[Medicamentous strategy for improving the quality of life in the senescence]

The striatum, in which the nigrostriatal dopaminergic neurons terminate, contains the highest amount of dopamine DA) in the brain. DA, released in the striatum, plays the rate limiting role in the control of motor functions by continuously inhibiting the release of acetylcholine (ACh) from the cholinergic interneurons of the caudate nucleus. DA content of the human caudate nucleus decreases by 13% per decade over the age of 45. Parkinson's disease seems to be a kind of selective, highly accelerated 'premature aging' of the nigrostriatal dopaminergic system, and the DA content of this neuron system shrinks within a short time to less than 10% of the normal level in the premorbid state. Clinical symptoms occur when the striatum loses more than 70% of its DA content. The chemical lesioning of the nigrostriatal dopaminergic neuron in the rat by 6-OH-dopamine (6-OHDA) leads to an increase of cholinergic activity in the striatum. The striatum taken from a rat pretreated with 6-OH dopamine is a useful experimental model for the rapid screening of compounds with potential therapeutic benefit in Parkinson's disease. A more specific neurotoxin than 6-OHDA is 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which kills the cells in the substantia nigra with high specificity and induces rapidly parkinsonian-like condition in men and monkeys. (-)Deprenyl, the selective inhibitor of B-type MAO protects the striatum from the neurotoxic effects of 6-OHDA and MPTP. The amount of ACh released from the striatum of the rat increases from 372.8 +/- 31.4 to 746.5 +/- 44.0 pmol/g/min in 6-OHDA treated rats, it remains normal (371.1 +/- 34.7) if (-)deprenyl is given 30 minutes before 6-OHDA administration, hut is further increased (956.3 +/- 79.3 pmol/g/min), if clorgyline os injected 30 minutes before 6-OHDA. (-)Deprenyl prevents in a similar manner the neurotoxicity of MPTP in monkeys, whereas clorgyline, the selective inhibitor of MAO-A, is ineffective. The most important effect of deprenyl in the brain is the sensitization of dopaminergic neurons to physiological and pharmacological influences without eliciting an acute increase in dopaminergic activity. The effect of deprenyl is due, on the one hand, to the inhibition of MAO-B and, on the other hand, to inhibition of the uptake of dopamine.(ABSTRACT TRUNCATED AT 400 WORDS)