dihydroergotoxine and Brain-Ischemia

Topics: Aged; Aging; Brain; Brain Ischemia; Cell Membrane; Cell Survival; Dihydroergotoxine; Drug Therapy; Humans; Hypoxia, Brain; Oxygen Consumption

Despite the high prevalence of chronic vascular encephalopathy, its diagnosis and treatment remain understudied. This observational multicenter trial assessed the efficacy and safety of vasobral in patients with cerebral ischemia.. The open observational study was carried out in 37 centers in 11 Russian cities and included 300 patients with confirmed diagnosis of chronic vascular encephalopathy, stages 1 and 2, without dementia. The patients received 1 tablet (4 mg α-dihydroergocryptine and 40 mg caffeine) 2 times a day during 3 months.. There was an improvement of cognitive and affective status as well as quality of life and a decrease of subjective signs of chronic vascular encephalopathy. Vasobral did not cause significant fluctuations of arterial pressure and was safe for patients with chronic vascular encephalopathy and arterial hypertension.

Topics: Adult; Aged; Brain Damage, Chronic; Brain Ischemia; Caffeine; Cerebral Small Vessel Diseases; Dihydroergotoxine; Drug Combinations; Female; Humans; Male; Middle Aged; Treatment Outcome

Topics: Age Factors; Aged; Aged, 80 and over; Brain Ischemia; Clinical Trials as Topic; Dihydroergotoxine; Drug Administration Schedule; Female; Humans; Male

Topics: Aged; Brain Ischemia; Clinical Trials as Topic; Dihydroergotoxine; Humans

alpha-Dihydroergocryptine (alpha-DHEC) is a well known dopaminergic agent successfully employed in the treatment of Parkinson's disease. alpha-DHEC showed a neuroprotective activity against total cerebral ischemia induced by MgCl2 in mice and histocytic anoxia by NaCN in mice and rats. Moreover the drug promoted the recovery of locomotor activity in rats after cerebral ischemic damage and protected mice against convulsions induced by intracerebroventricular injections of NMDA and glutamate. alpha-DHEC showed a protective activity on neuronal degeneration induced by MPTP in monkeys, as evaluated through animal's behaviour and morphological-cytochemical changes in the substantia nigra, suggesting a preservative effect on neuronal morphology and brain architecture. In the MPTP-treated monkeys, the alpha-DHEC administration induced a restoration of the unstimulated MDA values to control levels. The neuroprotective activity of alpha-DHEC is related to its peculiar activity on antioxidative enzymes of GSH system and to reduction of lipid-peroxide-induced cellular degeneration.

Topics: Animals; Brain Ischemia; Constriction; Dihydroergotoxine; Disease Models, Animal; Hypoxia, Brain; Injections, Intraventricular; Macaca fascicularis; Male; Mice; Mice, Inbred ICR; Motor Activity; Neuroprotective Agents; Parkinson Disease, Secondary; Rats; Seizures

The effect of incomplete 4 hr ischemia and subsequent 1 hr reperfusion of the rat brain on the density and affinity of alpha-adrenergic binding sites was investigated. To assess the involvement of oxygen-derived free radicals in the development of ischemic injury, we tested the effect of stobadine and vitamin E on putative changes of the binding parameters of alpha-adrenergic binding sites in ischemic and reperfused rat brains. Compared to the group of sham operated animals decreased density and increased affinity of [3H]dihydroergocryptine binding sites was found in cerebrocortical membranes of rats subjected to 4 hr incomplete ischemia and 1 hr reperfusion. The reduction of Bmax and Kd induced by ischemia and reperfusion of the brain was prevented by stobadine and vitamin E administration. Neither incomplete ischemia nor incomplete ischemia and subsequent reperfusion of the rat brain exerted significant effect on [3H]rauwolscine binding to alpha 2-adrenergic binding sites. Our results suggest that brain ischemia and reperfusion may affect the density and affinity of alpha 1- rather than of alpha 2-adrenergic binding sites. The beneficial effect of stobadine and vitamin E indicates that increased generation of oxygen free radicals might play a role in the development of these changes.

