography) and histologically at 7 days after ischemia. Durations of ischemia of 45 and 55 min were studied. Since recovery with IPC or Post-C alone, with 55 min of ischemia, did not achieve the same degree of effect (i.e., not complete recovery) exhibited in our previous studies of IPC using a different ischemia model, we also combined IPC and Post-C to test the hypothesis of the possible additive effects of the IPC and Post-C. We found that the recovery after Post-C was enhanced to a greater degree when ischemia was of longer duration. Post-C led to greater post-ischemic recovery compared to IPC. Both IPC and Post-C also attenuated structural damage to the retina. Contrary to our hypothesis, IPC and Post-C did not combine to enhance recovery after ischemia. In earlier studies, IPC attenuated post-ischemic apoptosis. To begin to examine the mechanism of Post-C, we studied its impact on apoptosis following ischemia. We examined apoptosis by determining the percentage of TUNEL-positive cells at 24 h after ischemia. Post-C attenuated apoptosis, but when combined with IPC, TUNEL was similar in the combined group to that of ischemia alone. We also examined the role of the recruitment of an inflammatory response in ischemia and Post-C. We found that inflammatory markers increased by ischemia were not altered by Post-C. We conclude that Post-C effectiveness depends upon the duration of ischemia; Post-C is not additive with IPC, and Post-C functions, in part, by preventing apoptotic damage to the inner retina. Post-C has considerable promise for clinical translation to eye diseases that cause blindness by ischemia. [Copyright &y& Elsevier]