Drug-induced parkinsonism in the rat- a model for biochemical investigation of the parkinson-syndrome. III. The incorporation of D-glucose-14C(U) in amino acids of brain and liver from rats pretreated with reserpine or with phenothiazines.

Following treatment with reserpine or alternatively with a combination of phenothiazines (Randolektil, Majeptil) a drug-induced parkinsonoid reaction was provoked in rats. Twenty min before decapitation, 18 muCi d-glucose-14C(U) was administered intravenously. Concentration and radioactivities of glutamic acid (glu), glutamine (gln), serine (ser), and glycine (gly) were assayed in some regions of brain and in liver. Separation was performed by a combination of paper electrophoresis and chromatography or by an automatic amino acid analyzer. 1 After reserpine, the concentrations of serine and glycine were increased ten-fold while their specific activities decreased by the same factor. The interconversion serine-glycine was not affected. The concentration of glutamic acid was reduced while its specific activity remained constant. 2. After phenothiazines, the concentrations of serine and glycine in brain were also increased but their specific activities were decreased to a different degree. This indicates an additional effect on the serine-synthesis from glucose. The interconversion serine-glycine was also altered. The concentration of glutamic acid was decreased but specific activity was constant except in the thalamus region tested. 3. The influence of both treatments on amino acid turnover in liver differed from the observed impairment of brain metabolism. 4. Possible correlations between the changes in amino acid metabolism, catecholamines, and the neurologic parkinsonian symptoms are discussed.

[Comparison between the effects of L-dopa, prodipine and amantadine on the serum and CSF amino acid levels in Parkinson's disease (author's transl)]. / Vergleichende Untersuchungen über die Wirkung von L-Dopa Prodipin und Amantadin auf den Aminosäurespiegel von Serum und Liquor beim Parkinson-Syndrom.

Patients with Parkinson's disease were treated with different antiparkinsonian drugs and the amino acid levels in serum and cerebrospinal fluid were determined. Results obtained in 43 patients (L-dopa [26]; prodipine [6]; amantadine [11]) are reported. All drugs investigated produced an increase in amino acids in serum and in CSF, this enhancement being most pronounced for neutral, long-chain amino acids. Amantadine, however, showed this effect for a short period, only. Our results lead us to assume that this increased pool of amino acids in the CSF facilities the biosynthesis of amines with transmitter function from their precursor amino acids.

[The activity of aminotransferases in serum and cerebrospinal fluid in neurological diseases (author's transl)]. / Uber die Aktivität der Aminotransferasen in Serum und Liquor cerebrospinalis bei neurologischen Erkrankungen

The activities of the aminotransferases, GOT and GPT, were determined in the serum and cerebrospinal fluid of patients with Parkinson's disease, Huntington's chorea, Wilson's disease, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, phenylketonuria, and head injuries. 1. In patients with Huntington's chorea the activity of SGOT was lower than in controls (P = 0.02); in Friedreich's ataxia LGPT activity was decreased (P less than 0.001); in patients suffering from ALS SGOT (P = 0.005), SGPT (P less than 0.001) and LGOT (P less than 0.001) activities were increased. 2. Long-term treatment of Parkinson's disease and Wilson's disease with L-dopa resulted in an increase in SGOT, LGOT, and SGPT activity over approximately 2 months, with subsequent normalization of these enzyme activities in spite of continued therapy. Guanidine treatment led to an increase in aminotransferase activities in patients with ALS. Penicillamine caused a decrease in SGOT and SGPT activities in Wilson's disease. These results illustrate the necessity of taking therapeutic measures into account in the interpretation of data on aminotransferase activities.

[The application of guanidine hydrochloride to the treatment of degenerative nervous and muscular diseases. I. Clinical results (author's transl)]. / Uber die Anwendung von Guanidinhydrochlorid in der Behandlung degenerativer Nerven- und Muskelerkrankungen.

This paper reports the results obtained on using guanidine hydrochloride in the treatment of patients with amyotrophic lateral sclerosis, degenerative diseases of the spinocerebellar system or the peripheral nervous system and dystrophic muscle diseases. A long-term effect of the substance was a diminution in the rate of progression of the diseases, with the exception of the group with dystrophic muscle diseases. Initial clinical improvement occurred in certain patients of both groups. The substance seems to be more effective in less-advanced cases than on administration in the later stages of the disease. The therapeutic dosage was 20 to 40 mg/kg/day. The most frequent side-effect was paraesthesia and sometimes gastric disturbance was reported. Therapy had to be discontinued in 3 patients due to leucopenia. In these patients the symptoms rapidly increased in severity after discontinuation of treatment. This supports the assumption that guanidine hydrochloride treatment slows down the progress of the disease.

[Clinical aspects of cystinuria and its treatment by thiola (author's transl)]. / Klinische Aspekte der Cystinurie und ihre Behandlung mit Thiola

Cystinuria is an inherited disorder of amino acid transport affecting the epithelial cells of the renal tubules and the gastro-intestinal tract. Treatment consists of the prophylaxis of recurrent urolithiasis, which is the clinical manifestation of the disease. Long-term treatment with alpha-mercapto-propionyl-glycine (MPG; Thiola) promises to be successful. 3 cytinuric patients with recurrent urolithiasis underwent treatment over a period of 6 months. Therapy was controlled by regular follow-up investigations of the urinary excretion and serum levels of cystine and di-basic amino acids. The results did not indicate any permanent decrease in cystine excretion. No recurrence of renal calculi was observed. The possibility is discussed of a direkt mechanism of action of the drug on the metabolism of the involved amino acids.

