Effect of a combination of coumarin derivatives and rutoside on venous and lymphatic circulations during severe constriction of the caudal vena cava in rabbits.

The effect of a coumarin (CAS 91-64-5) derivatives-rutoside (CAS 153-18-4) combination (Esberiven) has been investigated in an in vivo model of venous hind leg stasis elicited by severe constriction of the caudal vena cava in anesthetized rabbits. The vena cava flow is initially reduced by 80% compared to reference values; then, it significantly declines over time. The venous femoral pressure drops as well as the perfusion pressure whereas the peripheral resistance increases. The popliteal lymph flow gradually slows down after the constriction. Moreover, this venous constriction results in a marked reduction of the right ventricular stroke volume responsible for a left ventricle failure and for the exitus of 30% of the rabbits within 1-3 h post-constriction. A 5-day pretreatment (i.v.) with the coumarin derivatives-rutoside combination at a dose of 4 mg of coumarin derivatives + 200 mg of rutoside/rabbit/day increases the lymph flow but does not suppress the mechanically-induced venous flow decrease. The 6th-day treatment (infusion at the respective doses of 5 mg of coumarin derivatives + 250 mg of rutoside/kg or 10 mg of coumarin derivatives + 500 mg of rutoside/kg) induces a dose-related significant increase of both venous and lymph flows and of the femoral pressure. At the same time, the peripheral venous resistance decreases in a dose-response relationship. Furthermore, after administration of coumarin derivatives and rutoside, the right ventricle stroke volume increases and no death occurs.

Neuropharmacological study of aged MAM-treated rats.

After evaluation of activity in an open field, norepinephrine (NE), serotonin (5HT), 5-hydroxyindolacetic acid (5HIAA), homovanillic acid (HVA), and choline acetyltransferase (CAT) were investigated in cortex of 26-month-old rats poisoned with methylazoxymethanol (MAM) as compared to control rats of the same age. NE and 5HT concentrations showed a marked increase, but levels were normal when expressed as total content, just as in MAM-exposed young adults. Concentrations of 5HIAA were also increased but to a lesser extent than 5 HT. Aged MAM rats did not show any modification of spontaneous activity although hyperactivity is characteristic of young adults exposed to MAM. Together with this behavioral observation, a significant decrease in total HVA content was measured. Because HVA levels seem correlated with activity in MAM-exposed rats, we speculate that the behavioral abnormality recovers in old age. Total CAT activity was also reduced. These results indicate that the neurochemical pattern of young adult MAM-poisoned rats is conserved in aged rats except for some changes in the dopaminergic and cholinergic systems.

Experimental evidence of a potentiation by alpha,beta magnesium L-aspartate of the anxiolytic effect of diazepam. Four-plate test in mice and qEEG study in primates.

The anxiolytic dose 50 (AD50) of diazepam was determined in mice in the four-plate test and the EEG pattern elicited by diazepam was quantified by Fast Fourier Transformation in monkeys. The AD50 of diazepam was reduced by 2.7-fold after repeated treatment with alpha,beta magnesium L-aspartate. The increased EEG fast activity elicited by diazepam at the expense of slow activities was reinforced and more long lasting after alpha,beta magnesium L-aspartate treatment.

Effect of halothane on ischemic brain edema.

Halothane anesthesia (2%) given continuously during the ischemic and post-ischemic period in gerbils does not protect against cytotoxic edema but counteracts superimposed vasogenic edema due to the first BBB opening to serum protein during the reflow period, thus allowing specific gravity values at 1-hour reflow to return to initial levels. It seems likely that this effect of halothane is due to a reduction of the hyperemia by halothane, which reduces both blood pressure and brain metabolism. CBF measurements in halothane-treated animals also indicated that intense early postischemic hypoperfusion may well exist in the absence of brain edema.

The effects of dihydroergocryptine on the neurological and enzyme disorders induced by cerebral ischaemia in rats.

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.

Influence of monosialoganglioside inner ester on neurologic recovery after global cerebral ischemia in monkeys.