Topics: Animals; Antioxidants; Brain Ischemia; Carbolines; Cerebral Cortex; Dihydroergotoxine; Free Radicals; Kinetics; Male; Membranes; Rats; Rats, Wistar; Reactive Oxygen Species; Receptors, Adrenergic, alpha; Receptors, Adrenergic, alpha-1; Receptors, Adrenergic, alpha-2; Reperfusion; Vitamin E; Yohimbine

Ergot alkaloids are commonly used as cerebroprotective drugs. Their efficacy has been demonstrated experimentally in animals submitted to acute cerebral anoxia or ischaemia, at dose levels hugely superior to dose levels usually administered in humans. In the present experiments, dihydroergocryptine (DHEC), a constituent of dihydroergotoxine (DHET), was administered at doses closely related to human doses, preventively (in experiments where animals survived only for a short while after ischaemic insult) or curatively, and its efficacy tested through refined neurological and biochemical evaluation of experimental cerebral ischaemia sequelae. DHEC was administered orally (30 micrograms or 150 micrograms/kg body weight (bwt) twice daily) for 3 days, following transient cerebral ischaemia induced by a 60-min carotid occlusion plus sodium nitroprusside (1.1 mg/rat s.c.) injection, or, in a second experiment, prophylactically (60 micrograms or 300 micrograms/kg bwt/day) for 4 days prior to multiple cerebral infarct induced by sodium arachidonate injection into the left internal carotid artery. The neurological sequelae were evaluated by the Irwin visual placing response or by a battery of behavioural tests. Na-K-ATPase enzyme activity in cerebral homogenates was measured; decreases in this enzyme activity are considered to reflect the neuronal membrane consequences of the neurocell energetic metabolism alterations caused by cerebral ischaemia. Low dose oral DHEC treatment prevented the behavioural abnormalities and memory impairment arising after transient cerebral ischaemia and there was a marked trend in improving the behavioural abnormalities observed in animals submitted to massive cerebral infarction, in spite of the model severity. DHEC prevented reduction in cerebral Na-K-ATPase activity after cerebral multiinfarction. These effects of DHEC were observed with doses and administration route close to the usual therapeutic regimen.

Topics: Animals; Brain; Brain Ischemia; Cerebral Infarction; Dihydroergotoxine; Male; Neurologic Examination; Rats; Rats, Inbred Strains; Sodium-Potassium-Exchanging ATPase

The protective efficacy of pentoxiphylline, piracetam, and dihydroergotoxine against abrupt hypoxia was tested in a model of acute reversible respiratory failure, where repeated apnoeic attacks were induced by inhalation in repeated hypoxic exposures was reduced in control as well as in dihydroergotoxine-treated animals, it was increased after pentoxiphylline, and was not changed after piracetam. Repeated N2 inhalations reduced the duration of apnoea required for the development of mydriasis in all control cats. There were, however, no such reductions of the apnoeic interval in animals of the three groups treated with cerebroprotective drugs. The ratio between the total duration of hypoxia (hypoxic hyperventilation plus apnoea) and the time of recovery of breathing was significantly higher in the pentoxiphylline-treated animals already during the first hypoxic attack after drug application when compared both to the control and the dihydroergotoxine-treated animals. After piracetam the difference was apparent in the last hypoxic attack only. The model of acute reversible respiratory failure with apnoeic episodes induced repeatedly seems to be useful for testing some properties of cerebroprotective drugs during abrupt hypoxia.

Topics: Animals; Brain Ischemia; Cats; Dihydroergotoxine; Disease Models, Animal; Electrocardiography; Hypoxia; Nitrogen; Pentoxifylline; Piracetam; Respiration, Artificial; Respiratory Insufficiency

The CA 1 neurons in the gerbil hippocampus exhibiting necrosis with delayed onset following 5 min ischemia were reduced markedly by the systemic administration of dihydroergotoxine mesylate (Hydergine; HYG). Immediately after 5 min of forebrain ischemia, the animals were injected intraperitoneally with HYG. Seven days after ischemia, perfusion-fixed brains were processed by conventional histology. The number of neurons per millimeter in the CA 1 pyramidal cell layer were calculated and they were labelled neuronal density. In the control group, the neuronal density was 66.03 +/- 7.37 (mean +/- SEM), in the vehicle group, it was 11.25 +/- 4.93. The neuronal density in the HYG group was 69.19 +/- 6.49. The difference in the neuronal density between the HYG group and the control group was not statistically significant. These data indicate that HYG protects on the CA 1 neurons, and this suggest that the suppression of adrenoceptors by this drugs may be the main mechanism of action. This morphologic outcome may explain the functional amelioration of mental impairment by HYG.

