C60 adduct with L-arginine as a promising nanomaterial for treating cerebral ischemic stroke.

The work aimed to investigate the biocompatibility and biological activity of the water-soluble fullerene adduct C60-Arg. It was found that the material is haemocompatible, is not cyto- and genotoxic, possesses pronounced antioxidant activity. Additionally, this paper outlines the direction of application of water-soluble fullerene adducts in the creation of neuroprotectors. It has been suggested that a putative mechanism of the protective action of the C60-Arg adduct is associated with its antioxidant properties, the ability to penetrate the blood-brain barrier, and release nitrogen monoxide as a result of the catabolism of L-arginine residues, which promote vascular relaxation. The action of the C60-Arg adduct was compared with the action of such an antioxidant as Edaravone, which is approved in Japan for the treatment of ischemic and haemorrhagic strokes.

Remote vs. local ischaemic preconditioning in the rat heart: infarct limitation, suppression of ischaemic arrhythmia and the role of reactive oxygen species.

The unmet clinical need for myocardial salvage during ischaemia-reperfusion injury requires the development of new techniques for myocardial protection. In this study the protective effect of different local ischaemic preconditioning (LIPC) and remote ischaemic preconditioning (RIPC) protocols was compared in the rat model of myocardial ischaemia-reperfusion, using infarct size and ischaemic tachyarrhythmias as end-points. In addition, the hypothesis that there is involvement of reactive oxygen species (ROS) in the protective signalling by RIPC was tested, again in comparison with LIPC. The animals were subjected to 30-min coronary occlusion and 90-min reperfusion. RIPC protocol included either transient infrarenal aortic occlusion (for 5, 15 and 30 min followed by 15-min reperfusion) or 15-min mesenteric artery occlusion with 15-min reperfusion. Ventricular tachyarrhythmias during test ischaemia were quantified according to Lambeth Conventions. It was found that the infarct-limiting effect of RIPC critically depends on the duration of a single episode of remote ischaemia, which fails to protect the heart from infarction when it is too short or, instead, too prolonged. It was also shown that RIPC is ineffective in reducing the incidence and severity of ischaemia-induced ventricular tachyarrhythmias. According to our data, the infarct-limiting effect of LIPC could be partially eliminated by the administration of ROS scavenger N-2-mercaptopropionylglycine (90 mg/kg), whereas the same effect of RIPC seems to be independent of ROS signalling.

Neuroprotective activity of creatylglycine ethyl ester fumarate.

BACKGROUND: We have recently shown neuroprotective activity of the creatine amides in the focal cerebral ischemia in rats on the 280 mg/kg administration. In the present study, neuroprotective properties of creatylglycine ethyl ester fumarate (CrGEt) in rats with focal cerebral ischemia were explored in a wide dosage range (30-280 mg/kg, intravenous and intragastric). METHODS: Focal cerebral ischemia was induced by the middle cerebral artery occlusion (MCAO). RESULTS: The CrGEt administration 30 minutes before and at the last 5 minutes of MCAO dose dependently attenuated cerebral ischemic damage on 35%-65%, reduced neurobehavioral deficits, led to high neuronal survival in ischemic rat brains. The neuroprotective activity of CrGEt was mediated by its following abilities: (1) normalize the energy metabolism in the ischemic brains, maintaining adenosine triphosphate levels, and reducing lactate concentration; (2) inhibit the ischemia-reperfusion-related oxidative stress as evidenced by the increased activity of superoxide dismutase and the reduced levels of malondialdehyde. CrGEt served as a substrate for creatine kinase and a partial agonist of N-methyl-D-aspartate receptors; this partly explains mechanism of its neuroprotective action. CONCLUSIONS: In view of the previously mentioned results, CrGEt holds a promise as a compound for treatment of ischemic brain disorders.

Preservation of the donor heart: from basic science to clinical studies.

The methods of donor heart preservation are aimed at minimizing graft dysfunction caused by ischaemia-reperfusion injury (IRI) which inevitably occurs during the ex vivo transport interval. At present, the standard technique of heart preservation is cardiac arrest followed by static cold storage in a crystalloid heart preservation solution (HPS). This technique ensures an acceptable level of heart protection against IRI for <6 h. In clinical trials, comparable levels of myocardial protection against IRI were provided by various HPSs. The growing shortage of donor hearts is one of the major factors stimulating the development of new techniques of heart preservation. Here, we summarize new HPS formulations and provide a focus for optimization of the composition of existing HPSs. Such methods of donor heart preservation as machine perfusion, preservation at sub-zero temperature and oxygen persufflation are also discussed. Furthermore, we review experimental data showing that pre- and post-conditioning of the cardiac graft can improve its function when used in combination with cold storage. The evidence on the feasibility of cardiac donation after circulatory death, as well as the techniques of heart reconditioning after a period of warm ischaemia, is presented. The implementation of new techniques of donor heart preservation may contribute to the use of hearts from extended criteria donors, thereby expanding the total donor pool.

