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PubMed1980

Ergot alkaloids: interaction with presynaptic dopamine receptors in the neostriatum and olfactory tubercles.

Several ergot alkaloids, bromocriptine, ergocornine and lergotrile were shown to have potent agonist action at presynaptic dopamine receptors on striatal and mesolimbic nerve terminals in an in vivo model system. These agents blocked the increase in accumulation of striatal dihydroxyphenylalanine produced when impulse flow in the nigro-striatal dopamine system was inhibited by administration of gamma-butyrolactone. Administration of dopamine receptor blockers such as haloperidol prior to administration of the ergot alkaloids and apomorphine prevented the inhibitory effects of these agonists. However, when haloperidol was administered 50 min after the agonists although it completely blocked the effects of apomorphine it only partially antagonized the inhibitory effects of ergocornine and lergotrile and was ineffective in reversing the inhibitory effects of bromocriptine. Thus, this study in contrast to in vitro studies indicates that the ergot alkaloids do have potent effects on presynaptic dopamine nerve terminal receptors and that these agents, especially bromocriptine may interact non-competitively or irreversibly with presynaptic dopamine receptors.

4-Butyrolactone↗
PubMed1983

The selectivity of some ergot derivatives for alpha 1 and alpha 2-adrenoceptors of rat cerebral cortex.

The affinities of several ergot derivatives for rat cerebral cortex alpha 1- and alpha 2-adrenoceptors were assessed using radioligand binding techniques. In most cases both [3H]prazosin (labelling alpha 1-adrenoceptors) and [3H]rauwolscine (labelling alpha 2-adrenoceptors) binding were displaced by the ergot derivatives tested, but with markedly different potency. Generally compounds displayed selectivity toward the alpha 2-adrenoceptor, particularly CQ 32-084, which had a Ki value against [3H]rauwolscine binding of 35 nM, but had little effect on [3H]prazosin binding at concentrations in excess of 5 microM. Lisuride was the most potent displacer of [3H]rauwolscine binding with a Ki value of 0.54 nM. Only bromocriptine was relatively alpha 1-selective with a Ki against [3H]prazosin binding of 18 nM and against [3H]rauwolscine binding of 120 nM. The results indicate that the ergot derivatives tested display a marked affinity for alpha-adrenoceptors and that their actions at this receptor class should be considered when interpreting their pharmacological activity in vivo.

Animals↗
PubMed1986

Antagonism by some ergot derivatives of 5-HT-induced vasoconstriction.

The ability of a number of ergot derivatives to inhibit 5-hydroxytryptamine (5-HT)-induced vasoconstriction was examined in the perfused rat mesenteric artery preparation. 5-HT produced an increase in perfusion pressure indicative of vasoconstriction. The ergot derivatives inhibited the 5-HT-induced vasoconstriction in a manner that was predominantly not competitive in nature. As 5-HT2 antagonists the ergot derivatives ranged in potency from CQ 32-084 which abolished the 5-HT2 receptor mediated response at a concentration of 10 nM to LY-141865 which was inactive up to a concentration of 10 microM.

Animals↗
PubMed1992

Neurogenic versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine.

Sumatriptan and the ergot alkaloids are useful tools for deciphering drug mechanisms in migraine and related headaches. Both neuronal and vascular mechanisms have been proposed on the basis of actions of 5-HT at receptors resembling the 5-HT1D subtype. In this Viewpoint article, Michael A. Moskowitz argues that blockade of neural transmission and the neurogenic inflammatory response provides a mechanism by which sumatriptan and ergot alkaloids alleviate vascular headaches. He postulates, with similar arguments, that sumatriptan and ergot alkaloids may block headaches that develop from meningovascular inflammatory disorders such as from viral and bacterial meningitis and from the sequelae of head injury.

Ergot Alkaloids↗
PubMed2004

The determinant step in ergot alkaloid biosynthesis by an endophyte of perennial ryegrass.

Many cool-season grasses harbor fungal endophytes in the genus Neotyphodium, which enhance host fitness, but some also produce metabolites--such as ergovaline--believed to cause livestock toxicoses. In Claviceps species the first step in ergot alkaloid biosynthesis is thought to be dimethylallyltryptophan (DMAT) synthase, encoded by dmaW, previously cloned from Claviceps fusiformis. Here we report the cloning and characterization of dmaW from Neotyphodium sp. isolate Lp1, an endophyte of perennial ryegrass (Lolium perenne). The gene was then disrupted, and the mutant failed to produce any detectable ergovaline or simpler ergot and clavine alkaloids. The disruption was complemented with the C. fusiformis gene, which restored ergovaline production. Thus, the biosynthetic role of DMAT synthase was confirmed, and a mutant was generated for future studies of the ecological and agricultural importance of ergot alkaloids in endophytes of grasses.

