O.E. Fadyukova

Novel synthetic analogue of ACTH 4-10 (Semax) but not glycine prevents the enhanced nitric oxide generation in cerebral cortex of rats with incomplete global ischemia.

This work investigates whether nitric oxide production and lipid peroxidation contribute to the pathophysiology of ischemia and whether glycine and a novel Russian compound, Semax are neuroprotective via a mechanism involving the regulation nitric oxide (NO) and lipid peroxidation. In brief, nitric oxide and indices of lipid peroxidation were elevated following global ischemia. While glycine proved ineffective in reducing NO levels or ameliorating the neurological deficits following global ischemia, Semax proved to be highly effective in abating the rise in nitric oxide and restoring neurologic functioning.

Ischemic and hemorrhagic disturbances in cerebral circulation alter contractile responses of the rat middle cerebral artery

In our study, we examined middle cerebral artery (MCA) contractile responses in two animal models. After hemorrhagic disturbances in rats of Krushinsky-Molodkina strain (KMRs) a decrease in contractile responses to serotonin (5-HT) was observed. During incomplete global cerebral ischemia, MCAs had increased responsiveness to endothelin-1 (ET-1), but reduced responsiveness to serotonin. These findings suggest that cerebral circulation disorders alter cerebrovascular function possibly leading to secondary disturbances in brain circulation.

Changes in plasma membrane viscosity and hemoporphyrin conformation in erythrocyte hemoglobin under the conditions of ischemia and reperfusion of rat brain.

Hypoxia of various origin and localization is accompanied by changes in some physical and chemical properties of erythrocytes: deformability, plasma membrane viscosity, and the oxygen-binding capacity of hemoglobin [1, 4‐6]. Under the conditions of brain ischemia, these properties are studied insufficiently. After postischemic reperfusion (PIR) that restores blood circulation, the oxygen partial pressure in plasma increases, which may stimulate the generation of reactive oxygen species (ROS) and affect the erythrocyte functions. In blood plasma, Cu,Zn-superoxide dismutase (SOD) and ceruloplasmin (CP) are involved in utilization of superoxide anion radical ( ) that triggers ROS formation. In this study, changes in the viscosity of erythrocyte plasma membrane and the e 2 -binding ability of hemoporphyrin of deoxyhemoglobin were studied. SOD activity and CP level were also measured in blood plasma of rats with brain ischemia before and after brain PIR. White outbred male rats weighing 272 ± 11 g were used in experiments. The animals were divided into three groups: the sham-operated rats (the control) ( n = 10), the rats with brain ischemia ( n = 10), and the rats with postischemic brain reperfusion ( n = 7). One day before the experiment, both carotids of the anesthetized animals were underpinned with a fishing line (0.3 mm) that was later withdrawn under skin through the polyethylene tubes into the interscapular region. After one day, a one-stage complete occlusion of both carotids was induced by carotid retraction into the tubes by means of the fishing line; subsequent release of carotids led to PIR. Blood samples (3 ml of blood mixed with heparin, 10 U/ml) were taken from the jugular veins of

Reduction of Erythrocyte Deformability in Rats with Cerebral Ischemia

Erythrocyte deformability was studied by laser interferometry in rats with cerebral ischemia. Ninety minutes after ligation of both common carotid arteries the erythrocyte deformability coefficient decreased by 11±2% in experimental group in comparison with the baseline level and by 12% in comparison with sham-operated animals and remained 16% decreased after 4 days.

C-terminal Pro-Gly-Pro tripeptide in contrast to full-length neuropeptide semax exhibits no neuroprotective effect in experimental cerebral ischemia.

The C-terminal fragment Pro-Gly-Pro of semax does not modulate the development of symptoms of neurological deficiency and mortality in rats with incomplete global cerebral ischemia. Hence, previously revealed neuroprotective effects of semax are mainly determined by corticotropin ACTH4–7 fragment.

