Reinhard Horowski

Direct dopaminergic action of lisuride hydrogen maleate, an ergot derivative, in mice

Lisuride hydrogen maleate induced stereotyped behaviour in normal as well as in reserpinized mice. It antagonized the motor depression and hypothermia induced by reserpine. On i.p. administration the compound was about as effective as apomorphine and D-amphetamine. As with apomorphine and in contrast to D-amphetamine the effects of lisuride hydrogen maleate in reserpinized mice were not impaired by additional treatment with alpha-methyl-p-tyrosine methylester. In untreated mice, the substance was very potent in lowering body temperature with significant hypothermia measured after dosages as low as 0.10 mg/kg i.p. Occurrence of stereotyped behaviour and hypothermia could be prevented by the dopaminergic antagonist haloperidol. From these data it is concluded that lisuride hydrogen maleate in addition to its interaction with serotoninergic systems is a potent dopaminergic agonist with a probably direct action on dopaminergic receptors. Further arguments in support of such an action of lisuride hydrogen maleate are, in addition to biochemical data, its serum prolactin lowering effect in rats, its strong emetic action in dogs and its effects on rat behaviour.

The competitive NMDA antagonist CPP protects substantia nigra neurons from MPTP-induced degeneration in primates

SummaryDegeneration of nigrostriatal dopaminergic neurons is the primary histopathological feature of Parkinsons disease. The neurotoxin MPTP (1-methyl-4phenyl-1,2,3,6-tetrahydropyridine) induces a neurological syndrome in man and non-human primates very similar to idiopathic Parkinsons disease by selectively destroying dopaminergic nigrostriatal neurons. This gives rise to the hypothesis that Parkinsons disease may be caused by endogenous or environmental toxins. Endogenous excitatory amino acids (EAAs) such as l-glutamate could be involved in neurodegenerative disorders including Parkinsons disease. We report in this study that the competitive NMDA antagonist CPP (3-((±)-2-carboxypiperazin-4yl)-propyl-1-phosphonic acid) protects nigral tyrosine hydroxylase (TH) positive neurons from degeneration induced by systemic treatment with MPTP in common marmosets. This indicates that EAAs are involved in the pathophysiological cascade of MPTP-induced neuronal cell death and that EAA antagonists may offer a neuroprotective therapy for Parkinsons disease.

Differences in the dopaminergic effects of the ergot derivatives bromocriptine, lisuride and d-LSD as compared with apomorphine.

Abstract In normal mice, hypothermia induced by treatment with apomorphine or lisuride could be inhibited by pretreatment with sulpiride, whilst the stereotyped behaviour in these animals was not affected. In reserpine-pretreated mice, apomorphine, lisuride, d-LSD and bromocriptine restored motor activity at least in part, antagonised the hypothermia caused by reserpine, and, with the exception of bromocriptine, produced stereotyped behaviour. Only the effects caused by bromocriptine could be abolished completely by even very low doses of sulpiride, whilst high doses of this drug had no or only very little effect on the activity of the other dopaminergic agonists. Inhibition of tyrosine hydroxylase by α-methyl-p-tyrosine completely prevented the effects of bromocriptine, but affected only vey slightly the effects of lisuride d-LSD, and not at all the activity of apomorphine. These results clearly demonstrate that the same type of dopaminergic activation produced by ergot derivatives in mice can be obtained by two different mechanisms, one of which in the case of bromocriptine is easily inhibited by sulpiride at low doses. If one accepts the hypothesis of a high affinity of this drug to presynaptic receptors, then our data could be explained by the hypothesis that bromocriptine exerts its effects in our test system via an inhibitory effect on these presynaptic dopamine receptors, and that this effect can be counteracted by sulpiride. Other possibilities, however, are not excluded.

Pharmacological properties of a wide array of ergolines at functional alpha1-adrenoceptor subtypes

Ergot alkaloids act as (partial) agonists or antagonists at serotonergic, dopaminergic and α-adrenergic receptors. In contrast to their affinity at serotonergic (5-HT) and dopaminergic receptor subtypes, only limited information is available concerning their interaction with α-adrenoceptor subtypes. This especially holds true for native α-adrenoceptors. Therefore, we studied the pharmacological profile of 25 ergolines at α1A-, α1B- and α1D-adrenoceptors in vascular rings or strips of rat and guinea pig endowed with these receptors. Contractile responses were studied by measurement of isometric tension changes in rat tail artery (α1A, α1B), guinea pig spleen (α1B) and rat thoracic aorta (α1D). The anti-migraine drugs ergotamine and dihydroergotamine, the anti-parkinsonian drug lisuride and the anti-hyperprolactinemic drug terguride behaved as antagonists or low-efficacy partial agonists at all three α1-adrenoceptor subtypes with nanomolar receptor affinity. Derivatives of these drugs showed lower affinity at α1-adrenoceptors than the parent compounds. Each individual ergoline derivative tested showed low discriminatory capability at the subtypes, α1A, α1B, α1D. A low discriminatory power between the subtypes (α1A, α1B, α1D) seems to be a class effect of the ergolines. The nanomolar affinities of ergotamine, dihydroergotamine and lisuride for α1-adrenoceptors may affect their effectiveness as anti-migraine and anti-parkinsonian drugs, respectively.

