Antioxidant Effects of Tryptanthrin Oxime.

We studied the radical-binding and antioxidant activities of the alkaloid tryptanthrin (TR) and its new synthetic derivative tryptanthrin oxime (TR-Ox), as well as the cytoprotective activity of TR-Ox under conditions of oxidative stress. The antiradical activity of TR-Ox was revealed in the test of binding with stable chromogen radical 2,2-diphenyl-1-picrylhydrazyl and in the superoxide radical generation test (riboflavin photoreduction reaction with detection by NBT reduction). TR-Ox was inferior to ionol and dihydroquercetin by the antiradical activity.

Cardioprotective Action of the JNK Inhibitor Tryptanthrin Oxime in the Late Period after Myocardial Infarction.

In experiments on Wistar rats, the effect of a new selective JNK inhibitor tryptanthrin oxime (TR-Ox) on parameters of systemic hemodynamics, cardiohemodynamics, and post-infarction fibrosis was studied 4 months after acute myocardial ischemia (1 h) followed by reperfusion. TR-Ox was administered intraperitoneally at a dose of 12 mg/kg 20 min before reperfusion, and then once a day for the next 4 days. Administration of TR-Ox to animals in the acute phase of myocardial infarction contributed to more complete preservation of myocardial viability in the delayed period: a relative increase of muscle elements proportion in the scar, a decrease in the formation of connective tissue areas with complete and >50% replacement of the myocardium, and deceleration of fibrotic scarring in myocardium areas distant from the focus of injury, resulting in improved systolic and diastolic myocardial function.

Comparative Evaluation of Neuroprotective Activity of Tryptanthrin and Its Oxime in Middle Cerebral Artery Occlusion in Rats.

The neuroprotective activity of tryptanthrin and its oxime was compared in male Wistar rats with a model of intraluminal occlusion of the middle cerebral artery. Neurobehavioral tests were performed 4, 24, and 48 h after focal cerebral infarction (FCI) using a modified neurological severity score (mNSS); additionally, the horizontal stability test, the plantar sensitivity test of the fore and hind limbs, holding on the tilted cage top test, and negative geotaxis test were performed. The size of FCI and the severity of brain tissue swelling were examined on day 2 after occlusion.

Effect of IQ-1 on the Infarct Size and the Parameters of Cardiodynamic Indicators in the Acute Period after Myocardial Ischemia/Reperfusion in Rats.

The effect of a new JNK inhibitor IQ-1 (11H-indeno[1,2-b]quinoxalin-11-one oxime) was studied in male Wistar rats in a model of acute myocardial ischemia/reperfusion. Area at risk and myocardial infarct zones were studied in two series of experiments: 16 h after a single dose of IQ-1 (25 mg/kg intraperitoneally during cardiac ischemia) and on day 5 after its course administration (25 mg/kg intraperitoneally during cardiac ischemia and daily over 4 days). On day 5 after ischemia/reperfusion, cardiodynamic indicators were also studied: systolic, end-diastolic, and minimum pressure in the left ventricle, stress-time index, as well as the maximum rates of pressure rise and fall in the left ventricle (+dP/dt and -dP/dt).

Dose proportionality and bioavailability of quinoxaline-based JNK inhibitor after single oral and intravenous administration in rats.

The dose proportionality and bioavailability of the potential anti-inflammatory and neuroprotective JNK inhibitor 11-indeno[1,2-]quinoxalin-11-one oxime (IQ-1) were evaluated by comparing pharmacokinetic parameters after single oral (25, 50 and 100 mg/kg) and intravenous (1 mg/kg) IQ-1 administration in rats.IQ-1 and its major metabolite ketone 11-indeno[1,2-]quinoxalin-11-one (IQ-18) were isolated from plasma samples by liquid-liquid extraction. IQ-1 (E-isomer) and IQ-18 were simultaneously quantified in plasma by the validated method of liquid chromatography with triple quadrupole mass spectrometry (HPLC-MS/MS).

Pharmacokinetics of a New Neuroprotector - Indenoquinoxalinone Derivative after Intravenous Administration in Rabbits and Rats.