Alkyl and Aryl Transferases↗
PubMed2005

The ergot alkaloid gene cluster in Claviceps purpurea: extension of the cluster sequence and intra species evolution.

The genomic region of Claviceps purpurea strain P1 containing the ergot alkaloid gene cluster [Tudzynski, P., Hölter, K., Correia, T., Arntz, C., Grammel, N., Keller, U., 1999. Evidence for an ergot alkaloid gene cluster in Claviceps purpurea. Mol. Gen. Genet. 261, 133-141] was explored by chromosome walking, and additional genes probably involved in the ergot alkaloid biosynthesis have been identified. The putative cluster sequence (extending over 68.5kb) contains 4 different nonribosomal peptide synthetase (NRPS) genes and several putative oxidases. Northern analysis showed that most of the genes were co-regulated (repressed by high phosphate), and identified probable flanking genes by lack of co-regulation. Comparison of the cluster sequences of strain P1, an ergotamine producer, with that of strain ECC93, an ergocristine producer, showed high conservation of most of the cluster genes, but significant variation in the NRPS modules, strongly suggesting that evolution of these chemical races of C. purpurea is determined by evolution of NRPS module specificity.

Amino Acid Sequence↗
PubMed1998

Effect of amino acid ergot alkaloids on glutamate transport via human glutamate transporter hGluT-1.

Effect of amino acid ergot alkaloids on glutamate transport via the human glutamate transporter (hGluT-1) was investigated using hGluT-HeLaS3 cells, which stably expressed high levels of hGluT-1. Ergotamine enhanced the glutamate uptake of hGluT-HeLaS3 cells in a concentration-dependent manner, increasing the initial velocity of glutamate uptake by 1.45 times at 10 microM. Other amino acid alkaloids, bromocriptine and dihydroergotamine, also augmented glutamate uptake, whereas amine alkaloids, ergonovine or lisuride did not influence glutamate uptake. The accelerating effect required a preincubation longer than 5 min. Kinetic studies on hGluT-1 revealed that ergot alkaloids decreased a Michaelis constant (Km) for glutamate with unchanged maximum velocity. The effect of bromocriptine was not mediated by dopamine D1 or D2 receptors, and was independent of its antioxidant action. Amino acid ergot alkaloids may serve as a prototype for agents that regulate glutamate transporters. These results may be useful in exploring new agents for neurological diseases associated with glutamatergic neurotoxicity.

ATP-Binding Cassette Transporters↗
PubMed2004

[Chronic ergotism: spinal lesion and neuropathy].

INTRODUCTION: Neuropathologic manifestations due to chronic ergotism are rare. OBSERVATION: We report the case of a 40-year-old patient who presented clinical signs and symptoms of a spinal lesion and also the symptoms of neuropathy involving the right sciatic nerve, more precisely the internal and external popliteal nerves, following ingestion of methysergide. Complete recovery was achieved with calcium blocker treatment. CONCLUSION: Ergotism should be considered in patients treated by ergot alkaloids presenting an atypical clinical manifestations.

Adult↗
PubMed2002

[Critical ischaemia of the limbs and localized livedo in a case of ergotism].