Neurotherapeutic activity of the recombinant heat shock protein Hsp70 in a model of focal cerebral ischemia in rats.

Recombinant 70 kDa heat shock protein (Hsp70) is an antiapoptotic protein that has a cell protective activity in stress stimuli and thus could be a useful therapeutic agent in the management of patients with acute ischemic stroke. The neuroprotective and neurotherapeutic activity of recombinant Hsp70 was explored in a model of experimental stroke in rats. Ischemia was produced by the occlusion of the middle cerebral artery for 45 minutes. To assess its neuroprotective capacity, Hsp70, at various concentrations, was intravenously injected 20 minutes prior to ischemia. Forty-eight hours after ischemia, rats were sacrificed and brain tissue sections were stained with 2% triphenyl tetrazolium chloride. Preliminary treatment with Hsp70 significantly reduced the ischemic zone (optimal response at 2.5 mg/kg). To assess Hsp70's neurotherapeutic activity, we intravenously administered Hsp70 via the tail vein 2 hours after reperfusion (2 hours and 45 minutes after ischemia). Rats were then kept alive for 72 hours. The ischemic region was analyzed using a high-field 11 T MRI scanner. Administration of the Hsp70 decreased the infarction zone in a dose-dependent manner with an optimal (threefold) therapeutic response at 5 mg/kg. Long-term treatment of the ischemic rats with Hsp70 formulated in alginate granules with retarded release of protein further reduced the infarct volume in the brain as well as apoptotic area (annexin V staining). Due to its high neurotherapeutic potential, prolonged delivery of Hsp70 could be useful in the management of acute ischemic stroke.

Evidence of active regulation of cerebral venous tone in individuals undergoing embolization of brain arteriovenous malformations.

Cerebral venous drainage is generally believed to be regulated primarily by hydrodynamic forces. To gain further insight into the regulation of this process, we investigated the response of blood flow velocity and cross-sectional area (CSA) of the internal jugular veins (IJVs) to local hemodynamic shifts. All procedures and assessments were performed on patients (n = 30) undergoing embolization of brain arteriovenous malformations (AVMs). The procedure efficiency was verified by the postembolization reduction in time-averaged maximum blood flow velocities, as well as the elevation of pulsatility index and resistance index in the arterial feeders. In cerebral veins, the dominant IJV pressure remained unchanged during the procedure. At the same time, AVM embolization caused a significant reduction in maximal CSA (84 ± 7.6 to 68 ± 7.7 mm(2), P < 0.05) and minimal CSA (68 ± 7.0 to 51 ± 7.0 mm(2), P < 0.01) of the IJV located ipsilateral to the AVM, while the maximal linear blood flow velocity in the IJV remained unchanged (71 ± 4.9 and 85 ± 8.4 cm/s, P = 0.098). Consistent with previously published studies, the data obtained provide further evidence of active regulation of the venous outflow, probably mediated by certain neurogenic and/or endothelium-dependent mechanisms.

Myocardial protection against global ischemia with Krebs-Henseleit buffer-based cardioplegic solution.

BACKGROUND: The Krebs-Henseleit buffer is the best perfusion solution for isolated mammalian hearts. We hypothesized that a Krebs-Henseleit buffer-based cardioplegic solution might provide better myocardial protection than well-known crystalloid cardioplegic solutions because of its optimal electrolyte and glucose levels, presence of buffer systems, and mild hyperosmolarity. METHODS: Isolated Langendorff-perfused rat hearts were subjected to either global ischemia without cardioplegia (controls) or cardioplegic arrest for either 60 or 180 min, followed by 120 min of reperfusion. The modified Krebs-Henseleit buffer-based cardioplegic solution (mKHB) and St. Thomas' Hospital solution No. 2 (STH2) were studied. During global ischemia, the temperatures of the heart and the cardioplegic solutions were maintained at either 37°C (60 min of ischemia) or 22°C (moderate hypothermia, 180 min of ischemia). Hemodynamic parameters were registered throughout the experiments. The infarct size was determined through histochemical examination. RESULTS: Cardioplegia with the mKHB solution at moderate hypothermia resulted in a minimal infarct size (5 ± 3%) compared to that in the controls and STH2 solution (35 ± 7% and 19 ± 9%, respectively; P < 0.001, for both groups vs. the mKHB group). In contrast to the control and STH2-treated hearts, no ischemic contracture was registered in the mKHB group during the 180-min global ischemia. At normothermia, the infarct sizes were 4 ± 3%, 72 ± 6%, and 70 ± 12% in the mKHB, controls, and STH2 groups, respectively (P < 0.0001). In addition, cardioplegia with mKHB at normothermia prevented ischemic contracture and improved the postischemic functional recovery of the left ventricle (P < 0.001, vs. STH2). CONCLUSIONS: The data suggest that the Krebs-Henseleit buffer-based cardioplegic might be superior to the standard crystalloid solution (STH2).