Effects Of Nicergoline Research Articles

Nicergoline inhibits human platelet Ca(2+) signalling through triggering a microtubule-dependent reorganization of the platelet ultrastructure.

Recently, we demonstrated that a pericellular Ca(2+) recycling system potentiates agonist-evoked Ca(2+) signalling and granule secretion in human platelets and hypothesized a role for the membrane complex (MC) in orchestrating the accumulation of Ca(2+) in the pericellular region. Previous work has demonstrated that treatment with high concentrations of nicergoline may disrupt the MC through an ability to trigger a re-organization of the dense tubular system. Experiments were therefore performed to assess whether nicergoline-induced changes in platelet ultrastructure affects thrombin-evoked Ca(2+) fluxes and dense granule secretion. Thrombin-evoked Ca(2+) fluxes were monitored in Fura-2- or Fluo-5N-loaded human platelets, or using platelet suspensions containing Fluo-4 or Rhod-5N K(+) salts. Fluorescence microscopy was utilized to monitor microtubule structure and intracellular Ca(2+) store distribution in TubulinTracker- and Fluo-5N-loaded platelets respectively. Dense granule secretion was monitored using luciferin-luciferase. Nicergoline treatment inhibited thrombin-evoked Ca(2+) signalling and induced alterations in the microtubule structure and the distribution of intracellular Ca(2+) stores in platelets. Nicergoline altered the generation and spreading of thrombin-induced pericellular Ca(2+) signals and almost completely prevented dense granule secretion. Stabilization of microtubules using taxol reversed most effects of nicergoline on platelet Ca(2+) signalling and partially reversed its effects on dense granule secretion. Nicergoline-induced alterations to platelet ultrastructure disrupt platelet Ca(2+) signalling in a manner that would be predicted if the MC had been disrupted. These data suggest that nicergoline may be a useful prototype for the discovery of novel MC-disrupting anti-thrombotics.

The Effects of Nicergoline on Corneal Nerve Regeneration in Rat Corneas after Photorefractive Keratectomy

Purpose: We wanted to investigate the effect of nicergoline on corneal nerve regeneration in rat corneas after photorefractive keratectomy (PRK).Methods: Twenty Sprague–Dawley male rats were divided into two groups, the control group and the group that had been treated with nicergoline for 4 weeks. Corneal wound healing was evaluated by fluorescein staining after PRK. Immunofluorescent staining was performed in the rat corneas at 1 month after PRK with monoclonal antibodies for class III β-tubulin, calcitonin gene-related peptide (CGRP), and substance P (SP). The stained nerve areas were calculated using an image-analysis program.Results: The corneal wound healing rate was not significantly different between the nicergoline-treated rats and the control rats after PRK. At 1 month after PRK, the tubulin-positive, substance P-positive, and CGRP-positive nerve areas were significantly greater in the treatment group than those in the control group.Conclusion: Nicergoline treatment increased the corneal nerve area in the rats after they had undergone PRK. Nicergoline may help patients who have a decreased corneal sense, such as those with neurotrophic keratopathy and those patients after they undergo refractive surgery.

1- 13C]Glucose entry in neuronal and astrocytic intermediary metabolism of aged rats : A study of the effects of nicergoline treatment by 13C NMR spectroscopy

Age-related changes in glucose utilization through the TCA cycle were studied using [1- 13C]glucose and 13C, 1H NMR spectroscopy on rat brain extracts. Significant increases in lactate levels, as well as in creatine/phosphocreatine ratios (Cr/PCr), and a decrease in N-acetyl-aspartate (NAA) and aspartate levels were observed in aged rat brains as compared to adult animals following glucose administration. The total amount of 13C from [1- 13C]glucose incorporated in glutamate, glutamine, aspartate and GABA was significantly decreased in control aged rat brains as compared to adult brains. The results showed a decrease in oxidative glucose utilization of control aged rat brains. The long-term nicergoline treatment increased NAA and glutamate levels, and decreased the lactate levels as well as the Cr/PCr ratios in aged rat brains as compared to adult rats. The total amount of 13C incorporated in glutamate, glutamine, aspartate, NAA and GABA was increased by nicergoline treatment, showing an improvement in oxidative glucose metabolism in aged brains. A significant increase in pyruvate carboxylase/pyruvate dehydrogenase activity (PC/PDH) in the synthesis of glutamate in nicergoline-treated aged rats is consistent with an increase in the transport of glutamine from glia to neurons for conversion into glutamate. In adult rat brains, no effect of nicergoline on glutamate PC/PDH activity was observed, although an increase in PC/PDH activity in glutamine was, suggesting that nicergoline affects the glutamate/glutamine cycle between neurons and glia in different ways depending on the age of animals. These results provide new insights into the effects of nicergoline on the CNS.

