Effect Of Postconditioning Research Articles

Tim-3 cell signaling and iNOS are involved in the protective effects of ischemic postconditioning against focal ischemia in rats.

The protective effect of ischemic postconditioning (IPostC) against stroke has been well-established, and the underlying mechanisms are known to involve inhibited-inflammation and free radical production. Nevertheless, how IPostC affects protein expression of iNOS, nitrotyrosine, and COX-2 has not been characterized. In addition, the role of the galectin-9/Tim-3 cell signaling pathway--a novel inflammatory pathway--in IPostC has not been studied. We examined whether iNOS, nitrotyrosine, and COX-2, as well as galectin-9/Tim-3 are involved in the protective effects of IpostC in a rat focal ischemia model. Western blot and confocal immunofluoresent staining results indicate that IPostC significantly inhibited Tim-3 expression, and that galectin-9 expression was also inhibited. In addition, IPostC attenuated production of iNOS and nitrotyrosine, but not COX-2, suggesting that IPostC has distinct effects on these inflammatory factors. Furthermore, the inflammation inhibitor minocycline blocked Tim-3 and iNOS expression induced by stroke. Taken together, we show that the galectin-9/Tim-3 cell signaling pathway is involved in inflammation induced by stroke, and IPostC may reduce infarction by attenuating this novel pathway as well as the inflammatory factors iNOS and nitrotyrosine, but not COX-2.

Anti-inflammatory effect of B-type natriuretic peptide postconditioning during myocardial ischemia-reperfusion: involvement of PI3K/Akt signaling pathway.

High mobility group box 1 protein (HMGB1) plays an important role in myocardial ischemia-reperfusion (I/R) injury. B-type natriuretic peptide (BNP) postconditioning has been reported to reduce myocardial I/R injury. The present study investigated whether postconditioning of BNP could reduce myocardial I/R injury by inhibiting HMGB1 expression and the potential mechanisms in rats. The left anterior descending coronary arteries of rats were occluded to induce ischemia for 30 min and reopened to imitate reperfusion for 4 h. The rats were treated with BNP (0.03 μg/kg min, i.v.) 15 min before reperfusion until the end of the procedure, with or without treatment of LY294002 (an inhibitor of phosphoinositide 3-kinase (PI3K), 0.3 mg/kg, i.v.), which was injected 20 min before reperfusion. Lactate dehydrogenase (LDH), creatine kinase (CK), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and infarct size were measured. Phospho-Akt, total Akt, and HMGB1 expression were assessed by immunoblotting. The results showed that treatment of BNP postconditioning could significantly decrease the infarct size and the levels of LDH and CK after 4-h reperfusion (all p<0.05). BNP postconditioning could also significantly inhibit the increases of TNF-α and IL-6 (both p<0.05). In addition, BNP postconditioning could significantly inhibit HMGB1 expression induced by I/R (p<0.05). Administration of LY294002 abolished the effects of BNP postconditioning on myocardial I/R injury and the expressions of phospho-Akt and HMGB1 (all p<0.05). The present study suggests that postconditioning of BNP could protect against myocardial I/R injury which may be associated with inhibiting HMGB1 expression, while PI3K/Akt signaling pathway may be involved in the expression of HMGB1 and the protective effect of BNP postconditioning.

WITHDRAWN: Effect of post space conditioning and luting resin on the retentive strength of fiber-reinforced composite resin posts

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Neuroprotective mechanism of ischemic postconditioning in mice: a possible relationship between protein kinase C and nitric oxide pathways