We assessed the consequences of transitory global cerebral ischemia and the influence of monosialoganglioside inner ester (AGF 2) treatment on neurologic outcome, cerebral blood flow, and cerebral metabolic rate in monkeys over 48 hours. Global cerebral ischemia was produced by a cervical tourniquet and a lowering of blood pressure to 6.65 kPa; recirculation followed after 30 minutes. AGF 2 (30 mg/kg) was administered intravenously immediately after initiation of recirculation and intramuscularly twice a day for 48 hours. Our results show that treatment with AGF 2 significantly accelerated the rate of neurologic recovery. Improvement was evident 5 hours after ischemia; full neurologic recovery was observed in half of the monkeys 48 hours after ischemia. This recovery was associated with a less severe reduction in cerebral blood flow without a concomitant increase in the cerebral metabolic rate.

Effect of brain gangliosides on early and late consequences of a transient incomplete forebrain ischemia in the rat.

Rat transient incomplete forebrain ischemia was induced by 60 min of bilateral carotid artery occlusion associated with systemic hypotension. Intraperitoneal treatment with either GM-1 monosialoganglioside or its inner ester AGF-2 started 1 h after release of carotid clamps and was repeated twice a day. Ganglioside treatment was effective in reducing the increase of cerebral water content, nonetheless AGF-2 reduces significantly not only cerebral edema, but also potassium efflux and calcium overload. With respect to ischemic untreated rats, GM-1- and AGF-2-treated rats showed a higher incidence of conditioned response retention of a single training trial, associated with improvement in cerebral blood flow and electrocorticographic patterns. In addition, 4 weeks following ischemia, the extent of tissue necrosis was reduced, although not statistically significant, in both ganglioside-treated groups. However, all these improvements are more evident in the AGF-2-treated rats than in the GM-1-treated ones. In conclusion, these results suggest that, except in some cases with different potency, both monosialoganglioside GM-1 and its inner ester derivative, AGF-2, are able to improve outcome after brain ischemia.

Effects of new chemically and metabolically stable prostacyclin analogues (iloprost and ZK 96480) on early consequences of a transient cerebral oligemia, in the rat.

Transient incomplete cerebral ischemia (oligemia) has been obtained in rats by associating mild systemic hypotension with bilateral carotid artery occlusion for 60 min. Continuous i.v drug administration for 3 days, performed with Alzet osmotic minipumps so that to deliver 167 ng.kg-1.min-1 Iloprost, 5 ng.kg-1.min-1 ZK 96480 or their respective vehicle, started 1 hour post-oligemia. Both compounds which are stable prostacyclin analogues reduced the edematous reaction and the post-oligemic accumulation of calcium in the brain tissue but above all they improved, mainly ZK 96480, the learning capacity of injured animals. These results indicate that regarding its therapeutic effect toward early consequences of a transient cerebral oligemia, ZK 96480 has the same profile as Iloprost at a dose 20-fold lower. Thus, these data encourage further clinical studies, in ischemic stroke, in which PGI2 and Iloprost have been shown promising.

Experimental approach of treatment of cerebral ischemia by a combination of raubasine and almitrine.

Post-oligemic syndrome in rat results from transient reduction of cerebral blood flow obtained by bilateral carotid ligation for 60 min and mild systemic hypotension induced by s.c. injection of sodium nitroprusside. Over an acute phase of 3 days the syndrome consisted in a marked neurological deficit evidenced by a decrease in scores obtained by rats in "visual placing" test, a loss in learning ability substantiated by a decrease in the ability of rats to integrate and remember a passive avoidance reflex; biochemical disorders revealed by an increase in cerebral water, calcium and free fatty acids (FFA) contents associated with a decrease in cerebral potassium content. From 2 weeks until 4 weeks after ischemic insult a process of malacia of the cerebral tissue occurred. Treatment of rats with a combination of raubasine and almitrine (5023 SE, Duxil) by oral route (16.7 to 66.6 mg kg-1) twice daily from 1 h post-oligemia to sacrifice, in the acute phase, led to 1. an improvement of visual placing response, 2. an increase in learning ability, 3. a decrease in water and calcium cerebral contents associated with an increase in potassium cerebral contents. Enhancement of FFA contents was reduced when preventive treatment was associated with curative treatment. Incidence and extent of encephalomalacia was reduced by the drug in the chronic phase. It is concluded that in a rat model of post-oligemic syndrome and under these experimental conditions 5023 SE caused, 3 days after the ischemic insult, a significant reduction of cerebral disorders that may explain the therapeutic effect of the drug evidenced 4 weeks later.

