Chronic MPTP administration regimen in monkeys: a model of dopaminergic and non-dopaminergic cell loss in Parkinson's disease

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder clinically characterized by cardinal motor deficits including bradykinesia, tremor, rigidity and postural instability. Over the past decades, it has become clear that PD symptoms extend far beyond motor signs to include cognitive, autonomic and psychiatric impairments, most likely resulting from cortical and subcortical lesions of non-dopaminergic systems. In addition to nigrostriatal dopaminergic degeneration, pathological examination of PD brains, indeed, reveals widespread distribution of intracytoplasmic inclusions (Lewy bodies) and death of non-dopaminergic neurons in the brainstem and thalamus. For that past three decades, the MPTP-treated monkey has been recognized as the gold standard PD model because it displays some of the key behavioral and pathophysiological changes seen in PD patients. However, a common criticism raised by some authors about this model, and other neurotoxin-based models of PD, is the lack of neuronal loss beyond the nigrostriatal dopaminergic system. In this review, we argue that this assumption is largely incorrect and solely based on data from monkeys intoxicated with acute administration of MPTP. Work achieved in our laboratory and others strongly suggest that long-term chronic administration of MPTP leads to brain pathology beyond the dopaminergic system that displays close similarities to that seen in PD patients. This review critically examines these data and suggests that the chronically MPTP-treated nonhuman primate model may be suitable to study the pathophysiology and therapeutics of some non-motor features of PD.

Keywords: Acetylcholine; Extra-striatal dopamine; MPTP monkey; Nigrostriatal dopamine; Norepinephrine; Parkinson’s disease; Serotonin; α-Synuclein.

Figure 1

Photomicrographs of adjacent calbindin (CB) and tyrosine hydroxylase (TH) -immunostained coronal sections at the level of ventral midbrain of control (A,C) and MPTP-treated parkinsonian monkey (B,D). CB immunostaining was used to delineate TH/CB-positive neurons in the dorsal tier of the SNC (SNCd) and the ventral tegmental area (VTA) from TH-positive/CB-negative neurons in ventral tier of the SNC (SNCv). (E) Percentage loss of TH-positive neurons in SNCv, SNCd and VTA regions of three MPTP-treated monkeys (M1, M2 and M3) based on unbiased stereological estimates of total TH-positive cell counts. (see Masilamoni et al., 2011b for additional details)

Figure 2

Photomicrographs of TH-immunostained coronal sections at the level of the pre-commissural (A, B), commissural (C, D), post-commissural (E,F) striatum of a control (left column) and a MPTP-treated (right column) monkey. Abbreviations: CA: caudate nucleus; PU: putamen; GPe: globus pallidus, external segment; GPi: globus pallidus, internal segment; Th: thalamus.

Figure 3

Photomicrographs of TH-immunostained sections of the striatum in a control (A) and MPTP-treated asymptomatic monkey (B). (C,D) Pseudo-colored images (NIH ImageJ program) of TH-immunostained sections showed in A and B. MPTP treatment preferentially reduced TH immunoreactivity in presumed striatal patches (white asterisks). Abbreviations: CA: caudate nucleus; PU: putamen.

Figure 4

Photomicrographs of TH-immunostained coronal sections at the level of noradrenergic cell groups (A, B), 5HT-immunostained serotonergic cell groups (C, D) and ChAT-immunostained pedunculopontine nucleus (E, F) of a control (A,C,E) and a MPTP-treated (B,E,F) monkey. Abbreviations: A5,A7: Noradrenergic cell groups A5 and A7; PPN: pedunculopontine nucleus. (see Masilamoni et al., 201b for more details).

Figure 5

Photomicrographs of α-synuclein-immunostained coronal sections at the level of the ventral midbrain (A–D) of a control (left column) and a MPTP-treated (right column) monkey. Alpha-synuclein-positive aggregates in SNCd and VTA of chronically MPTP-treated monkeys are shown in B and D.