Anti-ischemic Effects Research Articles

Evaluating the possible role of mitochondrial ATP-sensitive potassium channels in the cardioprotective effects of morin in the isolated rat heart

AimsDuring heart ischemia, the lack of oxygen in the myocardial cells causes pH and ion disturbances and cell death through opening mitochondrial permeability transition pores (mPTP). Considering the inhibitory effects of mitochondrial ATP-dependent potassium channels (mt-KATP) on these pores and anti-ischemic effects of morin, we hypothesized that it may exert its positive effects via activating mt-KATP as well as its anti-oxidative effects. Main methodsIsolated rat hearts were perfused by Krebs-Henseleit solution enriched with the morin (0.25, 0.5 and 1 mg/L) or 5-hydroxydecanoate (5-HD, a mt-KATP blocker;100 μM) or both as needed 5 min before starting regional ischemia till the first 10 min of the reperfusion period. The reperfusion was developed with Krebs-Henseleit solution 60 or 120 min respectively for biochemical evaluations (lactate dehydrogenase and malondialdehyde level) or the assessment of myocardial infarct size. During the experiments, hemodynamic functions were recorded and cardiac arrhythmias were determined. Key findingsOur findings demonstrated that morin reduced the infarct size. Also, morin perfusion could remarkably prevent the malondialdehyde over-production during ischemia. Total ventricular ectopic beats had the same significant changes as the malondialdehyde level, in both ischemia and reperfusion phases. Morin could also relatively improve the ischemia-induced hemodynamic dysfunction. All mentioned protective effects of morin were reversed by concomitant perfusion of 5-HD. SignificanceMorin has protective effects against ischemic hearts through anti-oxidative effects. It also suggests a link between the cardioprotective effects of morin and mt-KATP. However, additional studies are required to prove this preliminary hypothesis.

Infusion therapy in treatment of patients with acute coronary syndrome

Objective. Introduction to the basic therapy of patients with acute coronary syndrome (ACS) without ST-segment elevation cardioprotective drug Tivorel (“Yuria-Pharm”) based on L-arginine and L-carnitine.
 Materials and methods. The present study was carried out in accordance with the requirements for clinical trials of drugs in the Department of Emergency Cardiology of the RSCEMPSF. Patients were admitted to the intensive care unit with a diagnosis of ACS without ST-segment elevation in the first 12 h after the onset of the disease. The study was carried out in two groups and included the following stages: screening and treatment period (10 days). The study involved 90 patients with ACS without ST segment elevation, who were allocated for treatment in the study and control groups in a 1:1 ratio. Patients of the study group, except for basic therapy (sublingual nitroglycerin, acetylsalicylic acid or clopidogrel, analgesics, β-adrenergic blockers or angiotensin-converting enzyme inhibitors), received the drug Tivorel 100 ml intravenously at a rate of 10 drops per minute for the first 10-15 min (then the rate of administration could be increased to 30 drops per minute) 1 time per day within 10 days. Control group patients were prescribed only basic therapy. Determination of markers of myocardial necrosis (troponin T), electrocardiography (ECG), echocardiography. Compulsory calculation of end-diastolic and end-systolic indices, left ventricular ejection fraction were performed.
 Results and discussion. It was found that the drug Tivorel, prescribed as part of complex therapy immediately after admission of patients to the hospital, improves the electrophysiological properties of the myocardium and prevents the appearance of temporary ECG disturbances, stabilizes the condition of patients. In patients of the main group, already in the first day after the development of acute myocardial infarction (AMI), late ventricular potentials were less often recorded, markers of the so-called arrhythmogenic substrate – 9.5 % compared to 18.7 % in patients in the control group. In the course of further observation, the prostate gland in the control group disappeared, and during treatment with Tivorel, it did not appear anymore. This suggests the presence of a pronounced anti-ischemic effect of the drug, which is also confirmed by clinical data. We have noted a reliably expressed positive dynamics of changes in the end part of the ventricular complex under the influence of therapy with Tivorel. Analysis of standard ECG and 24-hour monitoring data in a number of patients revealed rhythm disturbances. There were no significant differences between the groups in the frequency of occurrence of all manifestations of arrhythmic syndrome, both initially and after therapy, however, in the main group, during treatment, the number of cases of ventricular arrhythmias in the form of group ventricular extrasystole and ventricular tachycardia bursts significantly decreased. During the period of inpatient treatment, all patients showed positive clinical dynamics: a decrease in the frequency and severity of angina attacks, a decrease and stabilization of blood pressure, an increase in exercise tolerance. Already on the third day of treatment with the use of the study drug Tivorel, relapses of anginal pain occurred less frequently (21.9 % of cases in the main group and 33.0 % in the control group). At the same time, there was a decrease in the need for the use of nitroglycerin and narcotic analgesics in order to relieve recurrent pain syndrome (23.1 % and 35.3 % of cases, respectively). In addition, on the third day after the development of AMI in patients of the main compared with the control, a lower incidence of atrioventricular blockade was recorded (4.3 % and 13.6 %, respectively). In the course of the analysis of the entire hospital period, it was found that in patients receiving Tivorel, atrioventricular blockades occurred almost 3 times less often than in the control group. The frequency of registration of ventricular extrasystole decreased on the 7th (34.1 %) and 10th days (45.7 %) of the disease.
 Conclusions. The use of the drug Tivorel (“Yuria-Pharm”) in addition to basic therapy helps to optimize the management of ACS patients without ST-segment elevation. With complex treatment with the use of the drug Tivorel, a faster regression of clinical manifestations of ACS is observed. The use of Tivorel in ACS therapy without ST-segment elevation stabilizes the patient’s condition and reduces the incidence of complications.