Topics: Animals; Brain Ischemia; Cell Survival; Dihydroergotoxine; Gerbillinae; Hippocampus; Male; Nerve Degeneration; Synaptic Transmission

Topics: Aged; Brain Ischemia; Caffeine; Cerebrovascular Circulation; Dihydroergotoxine; Drug Combinations; Humans; Middle Aged; Psychometrics

Topics: Aged; Brain Ischemia; Cerebrovascular Disorders; Dihydroergotoxine; Female; Humans; Male; Middle Aged; Neurocognitive Disorders

In pharmacological screening tests for activity against the cerebral insults of hypoxia and ischaemia induced by MgCl2 or decapitation in mice, the combination of piracetam and dihydroergocristine has been shown to produce synergistic effects in prolonging the survival time. This was not the case in the model of histiocytic anoxia induced by KCN. Using an optimal combination of piracetam and dihydroergocristine (533:1, Diemil) significant increases in cerebral resistance to hypercapnic anoxia and reductions in the duration of the ensuing electrical silence on the electrocorticogram have been demonstrated in the rat. The same combination was also effective in antagonizing the memory ablating effects of anoxia in rats subjected to electric footshocks during a standard passive avoidance response. The absence of clear effects on gross cerebral blood flow and metabolism, together with considerations of the known pharmacological properties of the two components of the combination and the effects of standard drugs in the models used, lead to the conclusion that the explanation of the observed synergism probably lies in complimentary actions at the level of the cerebral neurones and is independent of simple vasodilation.

Topics: Anesthesia; Animals; Avoidance Learning; Brain Ischemia; Cerebrovascular Circulation; Dihydroergotoxine; Dogs; Drug Synergism; Hemodynamics; Hypercapnia; Hypoxia, Brain; Magnesium; Magnesium Chloride; Male; Mice; Pentobarbital; Piracetam; Pyrrolidinones; Rats; Rats, Inbred Strains; Reflex

The effects of a new eburnamenine derivative (3 beta,14 alpha, 16 alpha)-(+/-)-14,15-dihydro-20,21-dinoreburnamenin-14-ol (vindeburnol, RU 24722) on EEG, on brain energy metabolism and on local cerebral blood flow (LCBF) and in different experimental models of cerebral insufficiency were compared with those of vincamine, vinburnine (1-eburnamonine), dihydroergotoxine mesilate and nicergoline. Vindeburnol at 2 mg/kg i.v., increased the EEG resistance time in rats subjected to asphyxia anoxia and at 10 mg/kg s.c., significantly improved the electrocortical recovery of gerbils subjected to a 10-min cerebral ischemia. Vindeburnol (10 mg/kg i.p.) significantly retarded glucose, phosphocreatine and adenosine triphosphate utilization and lactate production in mouse brain during 10 s of decapitation ischemia. The cerebral metabolic rate was 10.34 mmol/kg/min, which was about 50% of the control value. At 10 mg/kg i.p., the product induced a slight and transient increase in LCBF. Vincamine improved the early phase of the postischemic electrocortical recovery in the gerbil, had no effect on cerebral energy substrates and slightly increased the LCBF for 15 min. Dihydroergotoxine mesilate improved the early phase of the electrocortical recovery in gerbils subjected to ischemia, did not significantly modify the energy substrates and rapidly increased the LCBF, which was normal after 30 min. Vinburnine and nicergoline were inactive in the cerebral insufficiency models used and did not significantly modify cerebral energy metabolism. These results show that vindeburnol has a different pharmacological profile from vincamine, vinburnine, dihydroergotoxine mesilate and nicergoline, and suggest that vindeburnol may be therapeutically effective in cerebral insufficiency.