BackgroundThe present study was conducted to pharmacologically investigate the role of protein kinase C (PKC) pathway in neuroprotective mechanism of ischemic postconditioning (iPoCo) and determine the influence of nitric oxide (NO) signaling in PKC-mediated effects. Materials and methodsBilateral carotid artery occlusion of 12 min followed by reperfusion for 24 h was used to produce ischemia and reperfusion (I/R)–induced cerebral injury in male Swiss mice. Memory was assessed using Morris water maze test. Degree of motor incoordination was evaluated using inclined beam-walk test, rota-rod test, and lateral push test. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Brain acetylcholinesterase activity, thiobarbituric acid reactive species, nitrite/nitrate, and reduced glutathione levels were also estimated. ResultsBilateral carotid artery occlusion followed by reperfusion produced significant rise in cerebral infarct size, acetylcholinesterase activity, and thiobarbituric acid reactive species levels along with the fall in nitrite/nitrate and glutathione levels. A significant impairment of memory and motor coordination was also noted. iPoCo consisting of three episodes of 10 s carotid artery occlusion and reperfusion significantly attenuated infarct size, memory impairment, motor incoordination, and altered biochemicals. iPoCo-induced neuroprotective effects were significantly abolished by chelerythrine (a nonselective PKC inhibitor). l-Arginine, an NO precursor significantly attenuated I/R-induced injury and mimicked the neuroprotective effect of postconditioning. Furthermore, this protective effect of l-arginine on I/R injury and iPoCo was abolished when it was coadministered with chelerythrine. ConclusionsIt may be concluded that neuroprotective mechanism of iPoCo involves PKC mediated pathway with NO signaling as an essential step.

Up-regulation of hypoxia-inducible factor-1&amp;alpha; enhanced the cardioprotective effects of ischemic postconditioning in hyperlipidemic rats

Hyperlipidemia is an independent risk factor in the development of ischemic heart disease, which can increase myocardial susceptibility to ischemia/reperfusion (I/R) injury. Ischemic postconditioning (PostC) has now been demonstrated as a novel strategy to harness nature's protection against myocardial I/R injury in normal conditions. However, the effect of PostC on hyperlipidemic animals remains elusive. It has been shown in our previous study that PostC reduces the myocardial I/R injury, and hypoxia-inducible factor-1α (HIF-1α) may play an important role in the cardioprotective mechanisms of PostC on normal rats. Here, we tested the hypothesis that the cardioprotection of PostC on hyperlipidemic rats is associated with the up-regulated HIF-1α expression. Male Wistar rats were fed with a high-fat diet for 8 weeks, and then randomly divided into five groups: sham, I/R, dimethyloxalylglycine (DMOG) + I/R, PostC, and DMOG + PostC group. The detrimental indices induced by I/R injury included infarct size, plasma creatine kinase (CK) activity and caspase-3 activity. The results showed that PostC could reduce the infarct size, when compared with the I/R group, which was consistent with the significant lower levels of plasma CK activity and caspase-3 activity, and that it increased the expression of HIF-1α in hyperlipidemic rats. When DMOG was given before PostC to up-regulate HIF-1α protein level, the degree of I/R injury was attenuated. In conclusion, these data suggested that the up-regulation of HIF-1α may be one of the cardioprotective mechanisms of PostC against I/R injury in hyperlipidemic rats.

PI3K-Akt/eNOS in remote postconditioning induced by brief pulmonary ischemia

Postconditioning, a series of brief ischemia-reperfusion sequences given before an ischemic heart undergoes sustained reperfusion, has been shown to lessen ischemia/reperfusion injury. The current study establishes a rabbit model of myocardial ischemia-reperfusion and studied the effects of pulmonary remote postconditioning in this model. Serum levels of creatine kinase (CK), superoxide dismutase (SOD), and malondialdehyde (MDA), protein expression of endothelial nitric oxide synthase (eNOS), Rho kinase (ROCK- 2), and protein kinase B (Akt) in myocardial cells and the apoptosis index of myocardial cells were examined. Pulmonary remote postconditioning decreased CK, significantly decreased MDA, and increased SOD. Postconditioning significantly increased eNOS protein expression. Administration of eNOS inhibitor, L-NAME, dramatically suppressed the postconditioning-induced eNOS protein expression and serum SOD level, but significantly increased MDA level. The two longer sessions of postconditioning increased Akt, although this increase was not accompanied by changes in levels of the Akt inhibitor, ROCK-2. Blocking eNOS activity with L-NAME had no visible effect on either Akt or ROCK-2. Our results suggest a role for Akt in remote postconditioning-induced myocardial protection, but do not support an involvement of eNOS in Akt-mediated action.

