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

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.

Fig. 1.

Time course of changes in the number of TH-IR neurons (A) and Nissl-stained cells (B) in the SNc. A,B,Filled squares represent the individual values (n = 5 in each group), theopen circle represents the mean value of each group, and the dark lines represent the kinetic fits. *Significant difference compared with D0, p < 0.05; +significant difference compared with the previous group,p < 0.05. C, Examples of cell-counting maps showing the typical patterns of degeneration in the SNc. TH-IR neurons are marked in red, whereas theblue symbols represent the Nissl-stained cells that were not TH-positive. The horizontal line above each map indicates the mean percentage of surviving cells (i.e., Nissl-stained). Note the selective disappearance of the dorsal tier of the SNc with time.

Fig. 2.

A, Examples of DAT binding autoradiographs showing the progression of striatal denervation at the caudal level. Note the homogenous degeneration and the severe lesion in the D25 group. The horizontal line under each example indicates the mean percentage of DAT binding. Nonspecific binding is shown on the bottom left corner of the panel.B, DAT loss in the caudal putamen. Mean data (open circles) and individual data from all quadrants of all animals (dark circles;n = 20 in D0, D12, D15, and D25 groups and n = 16 in D6 group) are presented. Dark line represents the kinetic fits. Data are presented as femtomoles per milligram of tissue equivalent.

Fig. 3.

Progressive decrease in striatal DA content (in picograms per microgram of protein) measured in the caudate nucleus (A) and in the putamen (B).Filled circles represent the individual values (n = 5 in D0, D12, D15, and D25 groups andn = 4 in D6 group), the open circlerepresents the mean value of each group, and the dark lines represent the kinetic fits. *Significant difference compared with D0, p < 0.05; +significant difference compared with the previous group, p < 0.05. C, Levels of (DOPAC+HVA)/DA ratio in the putamen of the different groups.

Fig. 4.

Examples of D₁(A) and D₂ (C) DAR binding autoradiographs at the caudal level of the striatum. Thehorizontal line under each example indicates the mean percentage of DAR binding. Nonspecific binding is shown on thebottom left corner of each panel. Below each of these examples, a scatter plot shows the mean binding data (open circles) of, respectively, D₁(B) and D₂ (D) ligands, measured in the putamen at the caudal level, all quadrants of all animals being plotted (dark circles,n = 20 in D0, D12, D15, and D25 groups andn = 16 in D6 group). Data are in femtomoles per milligram of tissue equivalent. D, Dark line interpolates the mean binding data of D₂ ligand to underline the biphasic changes.