Magdalena Dudek

Alpha lipoic acid protects the heart against myocardial post ischemia-reperfusion arrhythmias via KATP channel activation in isolated rat hearts.

The cardiovascular effects of alpha lipoic acid were evaluated in isolated rat hearts exposed to ischemia-reperfusion injury in vitro. Alpha-lipoic acid raised the level of sulfane sulfur playing an important role in the release of hydrogen sulfide. H2S was shown to prevent the post-reperfusion arrhythmias and to protect the cardiomyocytes from death caused by hypoxia. The activation of potassium ATP-sensitive channels (K(ATP) channels) is one of the most important mechanisms of action of hydrogen sulfide in the cardiovascular system. The aim of this study was to investigate whether alpha lipoic acid can prevent the occurrence of post-reperfusion arrhythmias in vitro using a Langendorff model of ischemia-reperfusion in rats affecting the K(ATP) channels. Alpha lipoic acid significantly improved post-reperfusion cardiac function (reducing incidence of arrhythmias), especially in a dose of 10(-7)M. These cardiovascular effects of this compound on the measured parameters were reversed by glibenclamide, a selective K(ATP) blocker. Alpha lipoic acid increased the level of sulfane sulfur in the hearts. This may suggest that the positive effects caused by alpha lipoic acid in the cardiovascular system are not only related to its strong antioxidant activity, and the influence on the activity of such enzymes as aldehyde dehydrogenase 2, as previously suggested, but this compound can affect K(ATP) channels. It is possible that this indirect effect of alpha lipoic acid is connected with changes in the release of sulfane sulfur and hydrogen sulfide.

Effects of Different Garlic-derived Allyl Sulfides on Peroxidative Processes and Anaerobic Sulfur Metabolism in Mouse Liver

Biological activity of garlic has been attributed to organosulfur compounds, most of all to oil‐soluble allyl sulfides, such as diallyl sulfide (DAS), diallyl disulfide (DADS) and diallyl trisulfide (DATS). This study evaluated the effectiveness of garlic‐derived allyl sulfides in influencing peroxidative processes, levels of thiols and sulfane sulfur and its metabolic enzymes in normal mouse liver cells. Various allyl sulfides (DAS, DADS and DATS) dissolved in corn oil were given intraperitoneally to mice for 10 days. After sacrificing the mice, biochemical assays were performed in liver homogenates and in plasma in order to establish liver function. All allyl sulfides under study had a beneficial effect in the mouse liver since they decreased reactive oxygen species and malondialdehyde levels and increased glutathione S‐transferase activity and non‐protein sulfhydryl group level. Moreover, DADS and DATS elevated total sulfane sulfur pool and activity of sulfane sulfur biosynthetic enzymes. The increase in sulfane sulfur level entailed augmentation of its antioxidant and regulatory capacities. Garlic‐derived allyl sulfides exhibited antioxidant action in the liver and elevated anaerobic cysteine metabolism leading to the formation of sulfane sulfur‐containing compounds. Thus, DADS and DATS showed beneficial action in the liver, which can be used for protection of normal liver cells during chemotherapy or for alleviation of liver damage. Copyright

Tissue distribution of gold nanoparticles after single intravenous administration in mice

BACKGROUND Nanoparticles (a part of matter which size is less than 100 nm) have numerous potential applications in biomedicine, due to their unique surface, electronic and optical properties. The goal of the present study was to examine the distribution of gold nanoparticles (GNPs) in mice after single intravenous administration. METHODS Spherical GNPs were synthesized by chemical reduction of tetrachloroauric acid with ascorbic acid as a reductant. GNPs were stabilized using polyvinyl alcohol (PVA, m.w. = 67000Da) a substance approved for use in the pharmaceutical industry. The size of colloidal gold particles (diameter equals 25 ± 8 nm) was determined using HR SEM and DLS techniques; ζ potential of GNPs was determined using Malvern Zetasizer Nano ZS and it equals -5.2 ± 5.4 mV. An aqueous dispersion of GNPs was administered to mice in a dose of about 10 cm(3)/kg and 24 h later the amount of gold in different organs was determined using the inductively coupled plasma mass spectrometer (ICP MS). Initial concentration of GNPs equals 29.55 mg/l. RESULTS GNPs after single intravenous administration preferentially accumulated in the liver (12.7% of the applied dose), while the other organs accumulated around 0.1% or less. CONCLUSION Colloidal GNPs of the used size (about 25 ± 8 nm) provide new potential route for direct delivery system to the liver, which may be important e.g., in liver cancer diagnosis.

Evaluation of anticonvulsant activity of novel pyrrolidin-2-one derivatives.

BACKGROUND The aim of this study was to examine the anticonvulsant activity of some novel pyrrolidin-2-one derivatives with considerable affinity to serotonin 5-HT1A and α1-adrenergic receptors. METHODS The maximal electroshock-induced seizure (MES) and pentetrazole (PTZ)-induced seizure models in mice were performed. RESULTS As a results of the conducted studies, three compounds showing anticonvulsant activity were selected. The EP-40 molecule significantly reduced incidence of seizures in the maximal electroshock test. The EP-42 and EP-46 compounds demonstrated activity in the pentetrazole-induced seizures. CONCLUSION The results may indicate that the decrease in the susceptibility to seizures induced by the new pyrrolidin-2-one derivatives is related to the significant affinity to serotonergic or α1-adrenergic receptors. Also putative mechanism of action of the test compounds can be linked with their GABA-ergic activity, because these novel derivatives are GABA analogs.