The specific JNK inhibitor and NO donor 11H-indeno[1,2-b]quinoxalin-11-one oxime (IQ-1) demonstrated pronounced neuroprotective properties in an in vivo model of ischemic stroke in rats. The pharmacokinetic behavior of IQ-1 was studied in two animal species (rats, rabbits) after intravenous administration in a dose of 1 mg/kg. IQ-1 concentrations in venous blood plasma were measured by the liquid chromatography-tandem mass spectrometry method.

Pharmacological Effects of a New Soluble Guanylate Cyclase Stimulator in Experimental Ischemic Stroke.

We studied the action of a new indolinone derivative GRS, acetylsalicylic acid (ASA), and their combination on platelet aggregation, vasodilatory endothelial function, neurological status, and cerebral infarction area in experimental focal cerebral ischemia/reperfusion in rats. GRS compound (10 mg/kg), ASA (10 mg/kg), and their combination in the same doses were administered orally once a day as a suspension in 1% starch solution over 5 days after pathology modeling. Sham-operated and control animals were administered 1% starch solution.

Neuroprotective Effects of Tryptanthrin-6-Oxime in a Rat Model of Transient Focal Cerebral Ischemia.

The activation of -Jun N-terminal kinase (JNK) plays an important role in stroke outcomes. Tryptanthrin-6-oxime (TRYP-Ox) is reported to have high affinity for JNK and anti-inflammatory activity and may be of interest as a promising neuroprotective agent. The aim of this study was to investigate the neuroprotective effects of TRYP-Ox in a rat model of transient focal cerebral ischemia (FCI), which involved intraluminal occlusion of the left middle cerebral artery (MCA) for 1 h.

Cardioprotective Effects of a Selective c-Jun N-terminal Kinase Inhibitor in a Rat Model of Myocardial Infarction.

Activation of c-Jun N-terminal kinases (JNKs) is involved in myocardial injury, left ventricular remodeling (LV), and heart failure (HF) after myocardial infarction (MI). The aim of this research was to evaluate the effects of a selective JNK inhibitor, 11-indeno [1,2-]quinoxalin-11-one oxime (IQ-1), on myocardial injury and acute myocardial ischemia/reperfusion (I/R) in adult male Wistar rats. Intraperitoneal administration of IQ-1 (25 mg/kg daily for 5 days) resulted in a significant decrease in myocardial infarct size on day 5 after MI.

Neuroprotective Effects of the Lithium Salt of a Novel JNK Inhibitor in an Animal Model of Cerebral Ischemia-Reperfusion.

The c-Jun -terminal kinases (JNKs) regulate many physiological processes, including inflammatory responses, morphogenesis, cell proliferation, differentiation, survival, and cell death. Therefore, JNKs represent attractive targets for therapeutic intervention. In an effort to develop improved JNK inhibitors, we synthesized the lithium salt of 11-indeno[1,2-]quinoxaline-11-one oxime () and evaluated its affinity for JNK and biological activity in vitro and in vivo.

Effect of p-Tyrosol on the Process of Left-Ventricular Remodeling in the Long Period after Myocardial Infarction.

The effect of p-tyrosol on the main hemodynamic parameters and contractile function of the heart was studied and a morphometric assessment of left-ventricular remodeling was performed in Wistar rats 2 months after acute 1-h myocardial ischemia followed by reperfusion. p-Tyrosol in a dose of 20 mg/kg was injected intraperitoneally 5 times: 20 min before the start of reperfusion, 4 h after the start of reperfusion, and then once a day over the next 3 days. Administration of p-tyrosol to animals in the acute period of myocardial infarction slowed down the formation of systolic and diastolic myocardial dysfunction, improved the pumping function of the heart, maintained the hemodynamic parameters at a significantly higher level, and reduced left-ventricular remodeling in the late period of myocardial infarction.

Effects of a New Antithrombotic Drug GRS, a Soluble Guanylate Cyclase Stimulator, on Endothelial Dysfunction in Rats with Myocardial Infarction.