Исследование нового производного оксима дибензофурана ГИЖ-272 на моделях очаговой эпилепсии и интрацеребральной посттравматической гематомы

Установлено, что новое производное оксима дибензофурана ГИЖ-272 (40 мг/кг) обладает отчетливой противосудорожной активностью на хронической модели парциальной (фокальной) эпилепсии, индуцированной кобальтом у крыс, ослабляя первично- и вторично-генерализованные очаги эпилептической активности как на этапе формирования, так и стабилизации эпилептической системы. Структурными мишенями действия ГИЖ-272 на этапе формирования эпилептической системы являются очаги в гиппокампе и гипоталамусе, а на стадии стабилизации — очаги в гиппокампе. ГИЖ-272 (10 мг/кг) обладает выраженным противоишемическим эффектом на модели интрацеребральной посттравматической гематомы, повышая выживание животных и ослабляя неврологический, моторный и когнитивный дефициты.

Analysis of the Cerebrovascular Effect of a Dibenzofuran Oxime Derivative

The cerebrovascular properties of 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one O-(4-cinnamoyl)oxime (C21H21NO3, GIZ-272) were studied. The ability of GIZ-272 to improve the brain blood supply in rats subjected to global transient ischemia and to a lesser extent in animals with a hemorrhagic stroke model was established. The compound had cerebrovascular anti-ischemic activity comparable to that of Mexidol and a duration of action longer than that of nimodipine. It is important to note that GIZ-272 did not cause a decrease in blood pressure and was superior to both Mexidol and nimodipine in this respect. An analysis of the cerebrovascular effect of GIZ-272 using bicucullin indicated that the GABA-ergic system of cerebral vessels participated in implementation of the anti-ischemic effect of the compound.

A succinyl isoflavone identified in natto promotes anti-ischemic effects in the middle cerebral artery occlusion rats

Abstract 6″-O-Succinyldaidzin is a daidzin derivative in natto with little bioactivity reports. We investigated the anti-ischemic effects and underlying mechanisms of 6″-O-Succinyldaidzin in MCAO model and used MRI to measure the infarct volume, and neurological scores to evaluate the effect of the injury after occlusion for 2 h and reperfusion for 24 h on male rats. Levels of Nrf2, Keap1, HO-1, ERK were measured by immunoblots to study the underlying mechanisms of 6″-O-Succinyldaidzin activity. Further, we confirmed our results in HT-22 cells using immunofluorescence to assay for the expression of Nrf2 and Keap1. 6″-O-Succinyldaidzin reduced both infarct areas and neurological scores of MCAO rats. Levels of ERK, HO-1, and nuclear-Nrf2 were upregulated after the administration of 6″-O-Succinyldaidzin. Immunofluorescence assays indicated that Nrf2 expressed in the nucleus while Keap1 remained in the cytoplasm after treatment with 6″-O-Succinyldaidzin. Our study shows that 6″-O-Succinyldaidzin of natto elicits an anti-ischemic effect and activates Nrf2-related antioxidant.