Haloperidol-induced changes in glutathione and energy metabolism: effect of nicergoline.

The aim of this study was to evaluate the possible effects of nicergoline, a semisynthetic ergot derivative, on the biochemical changes observed during chronic treatment with haloperidol in male Sprague–Dawley rats. Chronic treatment with haloperidol induced a significant decrease in the cellular glutathione (GSH) content in selected areas of the brain (cerebellum, striatum and cortex) and in the liver. Prolonged nicergoline administration was able to antagonize the haloperidol-induced GSH decrease, maintaining the GSH concentration at levels comparable to those observed in the control group. Analysis of the energy charge revealed changes similar to those observed for GSH: haloperidol induced a significant decrease in ATP and energy charge that was completely reversed by repeated nicergoline administration. In conclusion, chronic treatment with the classical antipsychotic haloperidol induces profound biochemical changes in the brain and in the liver. Nicergoline treatment is able to counteract the haloperidol-induced decrease in GSH levels and energy charge, suggesting a potential role of the drug in the treatment of neuroleptic-induced side effects.

Effects of nicergoline on age-related decrements in radial maze performance and acetylcholine levels.

The effects of chronic oral administration of nicergoline (5.0 mg/kg; bid) on locomotor activity, eight-arm radial maze performance plus striatal, cortical, and hippocampal acetylcholine (ACh) levels were examined in young and aged Wistar rats. Chronic nicergoline administration did not modify either the locomotor activity or radial maze learning in young rats. Young rats learned the radial maze procedure rapidly and improved their performance throughout the successive training sessions. Radial maze performance in young rats was characterised by very few arm reentries. Aged rats were hypoactive and did not explore or enter the radial maze arms, and consequently performed poorly in the radial maze throughout the training sessions. Nicergoline treatment did not significantly modify locomotor activity in aged rats. Aged rats treated with nicergoline also performed poorly initially but improved with repeated training in the radial maze. This improvement was associated with an increasing number of arms being entered and very few arm reentries. Reduced acetylcholine (ACh) levels were also associated with age. Aged rats had significantly reduced levels of ACh in the straitum and cortex, but not the hippocampus as compared to young rats. Nicergoline treatment did not change ACh levels in young rats, but substantially restored the reduced ACh levels in aged rats. These results indicate that nicergoline is an effective cognitive enhancer in a learning model of age-related deficits and that these results may be related to changes in the cholinergic system.

Modulation of hippocampal ACh release by chronic nicergoline treatment in freely moving young and aged rats

The effects of nicergoline on basal and K +-stimulated release of ACh in the hippocampus of 3- and 19-month old rats has been studied by microdialysis. A significant decrease of basal ACh release (59%) was found in aged vehicle treated rats in comparison to young rats. High-K + (100 mM) in the perfusate strongly increased the release of ACh by up to 6-fold over the baseline of both young and aged rats. Chronic oral administration of nicergoline to aged rats (5 mg/kg b.i.d. for 6 weeks) significantly reversed (93%) the age-related decrease of basal release of ACh, leaving the increase dur to K + depolarization unchanged. In young animals, nicergoline did not affect the basal output of ACh, but enhanced the K +-evoked release of ACh by 39%. Results from this study demonstrate that nicergoline treatment increases the ability of hippocampal cholinergic terminals to release ACh, and suggest that this drug can reset the cholinergic impairement associated with aging.

Effects of nicergoline on event-related potential (ERP)

“Oddball” paradigm studies of auditory P300 have yielded conflicting results in migraine. We therefore undertook an additional study of auditory event-related potentials (ERPs) using an improved method of EEG processing, strict criteria for patients selection, and comparison with behavioral data. Twenty-one healthy subjects were compared to 20 patients suffering from migraine without aura between attacks. Migraineurs differed significantly from control subjects on several parameters: shorter latency of N1 (Cz) evoked by standard stimuli, longer latencies of both P3a and P3b (Pz) evoked by target stimuli, longer interval between N1 and P3b (Cz), smaller P3b (Cz) amplitude, longer reaction time (RT), higher number of errors (false alarm and/or omissions) and higher mean score on Plutchik-Van Praag's (PVP) inventory for depression. Errors were significantly correlated with RT and PVP scores. From a behavioral perspective, these results may suggest that patients suffering from migraine without aura between attacks display a higher level of arousal and more superficial attention, but require more time for automatic and/or voluntary processes. According to the inverted U-shaped relationship between performance and arousal, these patients may have difficulties in adjusting their attention level to perform a task in a optimal way.Les études utilisant le paradigme “odd-ball” de la P300 ont montré des résultats contradictoires dans la migraine. Ainsi nous avons entrepris une étude additionnelle des potentiels auditifs liés à l'événement (ERPS), en utilisant une méthode électroencéphalographique améliorée, une sélection stricte des patients et une comparaison avec les données comportementales. Vingt et un sujets sains furent comparés à 20 patients présentant une migraine sans aura, entre des attaques. Les migraineux diffèrent significativement des contrôles sur plusieurs paramètres: une latence plus courte de N1(CZ) évoquée par des stimuli standards, une plus longue latence de P3a et de P3b (BZ) évoquée par le stimulus cible, un plus long intervalle entre N1 et P3b (CZ), une plus petite amplitude de P3b (CZ), un plus long temps de réaction (RT), un nombre plus élevé d'erreurs (fausse alarme et/ou omission) et un score moyen plus haut à l'échelle de Pluschnig Van Praag pour la dépression. Les erreurs étaient significativement corrélées avec le TR et le score de la PVP. Dans une perspective comportementale ces résultats peuvent suggérer que les patients souffrant de migraine sans aura présentent, entre les attaques, un plus haut niveau d'éveil et plus d'attention superficielle. Ils utilisent plus de temps pour les processus automatiques et/ou volontaires. En accord avec la relation en U inversé entre les performances et l'éveil, ces patients peuvent avoir des difficultés d'ajustement de leur niveau d'attention pour réaliser des tâches de façon optimale.