HISTORY AND ADMISSION FINDINGS: A 57-year-old woman, a heavy smoker and migraine sufferer, was admitted with severe resting pain in the right forefoot and painful localized tendril-shaped reddening on the right thigh. She had regularly been taking 1-2 mg ergotamine tartrate, several analgesics, some containing caffeine, and selective serotonin-uptake inhibitors. Clinical examination found all limbs to be cool. On the right leg the pulse was not palpable below the inguinal line, and the reddening corresponded to localized livedo. INVESTIGATIONS: The peripheral Doppler pressure indicated critical perfusion reduction in the right leg with a tibiobrachial pressure ratio of 0.14. Colour-coded duplex sonography showed generalized vasoconstriction with filiform hourglass stenosis of the right proximal superficial femoral artery without atherosclerotic changes. The history of drug intake and the characteristic sonographic findings indicated ergotism and an arteriography was deemed unnecessary. TREATMENT AND COURSE: All ergotamine and caffeine containing drugs were discontinued and the patient urged to stop smoking. Amlidopine, 2.5 mg orally, and prostaglandin E1, 60 microgram i.v., were administered daily. The resting pain was much reduced after the first infusion and the painful livedo disappeared. The documented high-grade stenosis of the right superficial femoral artery was reduced to 25-50% by the third day of infusion. At the end of 10 daily infusions both the Doppler pressure and the duplex sonography had become normal. Pizotifen was given for the migraine and the serotonin re-uptake inhibitor sertralin was discontinued. CONCLUSION: An interaction of the serotonin re-uptake inhibitor with ergotamine was presumably responsible for the development of ergotism under >>therapeutic<< ergotamine dosage. Vasospastic stenoses and occlusions can be demonstrated by duplex sonography and may in future not require additional angiographic confirmation. Intravenous rather than intraarterial infusion of prostaglandin is to be preferred if vessels at many sites are affected. Livedo is a transitory sign of ergotism.

Arm↗
PubMed2002

Effects of topical natural ergot alkaloids on intraocular pressure and aqueous humor dynamics in ocular normotensive rabbits.

Although it has been suggested that ergot derivatives may play a role in antiglaucoma therapy, little attention has been paid to the ocular hypotensive action of these drugs. Having previously reported in our laboratory that topical dihydroergocristine decreases intraocular pressure both in ocular normotensive and alpha-chymotrypsin-induced ocular hypertensive rabbits, the aim of the present work was to assess the effect of natural ergot alkaloids, ergocristine, alpha-ergocryptine and ergocornine, on the intraocular pressure and aqueous humor dynamics in ocular normotensive rabbits in order to further explore the ocular actions of these compounds. Intraocular pressure was measured with a pneumatonometer manometrically calibrated for the rabbit eye. Changes in tonographic facility of aqueous humor outflow and rate of aqueous humor inflow were evaluated in anesthetized rabbits. Natural ergot alkaloids were found to reduce intraocular pressure in ocular normotensive eyes in a dose-related fashion. These compounds decreased both tonographic outflow facility and, to a greater extent, aqueous humor inflow, which explains their final hypotensive effect.

Administration, Topical↗
PubMed1986

Intraarterial sodium nitroprusside infusion in the treatment of severe ergotism.

Treatment of migraine with ergot alkaloids may produce systemic vasospasm in patients, especially as a result of automedication and overconsumption but also due to individual hypersensitivity. Peripheral vasoconstriction may lead to gangrene of the extremities, necessitating amputation. Various treatments have been tried against ischemic complications during ergotism with varied and unpredictable results. We report two recent cases of severe acute peripheral ischemia due to ergotamine abuse successfully treated with continuous systemic sodium nitroprusside infusion. The doses used during intraarterial injection are well below those known to be toxic. Consequently, the adverse effects of cyanide toxicity can be avoided. We think that intraarterial infusion of sodium nitroprusside, associated with forced diuresis and the administration of hydroxycobalamin, constitutes the treatment of choice of extreme peripheral ischemia of ergotism.

Adult↗
PubMed1978

Quantitative determination of ergot alkaloids in biological fluids by radioimmunoassay.

1 Cross-reactivity of ergot alkaloids with an antiserum produced against lysergic acid conjugated with human serum, albumin was utilized to develop a radioimmunoassay for ergotamine, dihydroergotamine, dihydroergotoxine, ergometrine and methylergometrine in biological fluids. The antisera showed no cross-reactivity with simpler indole structures. 2 A procedure for extraction and concentration of alkaloids in biological fluids was developed. 3 The assay is sensitive for 1.8 ng/ml ergotamine, 1.5 ng/ml dihydroergotamine, 2.2 ng/ml dihydroergotoxine, 0.7 ng/ml ergotmetrine and 0.5 ng/ml methylergometrine. 4 The assay is sufficiently sensitive to permit the measurement of urine and plasma ergot alkaloid levels and it is suitable for determination in cases where a known ergot alkaloid is used.

Cross Reactions↗
PubMed1989

Induction of heat stress in beef cattle by feeding the ergots of Claviceps purpurea.