Inhaled Isoflurane Sedation During Therapeutic Hypothermia After Cardiac Arrest

Therapeutic hypothermia in the ICU requires mechanical ventilation and sedation. Hypothermia reduces the metabolism of commonly used IV sedatives. The use of long-acting sedative agents may confound neurologic assessment. Volatile anesthetics have been reported to provide protection against ischemia-reperfusion injury and have been safely used in the ICU to provide sedation in trials with shorter wake-up times. There are no clinical studies in this setting. We describe a case series and discuss potential benefits. Retrospective study. Ten-bed ICU, university hospital. Twelve patients resuscitated from cardiac arrest with Glasgow Coma Scale score less than or equal to 4. Isoflurane sedation with the AnaConDa during 24 hours therapeutic hypothermia, until rewarming. Data were extracted from the computerized ICU chart/monitors, hospital and prehospital charts, and the national death index. Patients were 49-76 years old. Median return of spontaneous circulation was 14 minutes. Glasgow Coma Scale scores were assessed within 24 hours from reaching normal body temperature and compared with outcomes at 6 months: six patients had poor Glasgow Coma Scale scores (< 8) that remained low and all died before 6-month follow-up, whereas another six patients had high scores (> 8) and survived to 6 months with good Cerebral Performance Category. In the ICU, four of the survivors were directly extubated after rewarming while two were once more sedated due to pneumonia requiring invasive ventilator therapy. All patients required norepinephrine to maintain adequate mean arterial pressure. Isoflurane sedation was changed to midazolam in two nonsurviving patients because of hemodynamic instability, which persisted despite the change. Sedation with volatile anesthetics during therapeutic hypothermia may be a feasible short-acting option with potential postconditioning effects protecting vital organs from ischemia-reperfusion injury. Its measurability and insignificant drug accumulation could facilitate early neurologic assessment. Prospective clinical trials are warranted.

Autophagy Is Involved in the Cardioprotection Effect of Remote Limb Ischemic Postconditioning on Myocardial Ischemia/Reperfusion Injury in Normal Mice, but Not Diabetic Mice

BackgroundRecent animal study and clinical trial data suggested that remote limb ischemic postconditioning (RIPostC) can invoke potent cardioprotection. However, during ischemia reperfusion injury (IR), the effect and mechanism of RIPostC on myocardium in subjects with or without diabetes mellitus (DM) are poorly understood. Autophagy plays a crucial role in alleviating myocardial IR injury. The aim of this study was to determine the effect of RIPostC on mice myocardial IR injury model with or without DM, and investigate the role of autophagy in this process.Methodology and ResultsStreptozocin (STZ) induced DM mice model and myocardial IR model were established. Using a noninvasive technique, RIPostC was induced in normal mice (ND) and DM mice by three cycles of ischemia (5 min) and reperfusion (5 min) in the left hindlimb. In ND group, RIPostC significantly reduced infarct size (32.6±3.0% in ND-RIPostC vs. 50.6±2.4% in ND-IR, p<0.05) and improved cardiac ejection fraction (49.70±3.46% in ND-RIPostC vs. 31.30±3.95% in ND-IR, p<0.05). However, in DM group, no RIPostC mediated cardioprotetion effect was observed. To analyze the role of autophagy, western blot and immunohistochemistry was performed. Our data showed that a decreased sequestosome 1 (SQSTM1/p62) level, an increased Beclin-1 level, and higher ratio of LC3-II/LC3-I were observed in ND RIPostC group, but not DM RIPostC group.ConclusionsThe current study suggested that RIPostC exerts cardioprotection effect on IR in normal mice, but not DM mice, and this difference is via, at least in part, the up-regulation of autophagy.

Protection of liver as a remote organ after renal ischemia-reperfusion injury by renal ischemic postconditioning.