Evaluation of antidepressant-like and anxiolytic-like activity of purinedione-derivatives with affinity for adenosine A2A receptors in mice

BACKGROUND It has recently been suggested that the adenosine A2A receptor plays a role in several animal models of depression. Additionally, A2A antagonists have reversed behavioral deficits and exhibited a profile similar to classical antidepressants. METHODS In the present study, imidazo- and pyrimido[2,1-f]purinedione derivatives (KD 66, KD 167, KD 206) with affinity to A2A receptors but poor A1 affinity were evaluated for their antidepressant- and anxiolytic-like activity. The activity of these derivatives was tested using a tail suspension and forced swim test, two widely-used behavioral paradigms for the evaluation of antidepressant-like activity. In turn, the anxiolytic activity was evaluated using the four-plate test. RESULTS The results showed the antidepressant-like activity of pyrimido- and imidazopurinedione derivatives (i.e. KD 66, KD 167 and KD 206) in acute and chronic behavioral tests in mice. KD 66 revealed an anxiolytic-like effect, while KD 167 increased anxiety behaviors. KD 206 had no effect on anxiety. Furthermore, none of the tested compounds increased locomotor activity. CONCLUSION Available data support the proposition that the examined compounds with adenosine A2A receptor affinity may be an interesting target for the development of antidepressant and/or anxiolytic agents.

Antiarrhythmic activity of new 2-methoxyphenylpiperazine xanthone derivatives after ischemia/reperfusion in rats

BACKGROUND We have previously shown significant prophylactic and therapeutic antiarrhythmic activity in adrenaline-induced arrhythmia, as well as α1-adrenolytic properties of new derivatives of xanthone. Herein, we investigated their antiarrhythmic activity in the model of ischemia/reperfusion in isolated hearts. Furthermore, we assessed antioxidant activity in biochemical studies. METHODS Antiarrhythmic activity in the model of ischemia/reperfusion in isolated perfused hearts was performed according to the Langendorff technique. Antioxidant activity was measured by lipid peroxidation level in tissue homogenate and in the FRAP assay. RESULTS All studied compounds (MH-94, MH-99 and MH-105) showed significant antiarrhythmic activity in the model of ventricular arrhythmias associated with coronary artery occlusion and reperfusion. However, they did not demonstrate antioxidant effect, probably, because of the lack of free hydroxyl group(s) at a key position in the xanthone scaffold. CONCLUSIONS The present study provides evidences for antiarrhythmic activity of some 2-methoxyphenylpiperazine derivatives of xanthone.

Contribution of the nitric oxide donor molsidomine and the antiparkinsonian drug l-DOPA to the modulation of the blood pressure in unilaterally 6-OHDA-lesioned rats.

BACKGROUND Interaction between dopaminergic and nitrergic neurotransmission in the brain plays a crucial role in the control of motor function and in the regulation of blood pressure (BP). In Parkinsons disease (PD), dopaminergic denervation of the striatum leads to disturbances in the nitrergic system in the basal ganglia. Recently, it has been demonstrated that addition of a low dose of the nitric oxide donor molsidomine to l-DOPA therapy improves dopaminergic neurotransmission in the denervated nigrostriatal system and weakens dyskinesias in rodent models of the disease. METHODS The aim of the present study was to examine the impact of chronic administration of molsidomine (2mg/kg) and l-DOPA (25mg/kg), alone and in combination, on systolic (SBP) and diastolic (DBP) blood pressure in the anesthetized, unilaterally 6-OHDA-lesioned rats. The measurement of SBP and DBP was performed 24h after the penultimate and immediately after the last drug doses. RESULTS In 6-OHDA-lesioned rats receiving saline, spontaneous, small decreases in SBP and DBP were observed during the measurements lasting 60min. Administration of molsidomine alone or in combination with l-DOPA distinctly decreased the BP in 6-OHDA-lesioned rats already after 10min compared to those treated with saline or l-DOPA alone, respectively. In both groups, the molsidomine-mediated declines in BP persisted till the end of measurement but they disappeared after 24h. CONCLUSIONS Our results indicate that in this PD model molsidomine evokes a short-lasting decrease in BP in contrast to conventional antihypertensive drugs that maintain long-term effect and worsen orthostatic hypotension in parkinsonian patients.

Antiarrhythmic activity in occlusion‐reperfusion model of 1‐(1H‐indol‐4‐yloxy)‐3‐{[2‐(2‐methoxyphenoxy)ethyl]amino} propan‐2‐ol and its enantiomers

Acute myocardial infarction (AMI) is a leading cause of mortality and morbidity worldwide, especially in developed countries. The most serious problem after myocardial infarction is reperfusion injury that manifests as functional impairment, arrhythmia, and accelerated progression of cell death in certain critically injured myocytes. Subsequently the infarcted myocardium develops features of necrosis and reactive inflammation. To reduce lethal reperfusion injury in patient with AMI antioxidants, anti‐inflammatory agents, adenosine, opioids, metabolic modulators (glucose, insulin, and potassium, nicorandil and agents which reduce intracellular Ca2+ overload and inhibit Na+‐H+ exchange) are used. In this study a novel compound (compound 9) 1‐(1 h‐indol‐4‐yloxy)‐3‐{[2‐(2‐methoxyphenoxy) ethyl]amino}propan‐2‐ol and its enantiomers are examined in arrhythmia associated with coronary artery occlusion and reperfusion in a rat model. Antioxidant properties are also determined for test compounds using the malondialdehyde (MDA) lipid peroxidation and ferric reducing antioxidant power (FRAP) tests. In summary, the tested compounds, especially the S enantiomer has a strong antiarrhythmic activity in a model of occlusion and reperfusion of the left coronary artery which is probably related to their adrenolytic action. In contrast to carvedilol, none of the test compound reduced the lipid peroxidation but increased ferric reducing antioxidant power. In the antioxidant effect, there was no difference between the optical forms of compound 9.