Anti-ischemic and antiarrhythmic activity of dibornol in conditions of multiple transitory myocardial ischemia in rats

Aim. To investigate anti-ischemic and antiarrhythmic activity of Dibornol in conditions of multiple transitory ischemia of myocardium from in vivo experiments with rats. Material and Methods. The experiment was performed on male Wistar rats with a model of myocardial ischemia caused by 5-time 3-minute occlusions of the left coronary artery, followed by 15-minute reperfusion periods. Rats of the experimental group received Dibornol 10 mg/kg intragastrically once for 4 days; control animals received an equivalent volume of 1% starch mucus. On the ECG, the magnitudes of the ST segment elevation were determined for minutes 1, 2, and 3 of each episode of ischemia and for minutes 5, 10, and 15 of reperfusion; the nature and duration of ventricular arrhythmias were determined as well. Results. In the control group, the ST segment was elevated during all five episodes of ischemia. During reperfusion periods, a decrease in the elevation of the ST segment was detected, but no normalization occurred. Ischemic and reperfusionrelated ventricular arrhythmias were observed in the rats of the control group. Mortality in the control group reached 67% (6 animals out of 9). In the experimental group, in animals receiving Dibornol at a dose of 10 mg/kg, the occlusion of the left coronary artery was associated only with a slight elevation of the ST segment and its rapid recovery during reperfusion. Magnitudes of the ST segment elevation were significantly lower than the corresponding control values during all the episodes of ischemia. During reperfusion periods, the differences with the control group were more significant during the first to fourth periods and at minute 15 of the fifth reperfusion period. The death rate in the experimental group (1 animal out of 9) was significantly lower relative to the corresponding value in the control group. Conclusion. The course preventive use of Dibornol in multiple myocardial ischemia/reperfusion had significant anti-ischemic and antiarrhythmic effects during reperfusion periods and significantly increased the survival rate in animal models.

Expert Council Resolution. Practical Aspects of the Diagnosis and Correction of Potassium and Magnesium Deficiency States

The article analyzes properties of potassium and magnesium, which may exert vasodilatory, anti-inflammatory, anti-ischemic, antiaggregant, and antiarrhythmic effects. These are extremely important microelements and potentially beneficial therapeutic agents for treatment of cardiovascular diseases.

Polydeoxyribonucleotide Exerts Therapeutic Effect by Increasing VEGF and Inhibiting Inflammatory Cytokines in Ischemic Colitis Rats.

Ischemic colitis is resulted from an inadequate blood supply to a segment or entire colon. Polydeoxyribonucleotide (PDRN), extracted from salmon sperm, has been reported to exert anti-inflammatory and anti-ischemic effects through the adenosine A2A receptor (A2AR). We investigated whether PDRN possesses therapeutic effectiveness on ischemic colitis rats. Ischemic colitis was induced by selective devascularization. The skin temperature on the ischemic colitis-induced region was determined. To assess the colonic damage score and collagen deposition, colonic tissue sections were stained with hematoxylin and eosin (H&E), and Masson trichrome staining was performed. Western blot analysis for A2AR, vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6, Bax, Bcl-2, and extracellular signal-regulated kinase 1/2 (ERK1/2) was performed. Skin temperature was increased and mucosal damage and collagen deposition were observed in the affected colonic tissues in the ischemic colitis rats. Expressions of inflammatory cytokines (TNF-α, IL-1β, and IL-6) and inflammatory mediator (COX-2) were upregulated in the ischemic colitis rats. Apoptosis was increased by decreasing the ratio of Bcl-2 to Bax and by suppressing the phosphorylated form of ERK1/2 expression in the ischemic colitis rats. Treatment with PDRN alleviated mucosal damage reduced the expressions of inflammatory cytokines and COX-2 and inhibited apoptosis in the ischemic colitis rats. PDRN treatment more enhanced the expressions of A2AR and VEGF in the ischemic colitis rats. PDRN showed therapeutic effectiveness on ischemic colitis by increasing VEGF expression and inhibiting inflammatory cytokines and COX-2 through enhancing A2AR expression.