Topics: Animals; Brain Ischemia; Cerebral Cortex; Cerebrovascular Circulation; Cerebrovascular Disorders; Dihydroergotoxine; Electroencephalography; Ergolines; Gerbillinae; Male; Mice; Mice, Inbred Strains; Nicergoline; Rats; Rats, Inbred Strains; Vinca Alkaloids; Vincamine

The influence of a new eburnamenine derivative RU 24722 [(3 beta, 14 alpha, 16 alpha)-(+/-)-14,15-dihydro-20,21-dinoreburnamenin -14-ol] on post-ischemic EEG recovery was studied in N2O anesthetized rats subjected to 1 min of global-compression cerebral ischemia. RU 24722 was compared with vincamine, dihydroergotoxine mesylate and nicergoline. Treatment with RU 24722 (2 mg/kg i.v.) significantly decreased the EEG recovery time and increased the electrocortical activity during the first phase of the post-ischemic recovery. Vincamine (2 mg/kg i.v.), dihydroergotoxine mesylate (0.5 mg/kg i.v.) and nicergoline (0.5 mg/kg i.v.) were devoid of activity. In an attempt to elucidate its mechanism of action, the influence of RU 24722 on changes in the cerebral metabolic energy reserves was studied in mouse brain after different periods of decapitation ischemia. The changes occurring during the first 10 s of ischemia were used to calculate the baseline cerebral metabolic rate (CMR). The activity of RU 24722 was compared with that of vincamine and pentobarbital. RU 24722 (10 mg/kg i.p.) significantly retarded glucose, phosphocreatine and adenosine triphosphate utilisation and lactate production. Vincamine (10 mg/kg i.p.) had no effect on cerebral energy substrates. Pentobarbital (100 mg/kg i.p.) markedly increased the tissue concentration of glucose and phosphocreatine and decreased lactate levels before and after ischemia. The improvement of EEG recovery suggests that RU 24722 may be therapeutically effective in cerebral insufficiency, and the decreased brain energy demand may be one of the mechanisms by which RU 24722 has a protective effect against cerebral ischemic damage.

Topics: Adenosine Triphosphate; Animals; Brain; Brain Ischemia; Dihydroergotoxine; Electroencephalography; Energy Metabolism; Glucose; Glycogen; Lactates; Lactic Acid; Male; Mice; Nicergoline; Phosphocreatine; Rats; Vasodilator Agents; Vinca Alkaloids; Vincamine

The effect of the alpha-adrenoblockers, nicergoline (N) and dihydroergotoxin (DHET), on the cerebral vessels and the systemic hemodynamics was studied in 152 patients with acute and chronic vascular diseases of the brain. It was established that the hypotensive action of alpha-blockers was the greater the higher was the initial arterial hypertension. REG conducted during an hour after the intravenous administration of N and DHET revealed an increase in the pulse blood filling and an improvement of the arterial tone. Changes in vascular resistance were heterogeneous. Both drugs induced the venous outflow but there were no signs of venous hypotension. An improvement in the systemic and cerebral hemodynamics correlated with clinical improvement.

Topics: Blood Pressure; Brain Ischemia; Cerebrovascular Circulation; Cerebrovascular Disorders; Dihydroergotoxine; Ergolines; Humans; Nicergoline; Plethysmography, Impedance; Subarachnoid Hemorrhage; Vascular Resistance

Topics: Aged; Brain Ischemia; Central Nervous System; Dihydroergotoxine; Female; Humans; Male; Middle Aged

