Polyamine pathway contributes to the pathogenesis of Parkinson disease.

The full complement of molecular pathways contributing to the pathogenesis of Parkinson disease (PD) remains unknown. Here we address this issue by taking a broad approach, beginning by using functional MRI to identify brainstem regions differentially affected and resistant to the disease. Relying on these imaging findings, we then profiled gene expression levels from postmortem brainstem regions, identifying a disease-related decrease in the expression of the catabolic polyamine enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1). Next, a range of studies were completed to support the pathogenicity of this finding. First, to test for a causal link between polyamines and α-synuclein toxicity, we investigated a yeast model expressing α-synuclein. Polyamines were found to enhance the toxicity of α-synuclein, and an unbiased genome-wide screen for modifiers of α-synuclein toxicity identified Tpo4, a member of a family of proteins responsible for polyamine transport. Second, to test for a causal link between SAT1 activity and PD histopathology, we investigated a mouse model expressing α-synuclein. DENSPM (N1, N11-diethylnorspermine), a polyamine analog that increases SAT1 activity, was found to reduce PD histopathology, whereas Berenil (diminazene aceturate), a pharmacological agent that reduces SAT1 activity, worsened the histopathology. Third, to test for a genetic link, we sequenced the SAT1 gene and a rare but unique disease-associated variant was identified. Taken together, the findings from human patients, yeast, and a mouse model implicate the polyamine pathway in PD pathogenesis.

Cerebral functional magnetic resonance imaging activation modulated by a single dose of the monoamine neurotransmission enhancers fluoxetine and fenozolone during hand sensorimotor tasks.

Fluoxetine inhibits the reuptake of serotonin, and dextroamphetamine enhances presynaptic release of monoamines. Although the excitatory effect of both noradrenaline and dopamine on motor behavior generally is accepted, the role of serotonin on motor output is under debate. In the current investigation, the authors evidenced a putative role of monoamines and, more specifically, of serotonin in the regulation of cerebral motor activity in healthy subjects. The effects on cerebral motor activity of a single dose of fluoxetine (20 mg), an inhibitor of serotonin reuptake, and fenozolone (20 mg/50 kg), an amphetamine-like drug, were assessed by functional magnetic resonance imaging. Subjects performed sensorimotor tasks with the right hand. Functional magnetic resonance imaging studies were performed in two sessions on two different days. The first session, with two scan experiments separated by 5 hours without any drug administration, served as time-effect control. A second, similar session but with drug administration after the first scan assessed drug effects. A large increase in evoked signal intensity occurred in the ipsilateral cerebellum, and a parallel, large reduction occurred in primary and secondary motor cortices (P < 10(-3)). These results are consistent with the known effects of habituation. Both drugs elicited comparable effects, that is, a more focused activation in the contralateral sensorimotor area, a greater involvement of posterior supplementary motor area, and a widespread decrease of bilateral cerebellar activation (P < 10(-3)). The authors demonstrated for the first time that cerebral motor activity can be modulated by a single dose of fluoxetine or fenozolone in healthy subjects. Drug effects demonstrated a direct or indirect involvement of monoamines and serotonin in the facilitation of cerebral motor activity.

Effects of the indirect dopaminomimetic diethylpemoline on local cerebral glucose utilization and local cerebral blood flow in the conscious rat.

The changes in local cerebral glucose utilization (LCGU) and local cerebral blood flow (LCBF) following the systemic application of the indirect dopaminomimetic diethylpemoline (50 mg/kg i.v.) were measured in conscious rats using the autoradiographic [14C]2-deoxyglucose and the [14C] iodoantipyrine technique. Increased rates of glucose utilization were observed in the sensorimotor cortex, parafascicular nucleus, ventrolateral nucleus of the thalamus, substantia nigra, caudate nucleus, globus pallidus, red nucleus, subthalamic nucleus, cerebellar cortex and vermis. Cingulate cortex, anteromedial, anteroventral nucleus of the thalamus, habenula and nucleus accumbens showed a decreased LCGU. The determination of LCBF revealed a similar pattern of altered blood flow values. Statistical evaluation of the relationship between glucose utilization and blood flow by regression analysis did not reveal any distinguishable difference between diethylpemoline-treated rats and controls. The data suggest that it is mainly the altered neuronal activity and metabolic demand after dopaminergic stimulation that effect the changes in blood flow rather than a direct dopaminergic effect on brain vasculature.

Determination of the psychostimulants pemoline, fenozolone and thozalinone in human urine by gas chromatography/mass spectrometry and thin layer chromatography.

Detection of the psychostimulants pemoline (Tradon), fenozolone (Ordinator) and thozalinone (Stimsen) in biological samples (urine) presents certain experimental difficulties. These substances were therefore converted by acid hydrolysis to their common hydrolysis product 5-phenyl-2,4-oxazolidinedione, which can be detected with high sensitivity and selectivity by thin layer chromatography. After silylation with N-methyl-N-trimethylsilyltrifluoroacetamide/trimethylchlorosilane quantitative results can be obtained from the same extract by the proposed GC/MS-method. After a single dose of 30 mg pemoline, levels ranging from one to four mg/l urine were observed.

[Effects of levophacetoperane, pemoline, fenozolone, and centrophenoxine on catecholamines and serotonin uptake in various parts of the rat brain]. / Effets du lévophacétopérane, de la pémoline, de la fénozolone et de la centrophénoxine sur la capture des catécholamines et de la sérotonine dans differentes régions du cerveau de rat.

These drugs, except centrophenoxine, inhibit in vitro in a competitive manner, norepinephrin uptake in Rat hypothalamus and cortex, and dopamine uptake in corpus striatum and cortex, at higher concentrations than d.l. amphetamine; this alone inhibits serotonin uptake in hypothalamus.