Insights into the role of PHLPP2/Akt/GSK3ß/Fyn kinase/Nrf2 trajectory in the reno-protective effect of rosuvastatin against colistin-induced acute kidney injury in rats.

OBJECTIVES: Oxidative stress-mediated colistin's nephrotoxicity is associated with the diminished activity of nuclear factor erythroid 2-related factor 2 (Nrf2) that is primarily correlated with cellular PH domain and leucine-rich repeat protein phosphatase (PHLPP2) levels. This study investigated the possible modulation of PHLPP2/protein kinase B (Akt) trajectory as a critical regulator of Nrf2 stability by rosuvastatin (RST) to guard against colistin-induced oxidative renal damage in rats. METHODS: Colistin (300,000 IU/kg/day; i.p.) was injected for 6 consecutive days, and rats were treated simultaneously with RST orally at 10 or 20 mg/kg. KEY FINDINGS: RST enhanced renal nuclear Nrf2 translocation as revealed by immunohistochemical staining to boost the renal antioxidants, superoxide dismutase (SOD) and reduced glutathione (GSH) along with a marked reduction in caspase-3. Accordingly, rats treated with RST showed significant restoration of normal renal function and histological features. On the molecular level, RST effectively decreased the mRNA expression of PHLPP2 to promote Akt phosphorylation. Consequently, it deactivated GSK-3ß and reduced the gene expression of Fyn kinase in renal tissues. CONCLUSIONS: RST could attenuate colistin-induced oxidative acute kidney injury via its suppressive effect on PHLPP2 to endorse Nrf2 activity through modulating Akt/GSK3 ß/Fyn kinase trajectory.

Modulation of miR-205/ EGLN2 by rosuvastatin mitigates colistin-induced nephrotoxicity in rats: Involvement of ATF4/ CHOP and Nrf2 pathways.

Although the beneficial role of microRNA has been investigated thoroughly, the reno-protective role of microRNA-205 (miR-205) against colistin-induced nephrotoxicity has not yet been tackled. Hence, our study sought to study the possible modulatory effect of rosuvastatin on miR-205 and its downstream target, Egl-9 family hypoxia-inducible factor 2 (EGLN2) to combat oxidative and endoplasmic reticulum (ER) stresses as pivotal contributors to colistin-associated renal injury. Rats were randomly divided into four groups; normal, colistin (300 000 IU/Kg/day; i.p), colistin pretreated with rosuvastatin (10 mg/kg; p.o) and colistin pretreated with rosuvastatin (20 mg/kg; p.o) for 6 successive days. Pretreatment with rosuvastatin attenuated renal injury induced by colistin and enhanced kidney function with a marked reduction in renal injury markers, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1. Besides, rosuvastatin upregulated renal miR-205 expression and suppressed gene expression of EGLN2. In addition, it downregulated ER stress-related genes (activation transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP)) along with caspases 12 and 3. It also induced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) as detected by immunohistochemical examination besides increased renal antioxidants, reduced glutathione, and superoxide dismutase. In conclusion, rosuvastatin triggered a series of protective mechanisms against colistin-induced nephrotoxicity through modulating miR-205 and EGLN2 expression. Rosuvastatin suppressed ATF4/ CHOP trajectory and activated the Nrf2 pathway to substantiate its antioxidant and anti-apoptotic capacities.

Molecular mechanisms involved in the effects of morin in experimental hepatic encephalopathy.

This study aimed to investigate the possible usefulness of morin flavonoid in comparison to silymarin as a hepatic/neuronal-supportive agent with similar effects and higher bioavailability in a rat model of hepatic encephalopathy (HE). Morin effects on rat liver and brain were evaluated post-induction of HE by thioacetamide (TAA; 200 mg/kg/day for 3 successive days). Then, the serum activities of aspartate transaminase (AST) and alanine transaminase (ALT) together with ammonia concentration were estimated to assess the liver function. Also, the degree of brain effects was evaluated via the assessment of brain contents of reduced glutathione (GSH), malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), and interleukin (IL-1ß) together with glutathione peroxidase (GPx) activity. In addition, the apoptotic and inflammatory changes in brain and liver tissues were also assessed via immunohistochemical examination. Our findings revealed a promising effect of morin against HE complications; as it corrected the liver functions, attenuated the brain/liver tissue injuries, and reduced the apoptotic and inflammatory insults of HE on both organs. These effects are comparable to those of silymarin. Morin could be introduced as a promising hepato- and neuro-therapeutic adjuvant in HE-associated neuronal complications especially in cases like silymarin intolerance.

