In an open trial, 15 patients with PD (mostly stage V) were treated with the partial DA agonist, terguride, a derivative of lisuride. To the basic therapy, consisting of L-dopa plus benserazide and amantadine, a slowly increasing dosage of TDHL up to a maximum of 1.5 mg/day t.i.d. was added. There were 3 drop-outs; 12 patients completed the trial which lasted for 12 weeks. At this time a significant improvement in total score, bradykinesia, and functional score was seen, as well as a marked improvement in tremors score in the patients who showed this symptom (Columbia Rating Scale). As side-effects, dyskinesias occurred in two patients, psychotic symptoms in one, and marked orthostatic symptoms in one patient. No significant differences before and after 12 weeks TDHL treatment were found in the concentrations of noradrenaline, adrenaline, serotonin, and 5-hydroxy-indole-acetic-acid in plasma. It is concluded that TDHL is effective even in advanced stages of PD, and it is speculated that partial DA agonists may become important in the treatment of PD and might possibly have an advantage over "classical" DA agonists.

Preliminary data of a postmortem brain study in a single case with Rett-syndrome compared to a single control case show a severe reduction of dopamine (DA), noradrenaline (NA), and serotonin (5-HT) in most regions studied and in two regions of adrenaline (A). A marked increase in the 3,4-dihydroxyphenyl acetic acid (DOPAC)/DA, homovanillic acid (HVA)/ DA, and the 5-hydroxyindole acetic acid (5-HIAA)/5-HT ratios indicates increased metabolism of DA and 5-HT. Also a marked reduction of3H-spiroperidol-binding in putamen was found. This agrees with the assumption that a defect in maturation processes of central monoaminergic systems could be an underlying cause of Rett-syndrome.

Preliminary biochemical analyses on plasma, urine, cerebrospinal fluid (CSF) and post mortem brain areas in the rare Rett syndrome indicate no gross disturbance of neurotransmitter function in the periphery. The amino acid pattern, the plasma catecholamines, dopamine, noradrenaline and adrenaline, serotonin in plasma and platelets, and monoamine oxidase (MAO) B-activity in platelets were not different from controls. Urinary metabolites of biogenic amines tended to be increased in the Rett syndrome. Amino acid and noradrenaline concentrations were not changed in lumbar CSF. In a single case of the Rett syndrome, lower values for most amino acids were notable in post-mortem human brain areas and this finding was accompanied by a severe reduction of dopamine, noradrenaline and serotonin, while the metabolite, DOPAC, most times is increased, and HVA and 5-HIAA are decreased. MAO activities, determined in four brain areas, showed no major abnormalities. 3H-spiroperidol binding was significantly below normal in the putamen and 3H tryptamine binding sites in the occipital cortex showed increased binding numbers with no changes in Hill-coefficients. In conclusion, our preliminary data indicate no severe changes in the peripheral neurotransmitter synthesis and turnover, while first post-mortem data indicate severe reduction of biogenic amine synthesis with enhanced turnover and reduced dopaminergic D-2 receptor activity in the advanced stage of a single case of the Rett syndrome.