Cerebral antioedematous effect of Teproside and of some vincamine derivatives.

Alkyltin compounds are known to produce in the rat a selective oedema of the CNS, especially of the white matter. Vincamine and vincamine derivatives, among which Teproside is the most potent, are able to prevent the occurrence of such an oedematous reaction whereas xanthine derivatives and papaverine fail to prevent this oedema. It is suggested that there may be a potentiation of the effect of vincamine by the xanthine part of the Teproside chemical structure.

[Cerebral blood flow and metabolism, and neurologic deficit in an experimental infarction. Application to the study of an ergot derivative]. / Débit sanguin, métabolisme cérébral et déficit neurologique au cours d'un infarctus expérimental. Application à l'étude d'un dérivé de l'ergot de seigle.

Both age and hypertension are risk factors for the brain. In the presence of a multiple cerebral infarction as obtained by the intra-carotid injection of sodium arachidonate, Hydergine is capable, in the young and old, hypertensive or normotensive rat, of limiting the extent of the edematous reaction, to prevent the intra-cerebral accumulation of Ca++ ions, and limit the fall in cerebral blood flow, all of these facts resulting in a significant improvement in neuromotor behaviour.

[Administration of procyanidolic oligomers in rats. Observed effects on changes in the permeability of the blood-brain barrier]. / Etude de l'administration d'oligomères procyanidoliques (OPC) chez le rat. Effets observés sur les altérations de la perméabilité de la barrière hémato-encéphalique.

Cerebral microvessel permeability disturbances following rapid injection of autologous blood into the carotid artery are evidenced in cross sections of the rat brain by extravascular dye leakage. Here, Evans blue was injected intravenously 2 hours after the blood injection and 30 minutes before sacrificing the animals. Five groups of 10 rats each were given Procyanidolic Oligomers (PCO) in respective doses of 10, 30 and 300 mg/kg by oral route and 10 and 30 mg/kg by intraperitoneal route. Three PCO doses were administered prior to blood injection, on D-2, D-1 and DO. At oral doses of 10 and 30 mg/kg, the blue color in the injected hemisphere was significantly less intense than in the untreated group. When administered intraperitoneally, PCO showed a preventive effect on both the degree and extent of lesions. The following mechanism of action of PCO has been put forward in this experimental model: these compounds may increase the resistance of the tight junctions of arteriolar capillaries, thus interfering with the sudden rise in pressure at the time of blood injection.

[Administration of procyanidolic oligomers in rats. Observed effects on changes in the cerebral biochemistry, secondary to multiple infarction]. / Etude de l'administration d'oligomères procyanidoliques (OPC) chez le rat. Effets observés sur les altérations de la biochimie cérébrale, secondaires à un infarctus multiple.

Sodium arachidonate injection into the carotid artery of rats produces multiple cerebral infarction, evidenced clinically by behavioral disorders (that can be qualified using standard tests) and biochemically by various disturbances including increased cerebral contents of water, sodium and calcium. This study was carried out in several groups of 20 rats each. Two groups were treated preventively with 100 and 200 mg/kg respectively, Procyanidolic Oligomers (PCO) daily, given by gastric route for ten days. Observed disorders were significantly less severe and biochemistry changes were partly corrected in treated groups compared with the untreated group. This preventive effect was more significant in the group given 200 mg/kg/day.