Linagliptin attenuates thioacetamide-induced hepatic encephalopathy in rats: Modulation of C/EBP-ß and CX3CL1/Fractalkine, neuro-inflammation, oxidative stress and behavioral defects.

The degree of neuroinflammation is correlated mainly with cognitive and motor dysfunctions associated with hepatic encephalopathy (HE). The current study was conducted to explore the possible protective potential of the antidiabetic drug; linagliptin (LNG; 10 or 20 mg/kg) against HE induced by thioacetamide (TAA) in rats. Animals received two consecutive intraperitoneal injections of TAA (200 mg/kg) on alternate days. Neurobehavioral tests were performed 24 h after the last injection, and rats were sacrificed 24 h later (48 h). The higher LNG dose more effectively protected against TAA-induced changes. Administration of LNG for 15 days before TAA notably mitigated TAA-induced acute liver injury and HE, as verified by the marked improvement in motor coordination, locomotor activity, and cognition function. LNG maintained both brain and liver weight indices and retracted the hyperammonemia with a prominent suppression in liver transaminases. This was accompanied by an evident modulation of hepatic and hippocampal oxidative stress markers; GSH and MDA. LNG attenuated both liver and hippocampal pro-inflammatory cytokine; IL-1ß while augmented the anti-inflammatory one; IL-10. It noticeably reduced hepatic and hippocampal COX-2 and TNF-α and maintained hepatic and brain architectures. It also induced a marked decrease in the inflammation-regulated transcription factor, C/EBP-ß, with a profound increase in hippocampi's anti-inflammatory chemokine, CX3CL1/Fractalkine. LNG modulated TAA-induced disturbances in hippocampal amino acids; glutamate, and GABA with a significant increase in hippocampal BDNF. In conclusion, the regulatory effect of LNG on neuroinflammatory signaling underlines its neuroprotective effect against progressive encephalopathy accompanying acute liver injury.

Crosstalk Among NLRP3 Inflammasome, ETBR Signaling, and miRNAs in Stress-Induced Depression-Like Behavior: a Modulatory Role for SGLT2 Inhibitors.