Dry Fasting Physiology: Responses to Hypovolemia and Hypertonicity

Objective: The aim of this study was to provide a deeper insight into dry fasting (DF) physiology. Design: Ten participants performed DF for 5 consecutive days. Methods: The following parameters were monitored daily: cortisol, aldosterone, high-sensitivity C-reactive protein (CRP), erythropoietin, albumin, uric acid, and vitamin C in serum; vasopressin (ADH), adrenocorticotropic hormone (ACTH), renin, angiotensin II, and total antioxidant capacity (TAC) in plasma; hematocrit and erythrocytes in whole blood; osmolality, noradrenaline, dopamine, adrenaline, Na⁺, and K⁺ in 24-h urine; waist circumference and body, urine, and stool weight. Results: The following parameters increased: ADH (60 ± 11%), ACTH (176 ± 34%), cortisol (495 ± 75%), urine osmolality (20 ± 4%), CRP (167 ± 77%), renin (315 ± 63%), angiotensin II (74 ± 21%), aldosterone (61 ± 21%), TAC (80.4 ± 17%), uric acid (103 ± 19%), albumin (18.4 ± 2.4%), erythrocytes (13.4 ± 2.2%), hematocrit (11 ± 1.8%), and the excretion of noradrenaline (40.3 ± 10%) and dopamine (17 ± 5%). The following parameters decreased: waist circumference (8.20 ± 0.61 cm), body weight (7.010 ± 0.3 kg), erythropoietin (65 ± 18%), and the excretion of adrenaline (38 ± 4%) and Na⁺ (60 ± 16%). The excretion of K⁺ remained unchanged. Vitamin C decreased, showing a half-life of 4.8 ± 0.7 days. The percent ratios of lost weight components were: urine (52.2 ± 3.7%), insensible water loss (32.2 ± 1.4%), stool (5 ± 0.3%), and respiratory gases, i.e., expired CO₂ – incorporated O₂ (10.6 ± 5.4%). Conclusion: The mechanisms underlying the hypertonicity and hypovolemia compensation and the ratio analysis of lost weight components were presented. DF demonstrated short-term antioxidant, anti-ischemic, immune-stimulating, anti-edematous, and anti-inflammatory effects. The results may have an impact on developing new concepts for the treatment of edema, obesity, and inflammatory and ischemic diseases.

Study of the new 4-phenylpyrrolidinone-2 derivative pharmacokinetics and neuroprotective effect in the ischemic stroke animal model

The development of methods of drug therapy and rehabilitation in different periods of ischemic cerebral lesion is currently an urgent problem. Our study was aimed to investigate the pharmacokinetics and anti-ischemic effect of the new 4-phenylpyrrolidone-2 derivative in rats. To study the drug pharmacokinetics, the Wistar rats were once administered with the substance at a dose of 250 mg/kg, then, the substance distribution in blood and cerebral cortex was evaluated. Elimination half-life value was determined, which was 83.2 min. The substance remained in the brain tissue for 24 hours. To assess the anti-ischemic effect, the stroke was modeled by endovascular middle brain artery transition occlusion, and the drug was administered intravenously for 5 days at two doses, 250 and 125 mg/kg. After that the lesion focus volume was evaluated by MRI, as well as the neurological deficit severity, locomotor and explorative behavior. The studied drug significantly decreased the neurological deficit in model animals compared to control group (1.72 vs 4.4, p < 0.05). According to the MRI data, the effect on the ischemic focus was negligible, while the explorative behavior significantly increased under the influence of the 4-phenylpyrrolidone-2 derivative (hole board test, horizontal activity 12.1 ± 6.8, 22.5 ±10.5, p < 0.05). The data obtained allow us to conclude that the studied substance penetrates the blood-brain barrier (BBB), and accumulates in the brain tissue promoting the neurological deficit correction and increasing the explorative behavior in the ischemic stroke model animals.

