André Barbeau

Angiotensin-Forming Enzyme in Brain Tissue

A renin-like enzyme is present in brain tissue and is independent of kidney and plasma renin. In the presence of homologous substrate it forms angiotensin. Administration of aldosterone significantly decreases this angiotensinforming enzyme activity, while administration of progesterone markedly enhances it.

ECOGENETICS OF PARKINSON'S DISEASE: 4-HYDROXYLATION OF DEBRISOQUINE

It is postulated that Parkinsons disease is the result of environmental factors acting on genetically susceptible individuals against a background of normal ageing. Many potentially neurotoxic xenobiotics are detoxified by hepatic cytochrome P450. The function of one such system was studied in forty patients with Parkinsons disease and forty normal control subjects. Significantly more parkinsonian than control subjects had partially or totally defective 4-hydroxylation of debrisoquine. Poor metabolisers of debrisoquine tended to have had earlier onset of disease.

Excretion of Dopamine in Diseases of Basal Ganglia

The urinary excretion of catecholamines has been measured in 32 patients with disorders of the basal ganglia. Sixteen patients with Parkinsonism (idiopathic, postencephalitic, and arteriosclerotic types) had a significantly lower amount of dopamine in the urine during a 24-hour period than a group of 24 normal control subjects. In a group of 16 patients with various striatal syndromes the excretion of dopamine and epinephrine was significantly higher than normal. Norepinephrine excretion was similar in the three groups. The lowest mean value of urinary dopamine was found in postencephalitic Parkinsonism; the highest occurred in Wilsons disease.

Ecogenetics of Parkinson's disease: prevalence and environmental aspects in rural areas

We make use of the unique combination of a homogeneous genetic and racial origin in the rural population of Quebec and the facilities of free and universal access to medical care, to study the distribution of the prevalence of Parkinsons disease in the 9 rural hydrographic regions of the Province. Through 3 different methods of ascertainment, confirmed by two control probes, we demonstrate that the prevalence of Parkinsons disease is of uneven distribution within rural areas. We further investigated the characteristics of the regions of high prevalence. These regions which are predominantly agricultural and areas of intensive market gardening were also the areas with the highest use of pesticides.

New data on the genetics of Parkinson's disease.

We investigated the clinical and metabolic characteristics of Parkinsonian patients whose illness started before the age of 40. A pilot study of 32 of our own such cases revealed the existence of 3 subgroups: 1. Post-Encephalitic, 2. Onset and course with predominant tremor, 3. Onset and course with akinesia and rigidity. In this early onset group of patients, there was a 46% incidence of familial cases (as opposed to 10-15% in the general Parkinson populations). The cases with tremor onset had a high prevalence of essential tremor in their families, while those with an akineto-rigid onset had a high familial incidence of other cases of Parkinsons Disease. Familial grey hair, hypertension, diabetes and thyroidopathies appeared to be in higher than expected frequency.

Comparative behavioral, biochemical and pigmentary effects of MPTP, MPP+ and Paraquat in Rana Pipiens

We demonstrate that injections of 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP), 1-methyl-4-phenyl-pyridinium ion (MPP+) and Paraquat (PQ+) produce in Rana Pipiens different behavioral, biochemical and skin pigmentation changes. MPTP causes in frogs the main symptoms of Parkinsonism (rigidity, akinesia and tremor) and it darkens the skin of animals. It also decreases brain and, less so, adrenal medulla dopamine. These effects are blocked by Pargyline. MPP+ causes the same symptoms but more rapidly. In contrast, skin pigmentation is clearly lightened. Brain and particularly adrenal dopamine reserves are nearly abolished. Pargyline increases these effects. Paraquat, in a cumulative fashion, eventually causes the same behavioral changes and a slight increase in pigmentation. It initially produces an increase in brain and adrenal dopamine concentrations, but later a significant dopamine concentration decrease. Pargyline potentiates these long term effects, blocks the dopamine increase, but reverses the PQ+ effect upon melanin, producing the same depigmentation as MPP+ alone.

Uptake and efflux of 14C‐dopamine in platelets Evidence for a generalized defect in Parkinson's disease

Thirty-five parkinsonian patients (five untreated, six with levodopa only, seven with levodopa plus Ro 4–4602, nine with anticholinergic and/or antihistaminic medication, and eight with the anticholinergic/antihistaminic medication plus amantadine) and 35 age-matched control subjects were studied. Platelets isolated from each individual plasma were incubated with 14C-dopamine. Uptake was found to be decreased to a significant degree in all treated or untreated parkinsonian patients when compared with control subjects. Anticholinergic and/or antihistaminic medication, with or without amantadine, further decreased the dopamine uptake into platelets, while levodopa alone or with Ro 4–4602 returned uptake values to near normal. Dopamine efflux paralleled exactly the uptake values. The fact that parkinsonian platelets exhibit impaired dopamine uptake, while age-matched control platelets do not, constitutes the first direct evidence in favor of a generalized dopamine defect in Parkinsons disease.

The specific vulnerability of the substantia nigra to MPTP is related to the presence of transition metals

We demonstrate that the high concentration of transition metals in the substantia nigra could be a major factor responsible for the specificity of cell damage by the Parkinsonism-causing neurotoxin MPTP. It will be shown that these metals in vitro, and MPTP, each potentiate the autoxidation of dopamine and the production of aminochrome through the generation of superoxide, hydroxyl radicals, hydrogen peroxide and reactive semiquinones. Moreover, the same metals contribute to the oxidation of MPTP itself, further enhancing dopamine autoxidation.

Use of L-Dopa in the Detection of Presymptomatic Huntington's Chorea

Abstract There is evidence that choreiform movements are related to an action of dopamine within the brain. In an attempt to identify subjects in whom Huntingtons chorea will develop, L-dopa was given to 28 subjects genetically at risk for this disease. Similar regimens of L-dopa or L-dopa in conjunction with a dopa decarboxylase inhibitor were given to 24 control subjects. Of the 28 subjects at risk, chorea developed in 10 (35.7 percent) while they were receiving L-dopa. The chorea always disappeared on discontinuation of the L-dopa. None of 24 control subjects manifested chorea. It is suggested that patients in whom signs of chorea appeared during this procedure will later have Huntingtons chorea. The failure of L-dopa to elicit abnormal movements in the controls suggests that there would be few false-positive results among the subjects at risk for Huntingtons chorea. The failure to manifest chorea is less important, and in subjects in this group chorea may still develop.

POTENTIATION OF LEVODOPA EFFECT BY INTRAVENOUS L-PROLYL-L-LEUCYL-GLYCINE AMIDE IN MAN

L-prolyl-L-leucyl-glycine amide (P.L.G.) has melanocyte-stimulating-hormone-inhibitory hormone (M.I.F.) activity. When injected intravenously as a bolus of 200 mg, it greatly potentiated the effect of an oral levodopa dose upon motor performance objectively measured by a battery of tests. This amelioration in motility was accompanied by improvement in intellectual functioning.