P Jenner

Deprenyl in the management of response fluctuations in patients with Parkinson's disease on levodopa.

Fluctuations in response to levodopa are a common and serious complication of long-term levodopa therapy. It may be possible to prolong the effect of each dose of levodopa by retarding the breakdown of dopamine. The selective monoamine oxidase type B inhibitor deprenyl, which is extensively metabolised to amphetamine and methamphetamine, has this effect as well as possible actions on dopamine release and re-uptake. In a double-blind crossover trial against placebo, deprenyl prolonged the action of levodopa and produced an objective improvement in mobility in five of 10 patients with dose-related response swings, and a subjective improvement in a further four patients. In another group of seven patients with random fluctuations in symptoms, only two noted subjective improvement, and there was an apparent increase in the severity of response swings in five patients. Deprenyl exacerbated dyskinesias, but had no serious side-effects. We conclude that deprenyl is unlikely to benefit patients with random response swings, and may cause deterioration in such cases. However, it may be a useful adjuvant in the management of dose-related response fluctuations in patients already on optional levodopa therapy.

Do thermodynamic studies provide information on both the binding to and the activation of dopaminergic and other receptors

BERNARD TESTA,*? PETER JENNER,

Inhibition of alpha-ketoglutarate dehydrogenase by isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

GAVIN J. KILPATRICK,

Interaction of neuroleptic drugs with rat striatal D-1 and D-2 dopamine receptors: a quantitative structure—affinity relationship study

NABIL EL TAYAR,* HAN VAN DE WATERBEEMD* and C. DAVID MARSDENS * School of Pharmacy, University of Lausanne, CH-1005 Lausanne, Switzerland; and

Cortical nicotinic receptors in Alzheimer's disease and Parkinson's disease.

Medical Research Council Movement Disorder Research Group, University Department of Neurology and Parkinson’s Disease Society Research Centre, Institute of Psychiatry and King’s College Hospital Medical School. London SE5 8AF, U.K.

Drug metabolism : chemical and biochemical aspects

&NA; Defects in complex I and &agr;‐ketoglutarate dehydrogenase (&agr;‐KGDH) occur in the substantia nigra in Parkinsons disease (PD). Isoquinoline derivatives structurally related to 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) or 1‐methyl‐4‐phenylpyridinium (MPP+) are implicated in the cause of PD as endogenous toxins and are inhibitors of complex I. However, their effects on &agr;‐KGDH and other mitochondrial non‐respiratory chain enzymes are unknown. We have examined the effects of six isoquinoline derivatives (isoquinoline, N‐methylisoquinolinium, N‐n‐propylisoquinolinium, 1,2,3,4‐tetrahydroisoquino‐line, N‐methyl‐1,2,3,4‐tetrahydroisoquinoline and salsolinol) and MPP+ on the activities of &agr;‐KGDH, citrate synthase (CS) and glutamate dehydrogenase (GDH) in mitochondrial fragments from rat forebrain. None of the compounds examined had any effect on CS or GDH activity. In contrast, all isoquinoline derivatives investigated and MPP+ inhibited &agr;‐KGDH activity in a concentration‐dependent manner with IC50s ranging from 2.0 to 18.9 mM. MPP+ was previously shown to inhibit &agr;‐KGDH, but this is the first report of inhibition of &agr;‐KGDH by isoquinoline derivatives. These findings may represent an additional mechanism contributing to mitochondrial dysfunction and cell death in Parkinsons disease.

Oxidative stress as a cause of nigral cell death in Parkinson's disease and incidental Lewy body disease. The Royal Kings and Queens Parkinson's Disease Research Group.

The quantitative structure—affinity relationships of two large and partly overlapping sets of neuroleptics are reported. D-1 and D-2 affinities of the first set (31 compounds) were taken from the literature, while the D-2 affinities of the second set (64 compounds) were determined in this study, as were the lipophilicities and basicity of all investigated compounds. Cluster analysis categorizes the compounds of the first set into a number of subgroups according to biological and structural properties. Bilinear relationships exist between lipophilicity and D-1 affinities or activities, with an optimal log kw0 value of 4.6-4.7. Linear relationships between lipophilicity and D-2 affinity exist only within some chemical classes. For congeneric orthopramides, a good correlation has been found between D-2 affinity and electronic properties of ring substituents, confirming a topographical model of the D-2 receptor previously deduced from molecular electrostatic potentials [25, 26].

Alterations in levels of iron, ferritin, and other trace metals in neurodegenerative diseases affecting the basal ganglia. The Royal Kings and Queens Parkinson's Disease Research Group.

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