This study was designed to investigate the protective effects of local renal ischemic postconditioning (POC) on liver damage after renal ischemia-reperfusion (IR) injury. Male rats were divided into three groups (n = 8). They underwent a right nephrectomy before induction of 45 minutes of left kidney ischemia or sham operation. POC was performed by four cycles of 10 seconds of ischemia and 10 seconds of reperfusion just at the beginning of 24 hours of reperfusion. Then blood and liver samples were collected to measure serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and liver oxidative stress parameters including superoxide dismutase (SOD) activity and malondialdehyde (MDA) level. Renal IR caused a significant increase in liver functional indices as demonstrated by increased serum AST and ALT compared to sham group. These parameters reduced significantly in POC group compared to IR group. Liver MDA levels increased and SOD activity decreased in IR group compared to sham group. Induction of POC reduced the elevated liver MDA levels and increased the reduced liver SOD activity. These results revealed that renal IR injury causes liver damage as a remote organ and POC protects liver from renal IR injury by a modification in the hepatic oxidative stress status.

The Effects of Ischemic Postconditioning on Myocardial Function and Nitric Oxide Metabolites Following Ischemia-Reperfusion in Hyperthyroid Rats

Ischemic postconditioning (IPost) could decrease ischemia-reperfusion (IR) injury. It has not yet reported whether IPost is useful when ischemic heart disease is accompanied with co-morbidities like hyperthyroidism. The aim of this study was to examine the effect of IPost on myocardial IR injury in hyperthyroid male rats. Hyperthyroidism was induced with administration of thyroxine in drinking water (12 mg/L) over a period of 21 days. After thoracotomy, the hearts of control and hyperthyroid rats were perfused in the Langendorff apparatus and subjected to 30 minutes global ischemia, followed by 120 minutes reperfusion; IPost, intermittent early reperfusion, was induced instantly following ischemia. In control rats, IPost significantly improved the left ventricular developed pressure (LVDP) and ±dp/dt during reperfusion (p<0.05); however it had no effect in hyperthyroid rats. In addition, hyperthyroidism significantly increased basal NOx (nitrate+nitrite) content in serum (125.5±5.4 µmol/L vs. 102.8±3.7 µmol/L; p< 0.05) and heart (34.9±4.1 µmol/L vs. 19.9±1.94 µmol/L; p<0.05). In hyperthyroid groups, heart NOx concentration significantly increased after IR and IPost, whereas in the control groups, heart NOx were significantly higher after IR and lower after IPost (p< 0.05). IPost reduced infarct size (p<0.05) only in control groups. In hyperthyroid group subjected to IPost, aminoguanidine, an inducible nitric oxide (NO) inhibitor, significantly reduced both the infarct size and heart NOx concentrations. In conclusion, unlike normal rats, IPost cycles following reperfusion does not provide cardioprotection against IR injury in hyperthyroid rats; an effect that may be due to NO overproduction because it is restored by iNOS inhibition.

Effects of ischemic postconditioning on the hemodynamic parameters and heart nitric oxide levels of hypothyroid rats.

BackgroundIschemic postconditioning (IPost) is a method of protecting the heart against ischemia-reperfusion (IR) injury. However, the effectiveness of IPost in cases of ischemic heart disease accompanied by co-morbidities such as hypothyroidism remains unclear.ObjectiveThe aim of this study was to determine the effect of IPost on myocardial IR injury in hypothyroid male rats.MethodsPropylthiouracil in drinking water (500 mg/L) was administered to male rats for 21 days to induce hypothyroidism. The hearts from control and hypothyroid rats were perfused in a Langendorff apparatus and exposed to 30 min of global ischemia, followed by 120 min of reperfusion. IPost was induced immediately following ischemia.ResultsHypothyroidism and IPost significantly improved the left ventricular developed pressure (LVDP) and peak rates of positive and negative changes in left ventricular pressure (±dp/dt) during reperfusion in control rats (p < 0.05). However, IPost had no add-on effect on the recovery of LVDP and ±dp/dt in hypothyroid rats. Furthermore, hypothyroidism significantly decreased the basal NO metabolite (NOx) levels of the serum (72.5 ± 4.2 vs. 102.8 ± 3.7 μmol/L; p < 0.05) and heart (7.9 ± 1.6 vs. 18.8 ± 3.2 μmol/L; p < 0.05). Heart NOx concentration in the hypothyroid groups did not change after IR and IPost, whereas these were significantly (p < 0.05) higher and lower after IR and IPost, respectively, in the control groups.ConclusionHypothyroidism protects the heart from IR injury, which may be due to a decrease in basal nitric oxide (NO) levels in the serum and heart and a decrease in NO after IR. IPost did not decrease the NO level and did not provide further cardioprotection in the hypothyroid group.