Terguride stimulates locomotor activity at 2 months but not 10 months after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment of common marmosets.

The mixed dopamine (DA) agonist/antagonist terguride acts as a DA antagonist on normosensitive receptors but shows DA agonistic properties at supersensitive DA receptors. Such a compound could offer an alternative to the treatment of Parkinsons disease with indirect or direct DA agonists. The present study compares the actions of terguride, 4-12 mg/kg i.p., in naive common marmosets with its effects in animals rendered parkinsonian by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 2 months or 10 months previously, in order to test its antiparkinsonian efficacy. Terguride reduced locomotor activity in naive common marmosets, similar to its effects in rodents and in line with the DA antagonistic activity of the compound. In marmosets treated with MPTP 2 months previously and exhibiting pronounced behavioural motor deficits, terguride stimulated locomotor activity, showing DA agonistic properties under these conditions. In contrast, the locomotor activity of animals that had recovered from MPTP treatment 10 months previously was not altered by terguride. It is concluded that terguride has anti-akinetic efficacy in this primate model of Parkinsons disease. In addition, terguride offers a unique opportunity to differentiate, pharmacologically, the extent of dopaminergic recovery from MPTP treatment in this primate species.

Hypothermic action of lisuride in rats and differences to bromocriptine in the antagonistic effect of neuroleptics

SummaryThe semisynthetic ergot derivative lisuride induced dose- and time-dependent hypothermia in rats placed in a cold environment (+4°C). As regards dosage, lisuride was more than 100 times more effective in this test model than bromocriptine. The effect of both drugs could be reduced by pretreatment with the dopamine antagonist haloperidol, which indicated a dopaminergic action of both drugs. In contrast, the hypothermic effect of lisuride could not be impaired by pretreatment with sulpiride, whilst the effects of bromocriptine were clearly antagonized by this drug. This results could be explained by a different affinity of these drugs to the same receptors, or, more likely, by a different mechanism of action by which lisuride and bromocriptine activate dopaminergic systems.

Characterization of the Molecular Fragment That Is Responsible for Agonism of Pergolide at Serotonin 5-Hydroxytryptamine2B and 5-Hydroxytryptamine2A Receptors

Cardiac-valve regurgitation observed in Parkinson patients treated with the ergoline dopamine receptor agonist 8β-methylthiomethyl-6-propylergoline (pergolide) has been associated with the agonist efficacy of the drug at 5-hydroxytryptamine2B (5-HT2B) receptors. 5-HT2A receptors may also play a role in pergolide-induced cardiac-valve regurgitation. We studied the pharmacological profile of pergolide and eight derivatives in porcine vascular rings endowed with 5-HT2B and 5-HT2A receptors to detect the molecular fragment of the pergolide molecule that may be responsible for agonism at these receptors. Pergolide derivatives showed a different substitution pattern at N(6), and the side chain at C(8) was modified by replacement of the sulfur against an oxygen atom. We demonstrate that the potent agonism of pergolide both at 5-HT2B and 5-HT2A receptors is retained when the N(6) propyl substituent is replaced by ethyl. However, agonism can be converted into antagonism if N(6) propyl is replaced by methyl. The N(6)-unsubstituted derivative was a low efficacy 5-HT2B receptor partial agonist and a 5-HT2A receptor antagonist. This pharmacological pattern was also applicable for pergolide congeners with an oxygen in the side chain at C(8). 6-Methylpergolide retained agonist efficacy and potency compared with pergolide at human (h) D2LONG(L) and hD2SHORT(S) receptors as determined by guanosine 5′-O-(3-[35S]thio)triphosphate binding. Based on the ability of pergolide to produce potent agonism at 5-HT2B receptors and the failure of 6-methylpergolide to act as an agonist but as a potent antagonist, we conclude that the N(6) propyl substituent of pergolide is crucial for 5-HT2B receptor agonism and thus a determinant of valvular regurgitation.

Effect of the new ergot derivative terguride on plasma PRL and GH levels in patients with pathological hyperprolactinemia or acromegaly.