Depression is an overwhelming health concern, and many patients fail to optimally respond to available standard therapies. Neuroplasticity and blood-brain barrier (BBB) integrity are the cornerstones of a well-functioning central nervous system, but they are vulnerable to an overly active NLRP3 inflammasome pathway that can also indirectly trigger the release of ET-1 and contribute to the ET system disturbance, which further damages stress resilience mechanisms. Here, the promising yet unexplored antidepressant potential of dapagliflozin (Dapa), a sodium-glucose co-transporter-2 inhibitor, was investigated by assessing its role in the modulation of the NLRP3 inflammasome pathway and ETBR signal transduction, and their impact on neuroplasticity and BBB integrity in an animal model of depression. Dapa (1 mg/kg/day; p.o.) with and without BQ-788 (1 mg/kg/day; i.p.), a specific ETBR blocker, were administered to adolescent male Wistar rats exposed to a 5-week chronic unpredictable stress protocol. The depressive animals demonstrated marked activation of the NLRP3 inflammasome pathway (NF-κB/NLRP3/caspase-1/IL/TNF-α), which was associated with both peripheral and central inflammatory responses. The ET system was disrupted, with noticeable reduction in miR-125a-5p and ETBR gene expression. Cortical ZO-1 expression was downregulated under the influence of NLRP3/TNF-α/miR-501-3p signaling, along with a prominent reduction in hippocampal BDNF and synapsin-1. With ETBR up-regulation being a cornerstone outcome, Dapa administration efficiently created an overall state of resilience, improved histopathological and behavioral variables, and preserved BBB function. These observations were further verified by the results obtained with BQ-788 co-administration. Thus, Dapa may exert its antidepressant action by reinforcing BBB integrity and promoting neuroplasticity through manipulation of the NLRP3/ET-1/ETBR/BDNF/ZO-1 axis, with a significant role for ETBR signaling. Graphical illustration for the proposed mechanisms of the anti-depressant potential of Dapa. Dapa suppressed NLRP3 inflammasome activation and assembly with subsequent inhibition of pro-inflammatory ILs. This results in attenuation of neuro-inflammation, BBB disruption, glial cell activation, TNF-α and ET-1 release, and the enhanced production of neurotrophins. The role of ETBR signaling was emphasized; Dapa possibly augmented ETBR expression, which is thought to boost neurotrophins production. The ETBR blocker, BQ-788, suppressed most of the positive outcomes of Dapa. Finally, miR-125a-5p and miR-501-3p that played major roles in these pathological pathways were modulated by Dapa. It is not yet clear whether Dapa has a direct or rather indirect effect on their expression. BBB, blood-brain barrier; Dapa, dapagliflozin; ET-1, endothelin-1; ETBR, endothelin B receptor; IL, interleukin; NF-κB, nuclear factor kappa B; NLRP3, nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3; TNF-α, tumor necrosis factor-α. Created with BioRender.com.

Regulation of liver regeneration by prostaglandin E2 and thromboxane A2 following partial hepatectomy in rats.

The implication of prostaglandin E2 (PGE2) and thromboxane A2 (TXA2) in the striking process of liver regeneration has been previously reported. However, their exact roles and downstream signals have not been utterly revealed. Therefore, the present study was conducted to explore whether inhibition of cyclooxygenase-2 (COX-2)-derived PGE2 by celecoxib and blocking of TXA2 action by seratrodast could alter the progression of liver regeneration after 70% partial hepatectomy (PHx) in rats. Celecoxib (20 mg/kg/day) and seratrodast (2 mg/kg/day) were given orally 1 h before PHx and then daily till the end of experiment (1, 3, or 7 days after the operation). Interestingly, celecoxib-treated rats showed a further increase in interleukin-6, p65 nuclear factor κB, and phosphorylated signal transducer and activator of transcription 3 as compared with PHx control rats. Furthermore, the liver contents of growth factors as well as ß-catenin and cyclin D1protein expressions were also enhanced by celecoxib. Accordingly, celecoxib significantly improved hepatic proliferation as indicated by the increase in Ki67 expression and liver index. Contrariwise, seratrodast hindered the normal regeneration process and completely abolished the proliferative effect of celecoxib. In conclusion, TXA2 has a major role in liver regeneration that could greatly mediate the triggering effect of celecoxib on hepatocytes proliferation following PHx.

Escitalopram Ameliorates Cardiomyopathy in Type 2 Diabetic Rats via Modulation of Receptor for Advanced Glycation End Products and Its Downstream Signaling Cascades.

Type 2 diabetes mellitus (T2DM) has been recognized as a known risk factor for cardiovascular diseases. Additionally, studies have shown the prevalence of depression among people with diabetes. Thus, the current study aimed to investigate the possible beneficial effects of escitalopram, a selective serotonin reuptake inhibitor, on metabolic changes and cardiac complications in type 2 diabetic rats. Diabetes was induced by feeding the rats high fat-high fructose diet (HFFD) for 8 weeks followed by a subdiabetogenic dose of streptozotocin (STZ) (35 mg/kg, i. p.). Treatment with escitalopram (10 mg/kg/day; p. o.) was then initiated for 4 weeks. At the end of the experiment, electrocardiography was performed and blood samples were collected for determination of glycemic and lipid profiles. Animals were then euthanized and heart samples were collected for biochemical and histopathological examinations. Escitalopram alleviated the HFFD/STZ-induced metabolic and cardiac derangements as evident by improvement of oxidative stress, inflammatory, fibrogenic and apoptotic markers in addition to hypertrophy and impaired conduction. These results could be secondary to its beneficial effects on the glycemic control and hence the reduction of receptor for advanced glycation end products content as revealed in the present study. In conclusion, escitalopram could be considered a favorable antidepressant medication in diabetic patients as it seems to positively impact the glycemic control in diabetes in addition to prevention of its associated cardiovascular complications.