[The influence of neuroleptic drugs on urinary excretion of non-protein nitrogen (author's transl)]. / Der Einfluss von Neuroleptika auf die Ausscheidung von Reststickstoffsubstanzen im Harn

During treatment with thioxanthenes or phenothiazines of schizophrenic patients non-protein nitrogen in urine was measured. The values were calculated in relation to the excretion of creatinine. a) Flupentixol or fluphenazine applied in optimal dosage, increased the excretion of urea and the amino acids asp, glu + gln, and gly. b) Moreover, if the drug induced a parkinsonoid (thioridazine) the excretion of ser and thr was increased, too. The usual desalting procedure by ion-exchanging resins before chromatography increases the contents of several amino acids, e.g. asp, asn, ala, gly, cys, ser, thr, indicating a breakdown of some instable products.

[Nocturnal levels of serum aminoacids and growth hormone]. / Nachtprofile der Serum-Aminosäuren und des Wachstumshormons.

During the night, mostly between 2 and 4 a.m., a peak of the concentrations of amino acids in human blood serum can be seen. The paper shows, that this phenomenon may be caused by the different secretion of the growth hormone depending on sleep or wakefulness of the person tested.

[Diurnal variations of human serum amino acid concentration]. / Tagesschwankungen der Aminosäurenkonzentration im Blutserum des Menschen.

In 5 healthy persons, as well as in 9 hospitalized patients with Parkinsonism and without metabolic disorders, diurnal variations of the concentrations of amino acids are determined in blood serum. It has been found that in addition to the peaks due to the digestion after meals, another peak in concentrations appeared. This peak was found between 2 and 4 a.m. and did not appear simultaneously for all amino acids. During this time, the urinary excretion of amino acids was also high.

Influence of phenothiazines or reserpine on the formation of 14C-glycine from U-14C-serine.

The influence of the psychopharmaceuticals reserpine, thioproperazine and chlorpromazine on the synthesis of 14C-glycine from U-14C-serine was examined in a rat brain preparation. At low serine concentration (2 times 10(-5) mol/l) glycine synthesis in inhibited by all drugs tested probably due to the inhibition of the serine influx into mitochondria. At higher concentration (10(-3) mol/l) and physiological cofactor levels, phenothiazines increase to the measurable amount of 14C-glycine while reserpine has no effect. We assume that at this higher concentration serine transport through the mitochondrial membranes is no longer rate limiting; following phenothiazine action, the membrane-bound glycine cleavage system might be inhibited more strongly than the partly soluble serine hydroxymethyltransferase.

[Biosynthesis of amino acids from glucose in the central nervous system in the Parkinson syndrome]. / Zur Biosynthese von Aminosäuren aus Glukose im Zentralnervensystem beim Parkinsonsyndrom.

The incorporation of labelled carbon from glucose U-14C into CSF amino acids was investigated in three patients with Parkinson's disease and in three control persons with comparable age and physical stature. Comparing the specific radioactivities of serum and CSF one can postulate that the labelled amino acids found in the CSF are synthesized mainly by brain tissue. The resorption of glucose into the CNS and therefore the synthesis of amino acids from glucose was more rapid in controls; labelled alanine and glutamine appeared later in the CSF of the patients. As expected, in the controls the specific radioactivity of glutamic acid was found to be higher than that of glutamine, in patients the labelling of glutamine was higher as was that of serine, glycine, aspartic acid and asparagine. From our knowledge concerning the compartmentation of the metabolism of glutamate, we assume that in Parkinsonism the metabolic activity of neurons is reduced but that of astroglia is enhanced.

Incorporation of [U-14 C]glucose into metabolites of brain, liver and blood of rats pretreated with reserpine or phenothiazines.

Parkinsonism was induced in rats by using phenothiazines (Butyrylperazin and Thioproperazin). (P-group), or reserpine, (R-group). [U-14 C)D-glucose was administered when the symptoms of Parkinsonism had become fully developed. Concentrations and radioactivities of different metabolites were studied in brain, liver and blood serum. 1. Both types of treatments resulted in a decrease in the synthesis of amino acids from [14C]glucose in the brain. The concentrations of amino acids and the glycogen remained uneffected. Phenothiazines enhanced the conversion of lipids, while reserpine increased their concentration. 2. Reduced de novo synthesis of amino acids was recorded in the liver. Phenothiazines resulted in the storage of glycogen and lipids; reserpine resulted in the storage of lipids and enhanced the conversion of glycogen. 3. Both treatments caused a fall in the amino acid concentration of the blood serum. A rise in the specific radioactivity of blood amino acids was observed in the P-group, while a decrease in specific radioactivity was observed in the R-group. A hyperglycemia was induced in the R-group with reduced specific radioactivity of glucose in both P-and R-groups. A reduction in lipid concentration of blood serum was achieved with an increased specific radioactivity in P-group and decreased radioactivity in R-group. 4. The changes in amino acids common to both treatments are also observed in human Parkinsonism.