Terguride, a derivative of lisuride, has been shown to possess a mixed dopaminergic-antidopaminergic activity in experimental models. We have studied the effects on PRL and GH levels of 0.2 mg po of terguride in 8 normal subjects, in 15 patients with pathological hyperprolactinemia (PHP) and in 17 patients with active acromegaly. In PHP, PRL levels were significantly reduced up to 300 min after terguride with a nadir (45 ± 4.0 % SE) significantly lower (p< 0.05) than the one observed in the 8 normal subjects (72 ± 3.5%). There was no significant difference in plasma PRL levels after 0.2 mg terguride or lisuride in 7 out of 15 patients tested with both drugs. Terguride did not significantly modify GH levels in PHP and in normals but when considering basal and peak (occurring between 60 and 150 min) GH values, a significant difference was found (p< 0.01 ). Mean peak of GH did not differ significantly between PHP (5.0 ± 1.1 ng/ml) and normals (6.8 ± 1.7 ng/ml). Plasma GH levels of 17 acromegalics were not modified by 0.2 mg of terguride but were significantly reduced by 2.5 mg of bromocriptine. Terguride and bromocriptine reduced PRL levels in acromegalics (p< 0.01 ) without any significant difference between the two drug. 0.2 mg terguride b i d given for 15 days to 7 healthy volunteers significantly reduced both basal and sulpiride (25 mg im) — stimulated PRL levels. Side effects were observed only in 4 out of 47 subjects tested with terguride and in 8 out of 34 tested with bromocriptine.

Multiple sclerosis and interferon β-1b, past, present and future

When Rudolf Virchow in Berlin coined the terms ‘myelin’ and ‘glia’ for his histological findings in the brain, multiple sclerosis (MS) could be defined as a chronic demyelinating disease causing disseminated lesions in the CNS which often end as a scar formed mostly by astroglia. This was the substrate for JeanMartin Charcot’s first description of ‘multiple sclerosis’*/hardening of brain and spinal tissue in various locations*/which he had observed at autopsy. Clinicians like him were, of course, aware that this dissemination, a dissociation in space, of MS lesions within the CNS was paralleled by a dissociation in time, i.e. variable neurological symptoms occurring at different times in the course of disease. Today, new imaging techniques such as magnetic resonance imaging (MRI) make it possible to visualize the lesions in different CNS locations and even to demonstrate, within the same investigation, a dissociation in time, if there are old inactive lesions as well as new active lesions present at the same time. This is done by using gadolinium, a first MRI contrast agent which had been developed in Berlin and which is detected only in new MS lesions with an opening of the blood /brain barrier. Earlier on, electrophoresis had made it possible to define cerebrospinal fluid (CSF) anomalies and proteins, which had been already investigated by Georg Schaltenbrand and by others, as oligoclonal bands, not present in the blood, in more than 90% of the patients. These two new technologies can support the clinical diagnosis of MS. MS remains a clinical diagnosis as we do not know its etiology and do not have any consistent genetic or biochemical marker. It is also a diagnosis of exclusion, which makes MS research even more difficult, as there are many other diseases and conditions with similar signs and symptoms, sometimes including comparable MRI and CSF findings. Borreliosis (Lyme disease) is just one recent example. This precedent of a previously unknown infectious CNS disease gives some hope that some day scientists might repeat the glorious success of Paul Ehrlich, founder of immunology, hematology and chemotherapy, and identify the ‘beast’, the unknown environmental factor linked to MS, thus making it possible to eradicate it either by vaccination or by drugs. Alas, all the many viruses, bacteria or parasites so far linked to MS have failed to meet Koch’s postulates for causative infectious agents. These many disappointments have favored a new school of thought which believes, based on the animal model of experimental allergic encephalitis [1,2], that MS is an autoimmune disease with T cell clones attacking various myelin and oligodendrocyte epitopes in a genetically vulnerable population. Unfortunately, however, these autoimmune phenomena may as well be secondary to some unknown primary pathogenetic factor since they can also be observed in healthy individuals. Furthermore, immunosuppressive treatments, in contrast to their effect in ‘real’ autoimmune conditions, are at best marginally effective, destroying both pro-inflammatory autoaggressive Tcells as well as anti-inflammatory suppressor T-cells. At this time it is fair to state that MS is an insidious, intermittent or chronic progressive inflammatory CNS disease of unknown origin with some indications of immune dysfunction. For people affected by MS it is a most frightening disease: at any time, a new lesion can affect new CNS functions, often altering human personality and impairing dignity. In the past, patients, their relatives and caregivers could do nothing but wait. Although in a minority of patients MS runs a benign course, with every new attack they would learn that their disease was not of that clinical type. When acquiring the disease at a young age, many patients are destined to a steady * Fax: /49-40-468-16695 E-mail address: reinhard.horowski@schering.de (R. Horowski). Clinical Neurology and Neurosurgery 104 (2002) 259 /264

Postreceptorial enhancement of neurotransmission for the treatment of cognitive disorders

Based on the assumption that the impairment of cognitive functions in normal ageing, depression in the elderly, Morbus Parkinson or Morbus Alzheimer reflects the gradually different injury of the signal propagation in circumscribed neuronal systems due to degenerative and functional deficiencies, it is proposed to strengthen the signalling function of the remaining intact neurons in neurodegenerative disorders via manipulation of the intraneuronal availability of second messengers. This is illustrated for the noradrenergic system where the therapeutic usefulness of selective neuronal cyclic AMP phosphodiesterase inhibitors like rolipram or denbufylline appears particularly promising.