Promising role of filgrastim and α-tocopherol succinate in amelioration of gastrointestinal acute radiation syndrome (GI-ARS) in mice.

The protective role of α-tocopherol succinate (α-TCS) and the therapeutic efficacy of filgrastim were investigated in gastrointestinal acute radiation syndrome (GI-ARS) induced following 10 Gy whole-body γ-irradiation. Mice were randomly allocated into 5 groups: [1] normal-control, [2] irradiated-control, [3] subcutaneous (s.c.) injection of filgrastim (5 µg/kg/day) for 4 consecutive days given 1 h post-irradiation, [4] s.c. injection with α-TCS (400 mg/kg) 1 day prior to irradiation, [5] s.c. injection with α-TCS (400 mg/kg) 1 day prior to irradiation and filgrastim (5 µg/kg/day) for 4 consecutive days 1 h post-irradiation. Histopathological analysis, serum citrulline level, intestinal interleukin-1ß (IL-1ß), reduced glutathione (GSH), and malondialdehyde (MDA) contents as well as myeloperoxidase (MPO) activity were measured. Intestinal caspase-3, p53, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) immunopositivity were examined. In irradiated-control, MDA increased (249%) and GSH decreased (25%) compared to normal and were unaffected by filgrastim. α-TCS alone significantly reduced MDA (84.5%) and normalized GSH. The combination significantly reduced MDA (59%) and dramatically increased GSH (1573%), pointing to a possible synergistic action. In irradiated-control, MPO and IL-1ß significantly increased (111% and 613%, respectively) compared to normal-control and both were significantly decreased in all treated groups. Compared to normal-control, citrulline significantly declined (68%) in irradiated-control; a significant elevation was achieved by treatments with α-TCS alone or combined with filgrastim (88% and 94%, respectively). The combination therapy significantly decreased the degree of irradiation-induced injury of the epithelium and cellular infiltration and showed the lowest histopathological scoring compared to the other groups (p ≤ 0.05). In irradiated-control, immune-reactive expressions of iNOS, COX-2, caspase-3, and p53 were remarkable (18.62%, 34.27%, 31.19%, and 27.44%, respectively) and after combination therapy were reduced (1.04%, 22.39%, 8.76%, and 4.91%, respectively). The current findings represent a first-hand strategy in dealing with GI-ARS with a potential preference to using a combined therapy of filgrastim and α-TCS.

Chrysin attenuates global cerebral ischemic reperfusion injury via suppression of oxidative stress, inflammation and apoptosis.

Global cerebral ischemia is a leading cause of mortality worldwide. Several biomechanisms play a role in the pathology of cerebral ischemia reperfusion damage, such as oxidative stress, inflammation, apoptosis and excitotoxicity. Chrysin, a natural flavonoid with many important biological activities, was investigated in the present study for its possible neuroprotective properties in a rat model of global ischemia reperfusion. Male Wistar rats were allocated into three groups: sham-operated, ischemia/reperfusion, and chrysin (30 mg/kg) groups. All animals were subjected to ischemia for 15 min followed by reperfusion for 60 min, except for the sham-operated group. Rats were decapitated, then both hippocampi were rapidly excised to evaluate several biomarkers that reflect ischemic injury. The obtained results showed that pre-treatment with chrysin attenuated ischemia-induced oxidative stress by: (i) restoring the glutathione level; and (ii) depressing the levels/activities of thiobarbituric acid reactive substances, the hippocampal NADPH, as well as the xanthine oxidase. Exposure to chrysin also suppressed the inflammation accompanying the ischemia/reperfusion (I/R) damage, through increasing the interleukin-10 level, while decreasing the levels of both interleukin-6 and tumour necrosis factor-alpha. Moreover, an increase in Bcl2 and a decrease in both BAX and Hsp90 levels were recorded following chrysin exposure, which was also accompanied with elevated glutamate and aspartate levels. In conclusion, chrysin has demonstrated an anti-ischemic potential, through attenuation of the mechanisms underlying I/R injury. These data add to the knowledge on the significance of natural flavonoids as neuroprotective agents.