Impaired intestinal mucosal barrier upon ischemia-reperfusion: "patching holes in the shield with a simple surgical method".

Mesenteric ischemia-reperfusion (IR) is associated with impairment of the gut barrier function and the initiation of a proinflammatory cascade with life-threatening results. Therefore methods directed to ameliorate IR injury are of great importance. We aimed at describing the effects of postconditioning (PC) on the alterations of the intestinal mucosal function and the inflammatory response upon mesenteric IR. Methods. Male Wistar rats were gavaged with green fluorescent protein-expressing E. coli suspensions. Animals were randomized into three groups (n = 15), sham-operated, IR-, and PC-groups, and underwent 60 minutes of superior mesenteric artery occlusion, followed by 6 hours of reperfusion. Postconditioning was performed at the onset of reperfusion. Blood and tissue samples were taken at the end of reperfusion, for histological, bacteriological, and plasma examinations. Results. The PC-group presented a more favorable claudin-2, claudin-3, claudin-4, and zonula occludens-1 membrane expression profile, and significantly lower rates of bacterial translocation to distant organs and plasma D-lactate levels compared to the IR-group. Histopathological lesions, plasma I-FABP, IL-6, and TNF-α levels were significantly lower in the PC-group compared to the IR-group. Conclusion. The use of postconditioning improved the integrity of the intestinal mucosal barrier upon mesenteric IR, and thus reduced the incidence of bacterial translocation and development of a systemic inflammatory response.

The Role of Receptor Transactivation in the Cardioprotective Effects of Preconditioning and Postconditioning

Analysis of published data indicates that the activity of receptors for adenosine, opioids, bradykinin, calcitonin-gene related peptides (CGRP) and epidermal growth factor (EGF) play important role in triggering the cardioprotective effects of ischemic preconditioning. Cannabinoids mimic the infarct-sparing effects of preconditioning. Endogenous adenosine, opioids, bradykinin and CGRP have also been implicated in infarct-reduction with ischemic postconditioning. Again, cannabinoids also mimic the protective effect of postconditioning. Recent works support heterodimerization of G-protein coupled receptors (GPCRs), and GPCR transactivation of EGF receptors. It was found that cross-talk between delta(j)-opioid receptors and adenosine A(1)-receptors is essential to cardiac protection. Furthermore, evidence implicates EGF receptor transactivation in cardioprotective effect of multiple GPCrs including adenosine, acetylcholine, bradykinin, and opioid receptors. Such findings support a convergent pathway in which multiple GPCRs may interact (or function independently) to transactivate EGF receptor-dependent kinase signaling and cytoprotection.

Effects of Sufentanil Postconditioning on Myocardial Ischemia-Reperfusion Injury in Rats &lt;i&gt;In Vivo&lt;/i&gt;

Objective.To investigates the effects of sufentanil post conditioning on Myocardial ischemia reperfusion injury in rats in vivo.Methods.To randomly divide 40 male SD rats equally into 4 groups, including Sham group, ischemia-reperfusion group (Group I/R ), ischemic post conditioning group (Group IPO) and sufentanil post conditioning group (Group SUF). The left anterior descending coronary arterys (LAD) of rats in 4 groups are ligated for 30 minutes and are re-perfused for 120 mins. To measure the myocardial infarction size (IS/AAR%) with double-staining with Even's blue and triphenyltetrazolium chloride, to calculate the concentration of cTnI, and to observe the HE staining and the expression of Bcl-2 and Bax.Result. Comparing with Group 1/R, the myocardial infarction size (IS/AAR%), and the concentration of cTnI in Group IPO and SUF all reduced significantly. Comparing with Group 1/R, cell morphological observation shows less change in pathology. And the expression of Bcl-2 increases and expression of Bax decreases in Group IPO and SUF than that in Group 1/R.Conclusion. Sufentanil post conditioning has protective effects on myocardial ischemia-reperfusion injury in rats in vivo.

