Susceptibility to a parkinsonian toxin varies during primate development

Abstract

Symptoms of Parkinson’s disease typically emerge later in life when loss of nigrostriatal dopamine neuron function exceeds the threshold of compensatory mechanisms in the basal ganglia. Although nigrostriatal dopamine neurons are lost during aging, in Parkinson’s disease other detrimental factors must play a role to produce greater than normal loss of these neurons. Early development has been hypothesized to be a potentially vulnerable period when environmental or genetic abnormalities may compromise central dopamine neurons. This study uses a specific parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), to probe the relative vulnerability of nigrostriatal dopamine neurons at different stages of primate development. Measures of dopamine, homovanillic acid, 1-methyl-pyridinium concentrations and tyrosine hydroxylase immunoreactive neurons indicated that at mid-gestation dopamine neurons are relatively vulnerable to MPTP, whereas later in development or in the young primate these neurons are resistant to the neurotoxin. These studies highlight a potentially greater risk to the fetus of exposure during mid-gestation to environmental agents that cause oxidative stress. In addition, the data suggest that uncoupling protein-2 may be a target for retarding the progressive loss of nigrostriatal dopamine neurons that occurs in Parkinson’s disease and aging.

Developmental expression of paraoxonase 2

“…However, the overall trend observed in both species reveals a possible window of susceptibility to oxidative stress in young adult mice and monkeys which may point to a change in cellular environment driving a decrease in PON2 expression. Of interest is that the developmental profile of PON2 in monkey brain seen in this study is in agreement with previous findings on susceptibility to MPTP- and methamphetamine-induced dopaminergic toxicity, with infant brain observed as the most resistant [40, 41]. Further study will be required to determine what biological changes are mediating the decrease in PON2, and whether these persist into later ages in mice as observed in monkeys.…”

MPTP Induces Systemic Parkinsonism in Middle-Aged Cynomolgus Monkeys: Clinical Evolution and Outcomes

“…The clinical severity corresponding to the Kurlan score at the end of the rapid progress stage in this study may represent the initial level of damage to the dopaminergic system induced by MPTP. The score of the monkey manifesting spontaneous recovery was 14 at the end of rapid progress stage, much lower than that of the other animals (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Studies have suggested that stable Parkinsonism occurs in severe cases despite varying degrees of response to MPTP treatment [20].…”

“…Primary PD mainly occurs in the elderly, and old age is an important factor underlying the incidence of PD. In human and non-human primates, the dopaminergic neurons in the substantia nigra degenerate with advanced age [41][42][43][44][45][46][47][48], especially when exposed to pathogenic factors [19,24]. The plasticity of the substantia nigra in the aged animal is relatively low, and this decreases the probability of spontaneous recovery in the PD model.…”

“…Previous studies have shown that the possibility of spontaneous recovery is minimal after creation of the model in older monkeys compared with in the young [24].…”

“…However, the MPTP-induced model of PD in non-human primates has the following limitations, which restrict its application [14][15][16][17][18][19][20][21][22][23][24]: (1) the large individual differences in response to a similar dosage of MPTP prevent easy comparison across different studies; (2) animals with mild to moderate injury show spontaneous recovery, which is inconsistent with the progressive features of severe PD; there is no scope for effective prediction of spontaneous recovery in the model; and previous studies focused on simulation of different PD stages, with a lack of comprehensive assessment of the clinical evolution and outcome of the entire process; and (3) the supply of old monkeys is limited, so most models have used younger monkeys although PD mainly occurs in middle-aged individuals. Previous studies have shown that the possibility of spontaneous recovery is minimal after creation of the model in older monkeys compared with in the young [24].…”