New antithrombotic drug GRS, a soluble guanylate cyclase stimulator, after repeated administration in a dose of 10 mg/kg alleviates the symptoms of endothelial dysfunction in rats with myocardial infarction; it restores antiplatelet activity of the blood vessel wall and vasodilatory function of the endothelium without producing significant effect on endothelium-independent vasodilation. GRS also has direct antiaggregant and antihypertensive effects in therapeutic doses. The obtained data suggest that GRS can be therapeutically useful in patients with cardiovascular diseases accompanied by endothelial dysfunction.

Neurodegeneration, Myelin Loss and Glial Response in the Three-Vessel Global Ischemia Model in Rat.

(1) Background: Although myelin disruption is an integral part of ischemic brain injury, it is rarely the subject of research, particularly in animal models. This study assessed for the first time, myelin and oligodendrocyte loss in a three-vessel model of global cerebral ischemia (GCI), which causes hippocampal damage. In addition, we investigated the relationships between demyelination and changes in microglia and astrocytes, as well as oligodendrogenesis in the hippocampus; (2) Methods: Adult male Wistar rats ( = 15) underwent complete interruption of cerebral blood flow for 7 min by ligation of the major arteries supplying the brain or sham-operation.

Neuroprotective Effects of a Novel Inhibitor of c-Jun N-Terminal Kinase in the Rat Model of Transient Focal Cerebral Ischemia.

A novel specific inhibitor of c-Jun N-terminal kinase, 11-indeno[1,2-]quinoxalin-11-one oxime sodium salt (IQ-1S), has a high affinity to JNK3 compared to JNK1/JNK2. The aim of this work was to study the mechanisms of neuroprotective activity of IQ-1S in the models of reversible focal cerebral ischemia (FCI) in Wistar rats. The animals were administered with an intraperitoneal injection of IQ-1S (5 and 25 mg/kg) or citicoline (500 mg/kg).

2,6-Diisobornyl-4-Methylphenol Reduces Postishemic Myocardium Remodeling in Delayed Period after Ischemia/Reperfusion in Rats.

2,6-Diisobornyl-4-methylphenol (Dibornol, 10 mg/kg intragastrically daily for 5 days after myocardial ischemia/reperfusion) 1.5-fold increased rat survival during the acute post-infarction period in comparison with the control group. In survivors, Dibornol reliably prevented post-ischemic progression of heart failure in the delayed post-infarction period (30 days after ischemia/reperfusion), which was seen from an increase in the left-ventricular developed pressure by 22%, left-ventricular contractility index by 19%, and +dP/dt by 34%.

Metabolism of a New Antiaggregant, Indolinone Derivative.

Cytochrome p450-mediated metabolism of GRS (indolinone antiaggregant) and its effects on activities of cytochrome p450 isoenzymes were studied. Inhibition of 6 isomers of cytochrome p450 in human liver microsomes was studied with the use of specific substrates. It was found that human liver cytochrome p450 enzymes could not induce degradation of GRS and that GRS was not an inductor or inhibitor of cytochrome p450 family members 1A2, 2C9, 2C19, 2D6, 2C8, and 3A4.

p-Tyrosol Enhances the Production of New Neurons in the Hippocampal CA1 Field after Transient Global Cerebral Ischemia in Rats.

This study aimed at assessing the regenerative effect of p-tyrosol in transient global cerebral ischemia modeled in adult male Wistar rats by reversible occlusion of the three major vessels originating from the aortic arch and supplying the blood to the brain. p-Tyrosol was administered intraperitoneally in a dose of 20 mg/kg over 10 days after surgery. The death of NeuN mature neurons and the number of newly formed DCX neurons were assessed in the CA1 field of the hippocampus that is highly susceptible to damage in this model.

Cardioprotective Activity of 2,6-Diisobornyl-4-Methylphenol in Acute Myocardial Ischemia/Reperfusion in Rats.

