Relationship between the Appearance of Symptoms and the Level of Nigrostriatal Degeneration in a Progressive 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Lesioned Macaque Model of Parkinson's Disease

TLDR

The threshold of dopamine depletion required to trigger Parkinson’s disease symptoms has not yet been experimentally defined in nonhuman primates, despite its widespread acceptance. The study aimed to delineate how Parkinsonian symptoms emerge relative to nigrostriatal degeneration and to characterize accompanying presynaptic and postsynaptic striatal changes, with the goal of informing early diagnostic tools and therapies that enhance compensatory mechanisms. Monkeys were chronically treated with 1‑methyl‑4‑phenyl‑1,2,3,6‑tetrahydropyridine in a regimen that induces progressive Parkinsonian degeneration. The study identified critical thresholds for symptom onset—43.2% loss of nigral tyrosine hydroxylase‑positive neurons and ~80% loss of striatal DAT binding and dopamine content—and found that early increases in dopamine metabolism are not adaptive, while D2‑like receptor binding shows a biphasic pattern, decreasing presymptomatically and upregulating once dopaminergic homeostasis is disrupted.

Abstract

The concept of a threshold of dopamine (DA) depletion for onset of Parkinson's disease symptoms, although widely accepted, has, to date, not been determined experimentally in nonhuman primates in which a more rigorous definition of the mechanisms responsible for the threshold effect might be obtained. The present study was thus designed to determine (1) the relationship between Parkinsonian symptom appearance and level of degeneration of the nigrostriatal pathway and (2) the concomitant presynaptic and postsynaptic striatal response to the denervation, in monkeys treated chronically with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine according to a regimen that produces a progressive Parkinsonian state. The kinetics of the nigrostriatal degeneration described allow the determination of the critical thresholds associated to symptom appearance, these were a loss of 43.2% of tyrosine hydroxylase-immunopositive neurons at the nigral level and losses of 80.3 and 81.6% DA transporter binding and DA content, respectively, at the striatal level. Our data argue against the concept that an increase in DA metabolism could act as an efficient adaptive mechanism early in the disease progress. Surprisingly, the D(2)-like DA receptor binding showed a biphasic regulation in relation to the level of striatal dopaminergic denervation, i.e., an initial decrease in the presymptomatic period was followed by an upregulation of postsynaptic receptors commencing when striatal dopaminergic homeostasis is broken. Further in vivo follow-up of the kinetics of striatal denervation in this, and similar, experimental models is now needed with a view to developing early diagnosis tools and symptomatic therapies that might enhance endogenous compensatory mechanisms.