Neuroprotective effects of pioglitazone against transient cerebral ischemic reperfusion injury in diabetic rats: Modulation of antioxidant, anti-inflammatory, and anti-apoptotic biomarkers.

BACKGROUND: Recent growing consensus introduced thiazolidinediones, agonists of the nuclear receptor peroxisome proliferator-activated receptor gamma as promising candidates in the management of ischemia in various organs. Thereby, interest was raised to investigate the neuroprotective effects of pioglitazone against transient ischemia/reperfusion (I/R) injury in diabetic rats targeting mainly the oxidative-inflammatory-apoptotic cascades which are involved in this insult. METHODS: Forebrain ischemia was induced in streptozotocin-diabetic rats by occlusion of the bilateral common carotid arteries for 15min followed by 1h reperfusion. Pioglitazone (10mg/kg; po) was administered daily for 2 weeks prior to I/R. RESULTS: The drug alleviated hippocampal injury inflicted by diabetes and/or I/R injury where it suppressed nuclear factor kappa (NFκB), and consequently the downstream inflammatory cytokines tumor necrosis factor-α and interleukin-6. In parallel, the anti-inflammatory cytokine interleukin-10 was elevated. Antioxidant potential of pioglitazone was depicted, where it reduced neutrophil infiltration, lipid peroxides, nitric oxide associated with replenished reduced glutathione. Decline of excitatory amino acid glutamate content is a main finding which is probably mediated by the NFκB signaling pathway as well as improved oxidant status. Pioglitazone exerted an anti-apoptotic effect as reflected by the reduction of the cytosolic cytochrome c and the key downstream executioner caspase-3. CONCLUSIONS: Pioglitazone is endowed with neuroprotective properties which are probably mediated by its antioxidant, anti-inflammatory, and anti-apoptotic mechanisms hence may provide a successful agent for the management of ischemic stroke.

Pretreatment with magnesium ameliorates lipopolysaccharide-induced liver injury in mice.

BACKGROUND: Lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria, is involved in the pathogenesis of sepsis. LPS administration induces systemic inflammation that mimics many of the initial clinical features of sepsis and has deleterious effects on several organs including the liver and eventually leading to septic shock and death. The present study aimed to investigate the protective effect of magnesium (Mg), a well known cofactor in many enzymatic reactions and a critical component of the antioxidant system, on hepatic damage associated with LPS-induced endotoxima in mice. METHODS: Mg (20 and 40mg/kg, po) was administered for 7 consecutive days. Systemic inflammation was induced 1h after the last dose of Mg by a single dose of LPS (2mg/kg, ip) and 3h thereafter plasma was separated, animals were sacrificed and their livers were isolated. RESULTS: LPS-treated mice suffered from hepatic dysfunction revealed by histological observation, elevation in plasma transaminases activities, C-reactive protein content and caspase-3, a critical marker of apoptosis. Liver inflammation was evident by elevation in liver cytokines contents (TNF-α and IL-10) and MPO activity. Additionally, oxidative stress was manifested by increased liver lipoperoxidation, glutathione depletion, elevated total nitrate/nitrite (NOx) content and glutathione peroxidase (GPx) activity. Pretreatment with Mg largely mitigated these alternations. CONCLUSION: Pretreatment with Mg protects the liver from the acute injury which occurs shortly after septicemia.

Sitagliptin attenuates transient cerebral ischemia/reperfusion injury in diabetic rats: implication of the oxidative-inflammatory-apoptotic pathway.