We studied the cardioprotective effect of 2,6-diisobornyl-4-methylphenol under conditions of myocardial ischemia/reperfusion in rats. Daily administration of 2,6-diisobornyl-4-methylphenol (100 mg/kg intragastrically) over 3 days before and 5 days after modeling of myocardial ischemia/reperfusion prevented the increase in the infarction area by almost 2 times in comparison with the control by day 5 after recirculation. The type and severity of pathological changes in ECG parameters reflecting necrotic changes in the myocardium under the action of the compound significantly decreased by day 35 of the experiment.

Anti-Ischemic Activity of n-Tyrozol under Conditions of Repeated Transient Myocardial Ischemia in Rats.

We studied anti-ischemic activity of n-tyrozol under conditions of repeated transient myocardial ischemia in rats caused by repeated (5×3 min) occlusion of the left coronary artery. n-Tyrozol administered intraperitoneally in a dose of 20 mg/kg daily over 4 days before the ischemia modeling (the last injection 15 min prior to the start of the experiment) produced a clear-cut anti-ischemic effect: it reduced ST elevation and promoted more complete recovery of ECG during reperfusion. During reperfusion periods, n-tyrozol significantly decreased the risk of ventricular fibrillation and shortened the duration of tachyarrhythmia episodes (ventricular tachycardia and fibrillation).

Effects of Fluoxetine on Hippocampal Neurogenesis and Neuroprotection in the Model of Global Cerebral Ischemia in Rats.

A selective serotonin reuptake inhibitor, fluoxetine, has recently attracted a significant interest as a neuroprotective therapeutic agent. There is substantial evidence of improved neurogenesis under fluoxetine treatment of brain ischemia in animal stroke models. We studied long-term effects of fluoxetine treatment on hippocampal neurogenesis, neuronal loss, inflammation, and functional recovery in a new model of global cerebral ischemia (GCI).

An improved three-vessel occlusion model of global cerebral ischemia in rats.

We developed an improved three-vessel occlusion model of global cerebral ischemia in rats. This method consists in cessation of cerebral blood flow by accessing a. carotis communis sinistra through the ventral surface of the neck as well as tr.

Dihydroquercetin Improves Microvascularization and Microcirculation in the Brain Cortex of SHR Rats during the Development of Arterial Hypertension.

The effects of dihydroquercetin (50 mg/kg intragastrically daily for 6 weeks) on the density of capillary network (mean number of capillaries per mm), mean capillary diameter, structure of capillary network, capillary diameter distribution (<3, 3-5, 5-7, and 7-9 μ), and local cerebral blood flow (by laser Doppler) in the visual cortex were studied in SHR rats during the development of arterial hypertension (from the 6th to the 12th week of life). Normally, the systolic and diastolic BP progressively increased in SHR rats during this period. Dihydroquercetin did not affect the development of arterial hypertension.

Bioavailability of the Phenolic Antioxidant 4-Methyl-2,6-Diisobornylphenol After Oral Administration.

We compared bioavailability of 4-methyl-2,6-diisobornylphenol after single intragastric administration to rats in a dose of 200 mg/kg in starch suspension and in almond oil. Absorption of 4-methyl-2,6-diisobornylphenol in the gastrointestinal tract after administration in almond oil was much more efficient than after administration in aqueous starch mucus.

Effect of Fluoxetine on Neurogenesis in Hippocampal Dentate Gyrus after Global Transient Cerebral Ischemia in Rats.

Changes in cerebral neurogenesis provoked by ischemia and the effect of fluoxetine on this process were studied using a three-vessel occlusion model of global transient cerebral ischemia. The global transient cerebral ischemia was modeled on male Wistar rats by transient occlusion of three major vessels originating from the aortic arch and supplying the brain (brachiocephalic trunk, left subclavian artery, and left common carotid artery). The cells expressing doublecortin (DCX, a marker of young neurons) were counted in the hippocampal dentate gyrus on day 31 after ischemia modeling.

Neuroprotective effects of p-tyrosol after the global cerebral ischemia in rats.

Background: Salidroside is a biologically active compound derived from Rhodiola rosea L. Studies showed that salidroside after i.v.