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

Effects of hyperbaric oxygen postconditioning of microglia on activation in rats model of neuropathic pain

Objective To investigate the antinociceptive effect of hyperbaric oxygen(HBO) on activation of microglia in rats with neuropathic pain (NP) produced by chronic constriction injury of the sciatic nerve.Methods Twenty four healthy male Sprague-Dawley rats were randomly divided into four groups (n=6):Sham group (group S),CCI group (group C),2.0 ATA HBO post-conditioning group (group H2.0) and 2.5ATA HBO post-conditioning group (group H2.5).Group CCI,group H2.0 and group H2.5 were received the surgery of the chronic constriction injury.One day later,surgery HBO of 2.0 ATA and 2.5 ATA was given respectively by hyperbaric oxygen cabin once a day for seven days.The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) of rats in each group were measured respectively 1 h after the surgery every day.The rats were killed after 7 days when MWT and TWL had already been measured.The lumbar segment L4-5 of the spinal cord was removed.Immunohistochemical technique was used to detect the activation of microglias in the spinal cord.Results Compared with group S,MWT and TWL were significantly decreased and the activation of microglias in the spinal cord was significantly enhanced after surgery in group C(P＜0.05).Compared with group C,MWT and TWL were significantly increased and the activation of microglias in the spinal cord was significantly inhibited after surgery in group H2.0 and H2.5 (P＜0.05).There was no significant difference in the activation of spinal microglias between group H2.0 and H2.5.Conclusions HBO post-conditioning may produce the antinociceptive effect by inhibiting activation of spinal microglias in rats model of neuropathic pain. Key words: Hyperbaric oxygen; Neuropathic pain; Microglia; Antinociception

Myocardial Postconditioning Is Lost in Vascular Nitrate Tolerance

Organic nitrates play an important role in the therapy of ischemic heart disease; however, their clinical application is limited by the development of vascular nitrate tolerance. We have previously shown attenuation of the cardioprotective effect of preconditioning in vascular nitrate tolerance. Here, we studied whether the development of vascular nitrate tolerance affects the infarct size, limiting effect of ischemic postconditioning (IPost) in the myocardium, and whether the activation of survival kinases plays a role in the molecular mechanism of postconditioning in the presence or absence of vascular nitrate tolerance. Male Wistar rats were treated with nitroglycerin/vehicle for 3 days to induce vascular nitrate tolerance. On the fourth day, isolated hearts were subjected to 30-minute coronary occlusion followed by 120-minute reperfusion with or without IPost. In nontolerant hearts, postconditioning significantly decreased infarct size as compared with ischemia/reperfusion; however, postconditioning failed to decrease infarct size in hearts of nitrate tolerant rats. Phosphorylation of ERK 1/2, Akt, or endothelial nitric oxide synthetase showed no significant differences between the groups at the 10th minute of reperfusion. Vascular nitrate tolerance interferes with the infarct size limiting effect of IPost. Activation of survival kinases is not crucial in the molecular mechanism of postconditioning, which remains unaffected in nitrate tolerance.

Propofol Attenuates Cerebral Ischemia/Reperfusion Injury Partially Using Heme Oxygenase-1