AIMS: Ischemic stroke is a major macrovascular complication of diabetes mellitus. Sitagliptin, a dipeptidyl peptidase-IV inhibitor, was recently shown to improve cognitive functions in diabetic rats; hence the present study was conducted to evaluate its protective effect against transient ischemia-reperfusion (I/R) in diabetic animals. MAIN METHODS: Diabetes was induced by streptozotocin (40 mg/kg). Six weeks later, cerebral I/R was induced by bicommon carotid occlusion for 15 min followed by 1h reperfusion. Sitagliptin (250 mg/kg; p.o.) was administered daily during the last 2 weeks before I/R. KEY FINDINGS: The drug alleviated hippocampal injury inflicted by diabetes and/or I/R injury where it suppressed nuclear factor kappa (NF-κ)B, and consequently the downstream inflammatory cytokines tumor necrosis factor-α and interleukin-6. In parallel, the anti-inflammatory cytokine interleukin-10 was elevated. Antioxidant potential of sitagliptin was depicted, where it reduced neutrophil infiltration, lipid peroxides and nitric oxide associated with replenished reduced glutathione. Decline of excitatory amino acid glutamate content is a main finding which is probably mediated by the NF-κB signaling pathway as well as improved oxidant status. Sitagliptin exerted an anti-apoptotic effect as reflected by the reduction of the mitochondrial matrix component cytochrome -C and the key downstream executioner caspase-3. Histopathological examination corroborated the biochemical data. SIGNIFICANCE: These findings suggest that sitagliptin is endowed with neuroprotective properties which are probably mediated by its antioxidant, anti-inflammatory, and anti-apoptotic mechanisms and hence may provide a novel agent for the management of ischemic stroke in diabetics.

Pinocembrin attenuates hippocampal inflammation, oxidative perturbations and apoptosis in a rat model of global cerebral ischemia reperfusion.

BACKGROUND: Pinocembrin is a major flavonoid molecule isolated from honey and propolis. It has versatile pharmacological and biological activities including antimicrobial, anti-inflammatory, antioxidant, and anticancer activities as well as neuroprotective effects against cerebral ischemic injury. The purpose of the current study was to determine the possible mechanisms of neuroprotection elicited by pinocembrin with specific emphasis on chronic prophylactic use before the induction of global cerebral ischemia reperfusion. METHODS: Global cerebral ischemia-reperfusion (I/R) was induced by bilateral carotid artery occlusion for 15min followed by 60min reperfusion period. Animals were randomly allocated into 3 groups (n=28): Sham operated, I/R control and rats treated with pinocembrin (10mg/kg, po) daily for 7 days then I/R was induced 1h after the last dose of pinocembrin. After reperfusion rats were killed by decapitation, brains were removed and both hippocampi separated and the following biochemical parameters were estimated; lactate dehydrogenase activity, oxidative stress markers (lipid peroxides, nitric oxide and reduced glutathione), inflammatory markers (myeloperoxidase, tumor necrosis factor-alpha, nuclear factor kappa-B, interleukin-6 and interleukin-10), apoptotic biomarkers (caspase 3 and cytochrome C), neurotransmitters (glutamate, gamma aminobutyric acid) and infarct size were assessed. RESULTS: Pinocembrin ameliorated damage induced by I/R through suppressing oxidative stress, inflammatory and apoptotic markers as well as mitigating glutamate and lactate dehydrogenase activity. One of the more significant findings to emerge from this study is that pinocembrin normalized the infarct size elevated by I/R. CONCLUSIONS: Pinocembrin showed a neuroprotective effects through antioxidant, anti-inflammatory and antiapoptotic mechanisms.

Cardioprotective effects of ozone oxidative preconditioning in an in vivo model of ischemia/reperfusion injury in rats.