Pharmacological evaluation of Mongolian medicine Syringa pinnatifolia fraction I against acute myocardial ischemia in mice

Syringa pinnatifolia Hemsl.( SP) is a representative Mongolian folk medicine with the effects of inhibiting Heyi related diseases,clearing heat and relieving pain. It has been used for the treatment of Heyi-induced heart tingling,heart palpitations,upset,insomnia and other symptoms. Total ethanol extract( T) and major fraction( M) of SP have been evaluated its anti-ischemic effects,and the mechanism was related to the regulation of cyclooxygenase( COX)-mediated inflammatory pathway and p53-mediated apoptosis pathway in our previous studies. This study reports the chemical fractionation on M by which to obtain subfractions( I and M_3),and the pharmacological evaluation of M,I,and M_3 against myocardial ischemia in mice. The result showed that I and M reduced the values of LVEDd and LVEDs,significantly increased EF and FS values,increased serum CK-MB and LDH levels in mice,and reduced in inflammatory cells infiltration and collagen deposition in the infarcted myocardial tissue,suggesting that M and I possess the same degree anti-myocardial is chemia equally whereas M_3 has no this effect. Related mechanism studies suggested that I can reduce the expression of COX-1,COX-2 and p53 protein in myocardial tissue in a dose-dependent manner. This study lays the foundation for further chemical segmentation and clarification of pharmacological substance groups,paving the way for the full use and benefits to be use of systematic biological methods to analyze the pharmacological basis of SP against myocardial ischemia.

Scutellarin attenuates hypoxia/reoxygenation injury in hepatocytes by inhibiting apoptosis and oxidative stress through regulating Keap1/Nrf2/ARE signaling.

Scutellarin is a natural flavonoid that has been found to exhibit anti-ischemic effect. However, the effect of scutellarin on hepatic hypoxia/reoxygenation (ischemia–reperfusion (I/R)) injury remains unknown. The aim of the present study was to explore the protective effect of scutellarin on I/R-induced injury in hepatocytes. Our results showed that scutellarin improved cell viability in hepatocytes exposed to hypoxia/reoxygenation (H/R). Scutellarin treatment resulted in decreased levels of reactive oxygen species (ROS) and malondialdehyde (MDA), and increased superoxide dismutase (SOD) activity in H/R-induced hepatocytes. In addition, scutellarin reduced cell apoptosis in H/R-stimulated hepatocytes, as proved by the decreased apoptotic rate. Moreover, scutellarin significantly up-regulated bcl-2 expression and down-regulated bax expression in hepatocytes exposed to H/R. Furthermore, scutellarin treatment caused significant decrease in Keap1 expression and increase in nuclear Nrf2 expression. Besides, scutellarin induced the mRNA expressions of heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1). Inhibition of Nrf2 significantly reversed the protective effects of scutellarin on H/R-stimulated hepatocytes. In conclusion, these findings demonstrated that scutellarin protected hepatocytes from H/R-induced oxidative injury through regulating the Keap1/Nrf2/ARE signaling pathway, indicating a potential relevance of scutellarin in attenuating hepatic I/R injury.

If Channel Inhibition - Ivabradine for the Treatment of Heart Failure

The novel first-in-class If channel antagonist, Ivabradine, is effective in improving clinical outcomes and functional capacity, in patients with HF, as well as demonstrating useful anti-anginal and protective anti-ischaemic effects. It can help improve heart rate control and can be usefully co-administered with beta blockers on HFrEF patients with residually elevated resting sinus rhythm heart rate. We review the clinical trial evidence for the benefits of Ivabradine in the treatment of heart failure.

The Mitochondrial Targets of Neuroprotective Drug Vinpocetine on Primary Neuron Cultures, Brain Capillary Endothelial Cells, Synaptosomes, and Brain Mitochondria

Vinpocetine is considered as neuroprotectant drug and used for treatment of brain ischemia and cognitive deficiencies for decades. A number of enzymes, channels and receptors can bind vinpocetine, however the mechanisms of many effects’ are still not clear. The present study investigated the effects of vinpocetine from the mitochondrial bioenergetic aspects. In primary brain capillary endothelial cells the purinergic receptor-stimulated mitochondrial Ca2+ uptake and efflux were studied. Vinpocetine exerted a partial inhibition on the mitochondrial calcium efflux. In rodent brain synaptosomes vinpocetine (30 μM) inhibited respiration in uncoupler stimulated synaptosomes and decreased H2O2 release from the nerve terminals in resting and in complex I inhibited conditions, respectively. In isolated rat brain mitochondria using either complex I or complex II substrates leak respiration was stimulated, but ADP-induced respiration was inhibited by vinpocetine. The stimulation of oxidation was associated with a small extent of membrane depolarization. Mitochondrial H2O2 production was inhibited by vinpocetine under all conditions investigated. The most pronounced effects were detected with the complex II substrate succinate. Vinpocetine also mitigated both Ca2+-induced mitochondrial Ca2+-release and Ca2+-induced mitochondrial swelling. It lowered the rate of mitochondrial ATP synthesis, while increasing ATPase activity. These results indicate more than a single mitochondrial target of this vinca alkaloid. The relevance of the affected mitochondrial mechanisms in the anti ischemic effect of vinpocetine is discussed.