To investigate the protective effects of propofol in brain ischemia/reperfusion injury and the role of heme oxygenase-1 (HO-1) in this process. Sprague-Dawley rats were randomly divided into 9 groups: sham-operated group; middle cerebral artery occlusion (MCAO) group; propofol 10, 20, and 50 mg/kg/h group (propofol 10, 20, 50 mg/kg/h infused at the onset of reperfusion for 30 min), ZnPPIX (a HO-1 activity inhibitor) group (ZnPPIX 20 μmol/kg administered 24 h before MCAO), and the other 3 groups received ZnPPIX followed by 10, 20, and 50 mg/kg/h propofol respectively. At 24 hours of reperfusion, neurological examinations were performed, and after neurological test, brain infarct size and volume, neuronal apoptosis, the level of HO-1 protein expression and HO-1 activity were observed in each group. Propofol significantly improved neurological deficits, reduced infarct volume, and attenuated neuron apoptosis compared with MCAO group alone. Increased HO-1 protein expression was observed in the ischemic penumbra and core of propofol group after transient MCAO. The selective HO-1 activity inhibitor, ZnPPIX, partially eliminated the neuroprotective effects of propofol. The neuroprotective effects of propofol postconditioning in brain ischemia/reperfusion injury may be partially through the induction of the HO-1 expression.

Morphofunctional Changes in Hippocampal Field CA1 in Mongolian Gerbils Using Ischemic Postconditioning

The aim of the present work was to study the effects of ischemic postconditioning (IPC) on neuron viability in hippocampal field CA1 and cytoplasmic lactate dehydrogenase (LDH) activity in these cells in 30 male Mongolian gerbils (Meriones unguiculatus). Ischemic brain damage was modeled by bilateral occlusion of the common carotid arteries for 7 min. IPC was produced using three episodes of reperfusion-ischemia, 15 sec/15 sec. Morphometric analysis and histoenzymological LDH assay in the cytoplasm of hippocampal field CA1 neurons were performed 48 h after reperfusion, with quantitative cytometric assessment of enzyme activity. The results showed that 7-min ischemia led to a decrease in the number of viable neurons (to 24%) and decreased their LDH activity (from 0.260 ± 0.009 to 0.190 ± 0.006 units). Use of IPC led to a significant increase in the number of viable hippocampal field CA1 neurons (to 52.9%, p < 0.01), which was accompanied by an increase in their LDH activity (to 0.240 ± 0.008 units, p < 0.001).

Neuroprotection of Ischemic Postconditioning by Downregulating the Postsynaptic Signaling Mediated by Kainate Receptors

Ischemic postconditioning, a brief episode of ischemia after a prolonged ischemic insult, has been found to reduce the delayed neuronal loss after stroke. However, the mechanisms underlying such endogenous neuroprotective strategy remain obscure. In this study, we try to explore the excitatory postsynaptic signal events associated with neuroprotective effect of ischemic postconditioning. Global cerebral ischemia was induced for 15 minutes by the 4-vessel occlusion method in male Sprague-Dawley rats. Ischemic postconditioning was conducted 10 minutes later by a single reocclusion for 3 minutes. A severe global cerebral ischemia after 5 days of reperfusion destroyed almost all hippocampal CA1 pyramidal neurons. A brief ischemic postconditioning robustly reduced the neuronal loss after ischemia. Preadministration of phosphoinositide 3-kinase inhibitor LY294002 blocked the neuroprotection of postconditioning, whereas mitogen-activated protein kinase kinase 1 inhibitor PD98059 had no effect. Ischemic postconditioning significantly increased the Akt phosphorylation (Ser473). In addition, postconditioning not only perturbed the binding of postsynaptic density protein-95 with glutamatergic kainate receptor subunit 2 and mixed lineage kinase 3 but also suppressed the downstream activation of mixed lineage kinase 3, mitogen-activated protein kinase kinase 7, and c-Jun N-terminal kinase 3. LY294002, but not PD98059, abolished the postconditioning-induced decreases in the assembly of glutamatergic kainate receptor subunit 2-postsynaptic density protein-95-mixed lineage kinase 3 complex and in the mixed lineage kinase 3-c-Jun N-terminal kinase 3 signaling. Akt inhibitor IV, a specific Akt inhibitor, showed the same effects as LY294002. Ischemic postconditioning protects neurons against stroke by attenuating the postsynaptic glutamatergic kainate receptor subunit 2-postsynaptic density protein-95-mixed lineage kinase 3-c-Jun N-terminal kinase 3 signal cascade via phosphoinositide 3-kinase-Akt pathway.