Effects of nicergoline (Sermion R) on basal and agonist-stimulated phosphoinositide turnover in the rat brain.

The effects of nicergoline on basal and K+-stimulated release of ACh in the hippocampus of 3- and 19-month old rats has been studied by microdialysis. A significant decrease of basal ACh release (59%) was found in aged vehicle treated rats in comparison to young rats. High-K+ (100 mM) in the perfusate strongly increased the release of ACh by up to 6-fold over the baseline of both young and aged rats. Chronic oral administration of nicergoline to aged rats (5 mg/kg b.i.d. for 6 weeks) significantly reversed (93%) the age-related decrease of basal release of ACh, leaving the increase dur to K+ depolarization unchanged. In young animals, nicergoline did not affect the basal output of ACh, but enhanced the K+-evoked release of ACh by 39%. Results from this study demonstrate that nicergoline treatment increases the ability of hippocampal cholinergic terminals to release ACh, and suggest that this drug can reset the cholinergic impairement associated with aging.

Clinical and biochemical effects of nicergoline in chronic schizophrenic patients.

To investigate the potential effect of Nicergoline, an alpha-adrenolytic drug, on negative symptoms in patients suffering from chronic schizophrenia, we administered this compound to 20 male chronic schizophrenics. Patients were previously maintained on long-term neuroleptic (NL) medication. Neuroleptic treatment was discontinued for 12 days, patients were then treated with 30 mg Nicergoline per day. Under NL (A), after 12 days NL-withdrawal (B), after 15 (C) and 30 (D) days Nicergoline treatment clinical ratings (BPRS and AMDP) and stimulation with clonidine (0.002 micrograms/kg body weight) were carried out. Norepinephrine (NE), epinephrine (E), and human growth hormone (HGH) were measured before and after application. Seventeen patients finished the study, 3 dropped out. Some ratings on the AMDP and BPRS scales showed an improvement. However, this improvement was only weak and accompanied by a worsening in other subscores. The withdrawal-induced decrease in NE serum levels continued after 15 days NIC, followed by an increase after 30 days. HGH response to clonidine stimulation was only attenuated after 30 days NIC. Epinephrine, blood pressure and heart rate showed no significant changes throughout the entire study. Our data suggest that NIC in the dosage applied shows no clear and pronounced alpha-2-adrenolytic effects and no specific clinical benefits for chronic schizophrenics. Further investigations are required to evaluate its effect on alpha-1-adrenoceptors.

Do Alterations in Prostanoid or Catecholamine Release Influence the Antiarrhythmic Activity of Nicergoline?

We examined the effects of nicergoline, an alpha-adrenoceptor blocking drug and an inhibitor of platelet phospholipase, on haemodynamics, blood gases, cardiac arrhythmias, and prostanoid and catecholamine release in anaesthetised greyhounds before, during, and after a 40-min occlusion of the left anterior descending coronary artery. Twenty-five minutes after commencing the intravenous infusion of nicergoline (50 micrograms kg-1 min-1) there were significant reductions in heart rate, arterial blood pressure, left ventricular dP/dtmax, and cardiac output. Nicergoline also increased the 0(2) extraction by the myocardium both before and during coronary artery occlusion. In contrast to control animals, heart rate decreased but there were no further reductions in arterial blood pressure during the occlusion period. Nicergoline improved survival (from 17 in control dogs to 50%) following the combined period of myocardial ischaemia and reperfusion and appeared to suppress the phase 1b occlusion-induced arrhythmias. The release of thromboxane B2 from the ischaemic myocardium was partially suppressed by nicergoline, and the ratio of 6-keto PGF1 alpha/thromboxane B2 (the stable breakdown products of prostacyclin and thromboxane A2, respectively) was increased. The washout of noradrenaline and adrenaline from the ischaemic myocardium following release of the occlusion was slightly enhanced by nicergoline. It is concluded that the beneficial metabolic and prostacyclin-promoting properties of nicergoline may be opposed by its action on noradrenaline washout, thus limiting its antiarrhythmic effectiveness.