BACKGROUND: Several studies have demonstrated the beneficial effects of ozone oxidative preconditioning in several pathologies characterized by cellular oxidative and inflammatory burden. The present study was designed to investigate the cardioprotective effects of oxidative preconditioning in ischemia/reperfusion (I/R) injury. METHODS: Rats were randomly assigned into five groups. Groups 1 and 2 were normal and I/R groups, respectively. Two of the other groups received two different doses of ozone therapies by rectal insufflations. The last group received vehicle (oxygen). Rats were subjected to myocardial I/R (40 min/10 min). Heart rate and ventricular arrhythmias were recorded during I/R progress. At the end of reperfusion, plasma creatine kinase-MB (CK-MB) activity and total nitrate/nitrite (NO(x)) were determined. In addition, lactate, adenine nucleotides, thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and myeloperoxidase (MPO) activity were estimated in the heart left ventricle. Histological examination was also performed to visualize the protective cellular effects. RESULTS: Both doses of ozone therapy were equally protective in reducing CK-MB release. However, the higher dose was more effective in reducing oxidative stress, lactate accumulation, elevated MPO activity and plasma NO(x) as well as preserving myocardial adenine nucleotides. Histological examination also revealed better improvement with a higher dose of ozone therapy compared to the I/R group. CONCLUSION: Ozone therapy can afford significant cardioprotection against biochemical and histological changes associated with I/R injury.

Comparative study of the cardioprotective effects of local and remote preconditioning in ischemia/reperfusion injury.

AIMS: Though the cardioprotective effects of local or remote preconditioning have been estimated, it is still unclear which of them is more reliable and provides more cardioprotection. The present investigation was directed to compare, in one study, the cardioprotective effects of different cycles of local or remote preconditioning in ischemia/reperfusion (I/R)-induced electrophysiological, biochemical and histological changes in rats. MAIN METHODS: Rats were randomly assigned into 10 groups. Groups 1 and 2 were normal and I/R groups, respectively. Other groups were subjected to 1, 2, 3, 4 cycles of local or remote preconditioning before myocardial I/R (40 min/10 min). Heart rate and ventricular arrhythmias were recorded during I/R progress. At the end of reperfusion, plasma creatine kinase-MB (CK-MB) activity and total nitrate/nitrite (NO(x)) were determined. In addition, lactate, adenine nucleotides, thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and myeloperoxidase (MPO) activity were estimated in the heart left ventricle. Histological examination was also performed to visualize the protective cellular effects of the effective cycle of local or remote preconditioning. KEY FINDINGS: In general, local preconditioning was more effective than remote preconditioning in reducing ventricular arrhythmias, CK-MB release, lactate accumulation and elevated MPO activity as well as preserving adenine nucleotides. Concerning the most effective group in each therapy, 3 cycles of local preconditioning provided more cardioprotection than that of remote preconditioning in the histological examination. SIGNIFICANCE: Despite being invasive, local preconditioning provided more effective cardioprotection than remote preconditioning in ameliorating the overall electrophysiological, biochemical and histological changes.

Pharmacological preconditioning with nicorandil and pioglitazone attenuates myocardial ischemia/reperfusion injury in rats.

The present investigation was designed to study the cardioprotective effects of nicorandil and pioglitazone preconditioning in myocardial ischemia/reperfusion-induced hemodynamic, biochemical and histological changes in rats. Oral doses of nicorandil (3 or 6 mg/kg) and pioglitazone (10 or 20mg/kg) were administered once daily for 5 consecutive days. Rats were then subjected to myocardial ischemia/reperfusion (40 min/10 min). Heart rate and ventricular arrhythmias were recorded during ischemia/reperfusion progress. At the end of reperfusion, plasma creatine kinase-MB activity and total nitrate/nitrite were determined. In addition, lactate, adenine nucleotides, thiobarbituric acid reactive substances, reduced glutathione and myeloperoxidase activity were estimated in the heart left ventricle. Finally, histological examination was performed to visualize the protective cellular effects of different pretreatments. Nicorandil (3 or 6 mg/kg) was effective in attenuating the ischemia/reperfusion-induced ventricular arrhythmias, creatine kinase-MB release, lactate accumulation and oxidative stress. Nicorandil (3 mg/kg) was more effective in improving the energy production and lowering the elevated myeloperoxidase activity. Both doses of pioglitazone (10 or 20 mg/kg) were equally effective in reducing lactate accumulation and completely counteracting the oxidative stress. Pioglitazone (10 mg/kg) was more effective in improving energy production and reducing ventricular arrhythmias, plasma creatine kinase-MB release and total nitrate/nitrite. It seems that selective mitochondrial K(ATP) channel opening by lower doses of nicorandil and pioglitazone in the present study provided more cardioprotection against ventricular arrhythmias and biochemical changes induced by ischemia/reperfusion. Histological examination revealed also better improvement by the lower dose of nicorandil than that of pioglitazone.