Improvement in mitochondrial function underlies the effects of ANNAO tablets on attenuating cerebral ischemia-reperfusion injuries.

ANNAO tablets derive from Chinese classical prescriptions of Angong Niuhuang Pills with modified compositions, which have been singly or combined used for stoke associated neurological disorders. However the underlying mechanism is not yet well-defined, the present study investigated its anti-ischemic effects in rat middle cerebral artery occlusion (MCAO) model and focused on mitochondrial quality control. Rats were subjected to 2 h of brain ischemia followed by 1 day or up to 7 days of reperfusion. Vehicle, ANNAO tablets or Edaravone were given at 1h after the start of reperfusion for 1 day or successive 7 days in MCAO rats. For the behavior assessment, Longa test and modified Neurological Severity Scores (m NSS) test were performed. Following the behavioral assessment, we assessed the protein expressions related to mitochondrial function. Moreover, we also assessed the neuroprotective effects of ANNAO tablets by immunohistochemical analysis. Compared with sham rats, ANNAO tablets improved the behavioral performance and decreased the infarction volume in the MCAO rats. Western blotting results showed that ANNAO tablets altered the expression level of multiple proteins related to mitochondrial function, elevated the ratio of Bcl-2/Bax and inhibited the apoptosis. Additionally, ANNAO tablets increased the number of NeuN positive neurons. The obtained data demonstrated that ANNAO tablets exhibited an obvious anti-cerebral ischemia-reperfusion effect, which could be attributed to the improvement of mitochondrial quality control.

Capillary-resident EphA7+ pericytes are multipotent cells with anti-ischemic effects through capillary formation.

The presence of pericytes (PCs) with multipotency and broad distribution along capillary suggests that microvasculature plays a role not only as a duct for blood fluid transport but also as a stem cell niche that contributes to tissue maintenance and regeneration. The lack of an appropriate marker for multipotent PCs still limits our understanding of their pathophysiological roles. We identified the novel marker EphA7 to detect multipotent PCs using microarray analysis of an immortalized PC library. PCs were isolated from microvessels of mouse subcutaneous adipose tissues, then EphA7+ PCs called capillary stem cells (CapSCs) were separated from EphA7− control PCs (ctPCs) using fluorescence‐activated cell sorting system. CapSCs had highly multipotency that enabled them to differentiate into mesenchymal and neuronal lineages compared with ctPCs. CapSCs also differentiated into endothelial cells and PCs to form capillary‐like structures by themselves. Transplantation of CapSCs into ischemic tissues significantly improved blood flow recovery in hind limb ischemia mouse model due to vascular formation compared with that of ctPCs and adipose stromal cells. These data demonstrate that EphA7 identifies a subpopulation of multipotent PCs that have high angiogenesis and regenerative potency and are an attractive target for regenerative therapies.

Adaptogenic effect of phlojodicarpus sibiricus extract on cerebral ischemia

The aim of the study was to determine the adaptogenic effect of the extract from the roots of Phlojodicarpus sibiricus during ischemic influence on the left hemisphere of the brain. Experiments were conducted on Wistar rats of both sexes weighing 200-220 g. Unilateral cerebral ischemia was induced by permanent occlusion of the left common carotid artery under ether anesthesia. Adaptogenic anti-ischemic effect of Ph. sibiricus was determined by the number of desquamated endotheliocytes, nitrogen oxide metabolites – nitrites in the blood, by the content of lipid peroxidation products – malondialdehyde (MDA) and the activity of the antioxidant defense system in the brain tissue. It is established that Ph. sibiricus has an anti-ischemic effect, reduces the number of endotheliocytes desquamated, increases the level of nitric oxide in the blood (p ≤ 0.05), stimulates SOD and catalase activity, reducing the intensity of lipid peroxidation and the accumulation of MDA in the brain during ischemic exposure (p ≤ 0.05). Preventive administration of Ph. sibiricus extract has an adaptogenic effect in unilateral cerebral ischemia, which consists in reducing desquamated endotheliocytes, increasing the production of nitric oxide by endothelium, increasing the antioxidant defense system and reducing the intensity of oxidative reactions in the brain. Adaptogenic effect of Ph. sibiricus extract is caused by endothelium protective and antioxidant effects.