Effects of nicergoline on cerebral energy metabolism in normal mice

Effects of nicergoline, a cerebral circulation and metabolism ameliorator, on cerebral energy metabolism were studied in normal mice by measuring contents of several major metabolites (creatine-P, adenosine triphosphate, glucose, glycogen, lactate and pyruvate) in the brain 30 min after intraperitoneal administration of the drug at doses of 1, 4 and 16 mg/kg and compared with those of dihydroergotoxine (DHE). In addition, influences of both drugs on cytochrome oxidase activity in normal mouse brain homogenate were studied in vitro. Both of nicergoline and DHE caused 12-20% increases in creatine-P contents and 10-37% decreases in lactate and pyruvate contents, but had no effect on glucose contents and energy reserve values. In vitro studies revealed that nicergoline had more potent activating action on cerebral cytochrome oxidase than DHE at final concentrations of 10 and 100 μM. These results suggest that nicergoline has a promoting action, similar to DHE, on cerebral energy metabolism of normal mouse.

Platelet-mediated thrombosis in stenosed canine coronary arteries: Inhibition by nicergoline, a platelet-active alpha-adrenergic antagonist

The effects of nicergoline, a new agent that blocks alpha-adrenergic receptors and inhibits platelet phospholipase, were evaluated in a canine model of platelet-mediated coronary thrombosis. In 48 open chest dogs, the circumflex coronary artery was stenosed by plicating the artery wall with a suture. Thirty-four of the 48 dogs exhibited cyclic reductions in flow in the stenotic vessel, followed by a sudden return to control levels. The reductions in flow were unabated in all but two dogs after heparin administration (1,000 U/kg per h), unaffected by large doses of nitroglycerin and nifedipine and associated with platelet aggregates in the stenotic segment (demonstrated by histologic and electron microscopic examination). These observations support the conclusion that the flow reductions were caused by platelet aggregation rather than by fibrin deposition or vasospasm. Twenty dogs were monitored for 1 hour after heparin administration and then assigned to a control (n = 7) or nicergoline-treated (n = 13; 1 mg/kg intravenously) group. In control dogs, cyclic reductions in flow continued unchanged for another hour, whereas in the treated group they were markedly decreased in 1 dog and completely abolished in the other 12 dogs. Aspirin (30 mg/kg intravenously) suppressed flow reductions in all control dogs, confirming the primary role of platelet aggregation in the phenomenon. This study provides a modified model of platelet-mediated thrombosis in stenosed coronary arteries. Furthermore, the results indicate that nicergoline can effectively interfere with platelet function in vivo. The potent antithrombotic activity exhibited by nicergoline might enhance the therapeutic usefulness of this vasodilator.

Simultaneous study of haemodynamic, metabolic and behavioural sequelae in a model of cerebral ischaemia in aged rats: effects of nicergoline.

Unilateral cerebral ischaemia was induced in 18-month-old Long-Evans rats by injection of 2,000 labelled microspheres (phi 50 microns) into the carotid blood stream. This results in an ipsilateral decrease in cerebral blood flow, development of severe oedema and modifications of glucose uptake and consumption. Furthermore, this ischaemia led to a deterioration of the avoidance response in conditioned animals. All these disturbances, including the cerebral oedema, diminished with nicergoline pretreatment.

The effects of nicergoline on spontaneously hypertensive rats and their offspring.

Six consanguine monogamous SHR couples (G1) were treated from 5 weeks of age on with an alpha blocker, nicergoline, 0.1 mg/kg/day i.p.. Male rats were treated without interruption; treatment was withheld in female rats from delivery to weaning. They were compare to six similar SHR couples who were only daily i.p. injected with the same volume of solvent in the same conditions as controls, as well as with naive (untreated) rats. Second (G2) and third (G3) generation rats (untreated) were studied. In G1 rats, systolic blood pressure (SBP), heart rate, heart weight/body weight ratio and bulbar noradrenaline content were decreased (compared to control or naive rats), while plasma renin activity (PRA) and hypothalamic noradrenaline content were not changed. In G2 rats, SBP and PRA were decreased, all other parameters being unchanged. No parameter was changed in G3 rats. This appears to be the first report of a preventive effect of antenatal treatment on the development of hypertension in SHR.