Enhancement of amlodipine cardioprotection by quercetin in ischaemia/reperfusion injury in rats.

OBJECTIVES: To investigate the possible modification of the cardioprotective effect of amlodipine when co-administered with quercetin in myocardial ischaemia/reperfusion-induced functional, metabolic and cellular alterations in rats. METHODS: Oral doses of amlodipine (15 mg/kg) and quercetin (5 mg/kg), alone or in combination, were administered once daily for 1 week. Rats were then subjected to myocardial ischaemia/reperfusion (35(min)/10(min)). Heart rates and ventricular arrhythmias were recorded during ischaemia/reperfusion progress. At the end of reperfusion, activities of plasma creatine kinase (CK) and cardiac myeloperoxidase were determined. In addition, cardiac contents of lactate, ATP, thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and total nitrate/nitrite (NO(x)) were estimated. Finally, histological examination was performed to visualize the protective cellular effects of different pretreatments. KEY FINDINGS: Combined therapy provided significant improvement in the amlodipine effect toward preserving cardiac electrophysiologic functions, ATP and GSH contents as well as reducing the elevated plasma CK, cardiac TBARS and NO(x) contents. CONCLUSION: Quercetin could add benefits to the cardioprotective effect of amlodipine against injury induced in the heart by ischaemia/reperfusion.

Hypericum perforatum extract demonstrates antioxidant properties against elevated rat brain oxidative status induced by amnestic dose of scopolamine.

This study was designed to investigate if the impairment of learning and memory induced by acute administration of scopolamine (1.4 mg/kg ip) in rats is associated with altered brain oxidative stress status. The passive avoidance paradigm was used to assess retrieval memory of rats after scopolamine treatment. Following retrieval testing, biochemical assessments of malondialdehyde (MDA), glutathione peroxidase (GSHPx), glutathione (GSH), and superoxide dismutase (SOD) levels/activities as oxidative stress indices were performed. This study also investigated the effect of acute administration of Hypericum perforatum extract (4.0, 8.0, 12.0, and 25.0 mg/kg ip), containing flavonoids with documented antioxidant activity, on brain oxidative status of nai;ve rats treated with amnestic dose of scopolamine. Results showed that administration of 1.4 mg/kg of scopolamine impaired retrieval memory of rats and that such amnesia was associated with elevated MDA and reduced GSH brain levels. In nai;ve rats, which have not been exposed to conditioned fear, scopolamine administration also increased MDA and reduced GSH levels, although with an increase in brain GSHPx activity. Pretreatment of the animals with Hypericum extract (4, 8, and 12 mg/kg) resulted in an antioxidant effect through altering brain MDA, GSHPx, and/or GSH level/activity. Since oxidative stress is implicated in the pathophysiology of dementia, the findings of this study may substantiate the value of scopolamine-induced amnesia in rats as a valid animal model to screen for drugs with potential therapeutic benefit in dementia. Exposure of animals to conditioned fear may be suggested to impair the balance between the rate of lipid peroxidation and the activation of GSHPx as a compensatory antioxidant protective mechanism. It is also concluded that low doses of Hypericum extract, demonstrating antioxidant activity, may be of value for demented patients exhibiting elevated brain oxidative status. Since depression commonly coexists with dementia, Hypericum extract as a drug with documented antidepressant action may also be a better alternative than several other antidepressant medications that have not been evaluated to test their effect on brain oxidative status during amnesia.