Two groups of 4 Hereford steers were housed in a controlled environment room and exposed to simulated high summer temperatures. Both groups were fed a barley grain and hay diet ad libitum. The barley in one diet contained 0.5% w/w ergots of Claviceps purpurea. Within one week of feeding the ergot diet mean rectal temperature was significantly elevated (P less than 0.05) each afternoon (up to 41 degrees C) but returned to normal overnight. Elevated rectal temperature was accompanied by other signs of heat stress, reduced feed intake, body weight loss and depression or serum prolactin concentration. Symptoms disappeared within 1 week of ceasing to feed the ergot diet.

Animal Feed↗
PubMed1986

Outbreak of bovine abortion attributed to ergot poisoning.

Eleven out of 36 suckler cows, all in late pregnancy, aborted seven to 10 days following introduction to a rye grass pasture heavily infested with ergot. On the basis of known heavy exposure to ergot infested grass and negative findings in a range of other investigations, details of which are given, a diagnosis of ergotism was made.

Abortion, Septic↗
PubMedDate not supplied

Differential binding of ergot compounds to human versus rat 5-HT2 cortical receptors.

Eleven ergot compounds were competed against [3H]-ketanserin-labelled 5-HT2 receptors in rat and human cortex. Four of the ergots are selective for rat 5-HT2 receptors--mesulergine, methysergide, nicergoline and metergoline, whereas pergolide, d-lysergic acid, ergonovine, ergotamine, d-lysergic acid diethylamide, lisuride and dihydroergotamine display selectivity for human 5-HT2 receptors. Rat-selective compounds contain a methyl substitution on the indole nitrogen, whereas human-selective compounds contain a hydrogen. This structural feature may allow the two groups of ergots to differentiate between the two species of receptors.

Animals↗
PubMed1978

Dopamine-mimetic activity of ergot derivatives, as measured by the production of cyclic AMP in isolated retinae of the rabbit.

The effects of several ergot alkaloid derivatives on the concentration of cyclic AMP in intact rabbit retinae were investigated in vitro. All compounds were found to be potent inducers of cyclic AMP production, half-maximal stimulation being obtained at 10(-6)M, and maximal stimulation at 10(-4)M concentrations. The range of effective concentrations was very well comparable with that of dopamine (or apomorphine) in the same experimental conditions. Furthermore, the accumulation of cyclic AMP induced by the ergot derivatives was blocked by fluphenazine, at 10(-4)-5 X 10(-4)M, or lithium, at 5 X 10(-2)M concentrations. Both antipsychotic drugs were found to be very potent inhibitors of dopamine-(or apomorphine-) induced production of cyclic AMP in the same preparation. A potential dopamine-mimetic activity of ergot derivatives (or of other dopamine-like drugs) can be specifically tested on isolated rabbit retinae in vitro, either before undertaking experiments in vivo or in correlation with behavioural studies.

Animals↗
PubMed1978

Interaction of ergot alkaloids with dopaminergic receptors in the rat striatum and nucleus accumbens.

Various ergot alkaloids and derivatives were investigated for their interaction with dopaminergic receptors at the level of the rat corpus striatum and nucleus accumbens. Dihydro(DH)-ergotoxine, DH-ergocornine, DH-ergocryptine, DH-ergocristine, 2-Br-alpha-ergocryptine, ergotamine and DH-ergotamine were shown to inhibit, at micromolar concentrations, the dopamine-stimulated adenylate cyclase activity of rat striatal and nucleus accumbens homogenates. Interestingly, the inhibitory effect of the ergot drugs was higher in the nucleus accumbens than in the striatum. Moreover, the ergot drugs were more active in displacing 3H-haloperidol than 3H-dopamine from striatal membranes. The results, which are in apparent contradiction with previously obtained behavioral, pharmacological and clinical data, are discussed in the light of the possible presence in the central nervous system of distinct dopaminergic receptors with different conformations.

Adenylyl Cyclases↗
PubMed1995

A role for platelet-derived growth factor in drug-induced chronic ergotism? A case report.

Generalized vasoconstriction in chronic ergot poisoning is attributed both to the ergotamine activity on alpha-adrenergic receptors and to its direct action on vascular smooth muscle cells. The authors propose that endothelial wall, chronically damaged by ergot alkaloids, releases platelet-derived growth factor (PDGF), which contributes to vasoconstriction and promotes further arterial obstruction. Their hypothesis is supported by the increased PDGF activity found in plasma of a patient suffering from chronic ergotism.

Chronic Disease↗