Der hepatischen Enzephalopathie (HE) liegen komplexe Stoffwechselstörungen zugrunde, die von tiefgreifenden Veränderungen an zentralen Neurotransmittersystemen begleitet sind. Das koordinierte Zusammenspiel vieler Neurotransmitter, die sich in einem Fließgleich-gewicht befinden, ist gestört durch Abnahme des zerebralen Dopamingehaltes, aber Anstieg der aromatischen Aminosäuren, insbesondere Tryptophan mit starker Zunahme von Serotonin (5-HT) im Hirnstamm und Striatum, bedingt durch Störung des Aminosäuretransportes durch die Blut-Hirn-Schranken (BHS). Ausgeprägte Pathomechanismen lassen sich sowohl bei ex vivo- als auch in vitro-Studien im serotonergen System nachweisen. Während die maximale Bindungskapazität der 5-HTl-Bindungsstellen stark erniedrigt ist, bleibt die des 5-HT2-Rezeptors fast unverändert, ebenso wie die Aktivität des dopaminergen D2-Rezeptors. Ammoniak (NH₄⁺) und L-Valin (VAL) verändern die 5-HT-Rezeptorkinetik sowohl in Membranen des menschlichen Frontalkortex aus postmortal gewonnenem Hirngewebe als auch im experimentell induzierten Koma im Tierversuch: Unter Einfluß von NH₄⁺ ist eine Reduktion der maximalen Bindungskapazität nachweisbar, L-VAL antagonisiert diesen spezifischen Effekt. Diese Modulatorwirkung wies bei Patienten mit Coma hepaticum eine signifikant höhere Sensitivität auf. Neben den bekannten Wirkungsmechanismen von verzweigtkettigen Aminosäuren an der BHS ist die therapeutische Effizienz von L-VAL als molekulare Interaktion, durch Ausbildung von reversiblen Schiff-Basen bzw. auch Elektronenpaar-Donor und -Akzeptor-Wechselwirkung zu verstehen. Dieser direkte Bindungsmechanismus von VAL und Leuzin (LEU) an neuronalen Membranen ist kinetisch erfaβt worden. Die tryptamin-erge Bindungskapazität als Modulator des serotonergen Systems ist dagegen in der HE erhöht. Ein in-vitro-Einfluß von L-VAL als auch NH₄⁺ konnte nicht nachgewiesen werden. Auch der überwiegende Teil der inhibitorisch wirkenden Synapsen, die mit γ-Aminobuttersäure (GABA) als Transmitter operieren und auf das zentrale Nervensystem (ZNS) beschränkt sind, zeigen eine Erniedrigung ihrer Aktivität im schweren Coma hepaticum. Dieser Effekt ist aber unabhängig vom Einfluß der NH₄⁺-Konzentration. Glutamin- und Asparaginsäure, die exzitatorisch auf die meisten Nervenzellen wirken, weisen im experimentellen Coma hepaticum eine Verringerung ihrer Bindungskapazität auf, wobei die Glutaminbindung durch L-LEU beeinflußbar war. Die Glycin-Aktivität ist erhöht, während Naloxon- und D-ala₂-Methionin-Enkephalinamid-Bindung, die mit Opiat-Rezeptoren gekoppelt sind, nicht verändert sind. Diese Ergebnisse zeigen eine unterschiedliche Beeinflussung von verschiedenen Gehirnrezeptoren- bzw. Bindungsstellen bei HE und weisen damit auf differenzierte Störungen von (neuronalen) Membranen hin. Gestörte interneuronale Dynamik dürfte daher als Pathomechanismus der HE in Betracht zu ziehen sein.

In hepatic encephalopathy (HE) brain uptake of large neutral amino acids is impaired with tryptophan crossing the blood brain barrier (BBB) to a much larger extent than all other competing amino acids (AA). The disturbance in the steady-state of transmitter is paralleled to the change of their kinetic data. This is reflected by an increase in serotonin (5-HT) synthesis and turnover, while the number of post-synaptic 5-HT1-binding sites is decreased, 5-HT2-receptor activity is dropping to a much smaller extent. On the other hand, presynaptic dopaminergic activity remains unchanged with no change in D2-receptor activity. Valine (VAL) improves the postsynaptic 5-HT function via modulating activity due to a regulatory mechanism at the membranal level in vitro and ex vivo. Furthermore, VAL leads to a significant reduction of serum ammonia (NH4+) and brain NH4+ concentration. VAL is able to antagonize the binding density diminishing effects of NH4+ on 5-HT binding sites. This effect could be characterized by the measurement of VAL binding sites being 5 to 10 fold higher than the number of leucin (LEU)-sites. Considering the chemical bonds involved in the attachment of biogenic amines and aminoacids (Schiff-bases equilibria) the modulating action of NH4+ on neural transmission may be clarified. Tryptamine can displace the postsynaptic binding of 5-HT in brain tissue and is a possible antagonist to physiological and pharmacological effects of 5-HT. The dynamic changes of the kinetic behaviour of tryptamine-binding might demonstrate a compensating effect as shown in an increase of tryptaminergic receptor activity. As a working hypothesis, the different relative strengths of electron-pair donor and -acceptor sites of both compounds are suggested to their complementary physiological interaction. GABA, an inhibitory transmitter of the CNS is diminished in its maximal binding capacity in severe HE and is independent of NH4+ influence. Furthermore, glutamate and aspartate-receptors decrease in experimentally induced hepatic coma. L-LEU shows modulating effects of glutamine binding. Glycin-activity is increased, while naloxone- and D-ala2-methionine-encephalinamid binding are not different from controls. These data demonstrate a different influence of various brain receptors and binding sites by HE and indicate a differentiated disturbance of (neuronal) membrane activity. Therefore disturbed interneuronal dynamics might be important pathophysiological mechanisms underlying hepatic coma.