Long-term normalization of blood pressure in SHR and 1-kidney 1-clip rats by synthetic precursor of stable PAF analogue without systemic effects in normotensive rats

This study characterized the actions of the newly synthesized PAF precursor 1-hexadecyl-2-alkylcarbamoyl-glycerol (HAG) on blood pressure (BP) in male spontaneously hypertensive rats (SHR), SHR-stroke prone (SHRSP) and Wistar rats with 1-kidney 1-clip (1K1C) renovascular hypertension used as experimental models of human primary and secondary hypertension. Systolic blood pressure (SBP) in the tail artery and mean arterial pressure (MAP) in the abdominal aorta were measured by tail plethysmography and invasive pressure transducer, respectively. Intravenous treatment with 1mg/kg HAG in SHR resulted in a rapid decline of MAP from 151±4 to 127±4mmHg in 50min (p<0.001) that was maintained for 24h after injection (128±5mmHg, p<0.01). We also observed a profound hypotensive effect of HAG in SHRSP but not in normotensive Wistar rats. In 1K1C rats, the magnitude of the BP decline evoked by HAG was correlated with MAP measured before drug administration (R=0.74, p<0.005). In 1K1C rats with SBP>140mmHg, 5mg/kg/48h HAG, given orally for 14 days, decreased SBP by 20-30mmHg without an increase in the death rate and other adverse effects. Thus, our results show that intravenous and oral administration of HAG led to a long-lasting reduction of BP in experimental models of primary and secondary hypertension. In contrast to PAF and its derivatives, the hypotensive action of HAG was preserved for 24h after a single administration, was absent in normotensive animals, and was not accompanied by visible side-effects, at least during 2 weeks of treatment.

Reduced erythrocyte deformability in Krushinsky-Molodkina rats with acute hemorrhagic stroke

Acute hemorrhagic stroke in Krushinsky-Molodkina rats was used to assess the ability of erythrocytes to change their shape in a shear flow. Membrane rigidity and internal viscosity of erythrocytes were measured by laser diffractometry (i.e., obtaining a diffraction pattern from a thin layer of an erythrocyte suspension in a shear flow followed by computer processing of the image). The results testify to reduced deformability of erythrocytes under hemorrhagic stroke.

Reactivity of the basilar artery in Krushinsky-Molodkina rats 24 hours after an audiogenic epileptic seizure

Examination of the reactivity exhibited by the basilar artery of the brain in Krushinsky-Molodkina rats before and after an induced epileptiform seizure accompanied by subarachnoid hemorrhages showed increased contractility of this artery in response to endothelin-1 and its reduced sensitivity to ATP 24 h after the seizure. Such changes in the reactivity of brain vessels may contribute to the development of vasospasm and secondary ischemia of the brain after an epileptic seizure.

Semax increases erythrocyte deformability in the shearing blood stream in intact rats and rats with cerebral ischemia.

208 Cerebral ischemia changes the rheological proper� ties of the blood, including the erythrocyte deform� ability (ED) (1). Its decrease may additionally aggra� vate brain microcirculation and worsen the pathologi� cal process. The synthetic drug Semax (ACTH4-7 - ProGlyPro), which has no hormonal properties, demonstrates neuroprotective effects during cerebral ischemia (2, 3). One of the mechanisms of the protec� tive action of Semax against brain ischemia is probably related to its influence on ED and, respectively, on the blood microcirculation. In this study, we examined in vitro the effects of Semax on ED in intact rats and rats with cerebral ischemia. Male Wistar rats weighing 210 ± 5 g were used for the study. In the first series of experiments, we studied the effects of Semax on ED in intact rats (n = 8). In the second series of experiments, we studied the effects of Semax on ED in rats with cerebral ischemia induced by simultaneous occlusion of the common carotid arteries performed under ether anesthesia (n = 8). For this purpose, the blood was sampled prior to and 90 min after the surgery. The blood was sampled from the jugular vein into test tubes containing 7% EDTA. The blood samples were divided into aliquots, which were mixed with a Semax solution with final concen� trations from 2 × 10 -9 to 2 × 10 -5 M or with a 0.9% NaCl solution, and incubated for 1 h. Then, these samples were diluted with a solution of polyethylenox� ide (MM = 5 × 10 6 ) at a ratio of 1 : 300 in order to get a suspension with a viscosity of 13 cP. We measured the ED in the shearing blood stream using a laser rota� tional diffractometer (7). The shear rate in the stream of erythrocyte suspension in the rheological gap of the diffractometer was changed by steps in the range from 13.8 to 1550 s

Reactivity of rat basilar artery to serotonin after short-term ischemia of hindbrain and during chronic vertebrobasilar insufficiency.

Contractile responses of the basilar artery to serotonin were examined in vitro on two models of circulation disturbances in the vertebrobasilar region of the brain. Two days after 30-min reversible occlusion of vertebral arteries, the sensitivity of the basilar artery to serotonin decreased, while chronic vertebrobasilar insufficiency had no effect on serotonin-induced contraction.