The effect of dihydroergocristine on energy metabolism was studied in the isolated perfused rat brain affected by ischemia and in cultivated C-1300 neuroblastoma cells deprived of oxygen and glucose. Creatine phosphate, ATP, ADP, AMP, glucose, glucose-6-phosphate, fructose-6-phosphate, fructose-1,6-diphosphate, pyruvate, and lactate were measured enzymatically. After a perfusion period of 30 min, the cortex of the isolated perfused rat brain exhibited an energy state not different from that in vivo. Dihydroergocristine added to the perfusion medium (5 mumol/L) did not influence these substrate levels under normal perfusion conditions. However, this drug was able to retard the breakdown of high-energy phosphates during ischemia and to accelerate the restoration of the energy state during the postischemic reperfusion period. The perfusion rate was not changed by the drug, and therefore it was assumed that dihydroergocristine could act directly on cell metabolism. This view was supported by the results obtained from experiments using cultivated N-2a neuroblastoma cells. These cells were incubated in a buffered salt solution deprived of glucose and oxygen for 15 min. Under these conditions, dihydroergocristine (2 mumol/L) added to the incubation medium caused changes in the concentrations or the high-energy phosphates similar to those in the isolated brain preparation: It increased the ATP concentration and decreased the ADP concentration significantly.

Topics: Adenosine Triphosphate; Animals; Brain; Brain Ischemia; Cells, Cultured; Dihydroergotoxine; Electroencephalography; Energy Metabolism; Glucose; Neuroblastoma; Oxygen Consumption; Rats

The effects of ageing in normal and pathological rats were studied. Learning (spatio-temporal test) was measured simultaneously with the local cerebral blood flow, determined by a diffusible indicator (iodoantipyrine) and with the uptake and consumption of glucose, determined by the deoxyglucose. Normal ageing disturbs the learning with a decrease in acquisition speed and an increase in the number of errors. Furthermore, normal ageing induces a decrease in glucose uptake and in glucose consumption in the brain structures such as hippocampus or corpus striatum, with only a slight decrease in local cerebral blood flow. Dihydroergotoxine partially reestablishes the performances of the rats and increases the glucose consumption in the areas involved in learning. Pathological ageing, produced by the administration of microspheres and corresponding to the multi-infarct dementia, is correlated to a large decrease in glucose consumption and local blood flow. Dihydroergotoxine treatment partially suppresses the micro-infarct effects before the reestablishment of rat performance in behavioral tests.

Topics: Acute Disease; Aging; Animals; Brain; Brain Ischemia; Cerebrovascular Circulation; Dihydroergotoxine; Learning; Rats

Topics: Acute Disease; Animals; Arachidonic Acid; Arachidonic Acids; Blood-Brain Barrier; Brain Ischemia; Cerebral Infarction; Cerebrovascular Circulation; Dihydroergotoxine; Dogs; Ergot Alkaloids; Free Radicals; Membrane Lipids; Rabbits; Rats

Topics: Adenosine Triphosphate; Animals; Brain Edema; Brain Ischemia; Cerebral Cortex; Cyanides; Dihydroergotoxine; Disease Models, Animal; Hypoxia; Indoles; Indoramin; Rats

Glycolytic substrates and metabolites (glycogen, glucose, glucose-6-phosphate, pyruvate, lactate), tricarboxylic acid cycle intermediates (citrate, alpha-ketoglutarate, succinate, fumarate, malate), related amino acids (glutamate, glutamine, alanine, gamma-aminobutyrate) and energy mediators (ATP, ADP, AMP, creatine phosphate) were evaluated in the cerebral cortex of rats after 5 min of complete compression ischemia as well as after 3, 15 or 30 min of recirculation following 5 min ischemia. The post-ischemic recovery was studied in control animals or in animals treated (30 min before ischemia and during discovery) by intravenous perfusion of vincamine, theophylline, dihydroergocristine and alanine. Interrelated changes of intermediates of the carbohydrate and the amino acid metabolism have been observed. It is concluded that alanine perfusion induced a partial detour of the lactacid anaerobic process towards the succinate-related alactacid cycle, leading to an increase in the cortical gamma-aminobutyrate content. Vincamine and dihydroergocristine acted in the opposite direction.

Topics: Alanine; Amino Acids; Animals; Brain Ischemia; Cerebral Cortex; Dihydroergotoxine; Energy Transfer; Glycolysis; Male; Rats; Theophylline; Vincamine

Topics: Adult; Aged; Blood Pressure; Brain Ischemia; Carbon Dioxide; Cerebrovascular Circulation; Dihydroergotoxine; Female; Humans; Hyperemia; Male; Middle Aged; Partial Pressure; Xenon Radioisotopes