Anti-Ischemic Activity of Triamine ALM-802 under Conditions of Endothelial Dysfunction.

Anti-ischemic activity of N1-(2,3,4-trimethoxybenzyl)-N2-{2-[(2,3,4-trimethoxybenzyl)amino] ethyl}-1,2-ethanediamine (ALM-802) based on the structure of standard p-FOX inhibitors trimetazidine and ranolazine was studied on the model of endocardial ischemia in intact rats and animals with endothelial dysfunction. Acute endocardial myocardial ischemia was caused by infusion of isoproterenol (20 μg/kg/min intravenously). Endothelial dysfunction in rats was modeled by inducing hyperhomocysteinemia (3 g/kg methionine intragastrically one a day over 7 days). The reference drugs trimetazidine (30 mg/kg, intravenously) and ranolazine 10 mg/kg, intravenously) that were effective only in intact rats. In contrast, ALM-802 (2 mg/kg, intravenously) showed a pronounced anti-ischemic effect in animals with endothelial dysfunction, which suggests that the mechanisms of its cardioprotective action differ from those known for p-FOX inhibitors.

Crocin induces anti-ischemia in middle cerebral artery occlusion rats and inhibits autophagy by regulating the mammalian target of rapamycin

Crocin, an active compound found in Gardenia jasminoides Ellis, has been shown to possess neuron-protective properties, but its potential mechanisms of action still remain poorly understood. In this study, the anti-ischemic effect and underlying mechanism of action of crocin were investigated in male rats with right middle cerebral artery occlusion/reperfusion. Computed tomography and magnetic resonance imaging were used to evaluate the area of infarction 24 h after reperfusion. Neurological scores were employed to evaluate nerve injury. Direct 2,3,5-triphenyltetrazolium chloride staining was used to calculate the infarct ratio 120 h after reperfusion. Finally, HT22 cells and Western blot were used to study the underlying mechanisms. Crocin showed a decreased infarct volume and neurological score in vivo, while the expression of LC3-II/I and AMP-activated protein kinase was remarkably down-regulated with increased levels of p62 and mammalian target of rapamycin (mTOR) expression. However, rapamycin significantly inhibited mTOR, which can impact the anti-ischemic effect of crocin in vitro. These results suggest that crocin may elicit an anti-ischemic effect probably through the mTOR pathway.

Pharmacodynamics of Five Anthraquinones (Aloe-emodin, Emodin, Rhein, Chysophanol, and Physcion) and Reciprocal Pharmacokinetic Interaction in Rats with Cerebral Ischemia.

(1) Background: Rhubarb anthraquinones—a class of components with neuroprotective function—can be used to alleviate cerebral ischemia reperfusion injury. (2) Methods: The three pharmacodynamic indicators are neurological function score, brain water content, and cerebral infarction area; UPLC-MS/MS was used in pharmacokinetic studies to detect plasma concentrations at different time points, and DAS software was used to calculate pharmacokinetic parameters in a noncompartmental model. (3) Results: The results showed that the pharmacodynamics and pharmacokinetics of one of the five anthraquinone aglycones could be modified by the other four anthraquinones, and the degree of interaction between different anthraquinones was different. The chrysophanol group showed the greatest reduction in pharmacodynamic indicators comparing with other four groups where the rats were administered one of the five anthraquinones, and there was no significant difference between the nimodipine group. While the Aloe-emodin + Physcion group showed the most obvious anti-ischemic effect among the groups where the subjects were administered two of the five anthraquinones simultaneously. Emodin, rhein, chrysophanol, and physcion all increase plasma exposure levels of aloe-emodin, while aloe-emodin lower their plasma exposure levels. (4) Conclusions: This experiment provides a certain preclinical basis for the study of anthraquinone aglycones against cerebral ischemia and a theoretical basis for the study of the mechanism of interaction between anthraquinones.