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.

Figure 1

Quantification of MPTP-induced loss of TH-ir in A9 and A10 regions during different stages of development. An MPTP-induced loss of TH-ir neurons occurred at mid-gestation, but not later in development. Abbreviations: Gest, gestation. There were 3 samples in each control and MPTP group. * indicates a statistically significance decrease compared with appropriate control group. See text for details of statistical analyses.

Figure 2

Images showing that the extent of MPTP-induced loss of TH-ir in SN varied during development. The tract of neurons containing the highest density TH-ir neurons is the pars compacta region of the SN. The significant impact of MPTP exposure at the mid-gestational age is shown in panel A (scale bar is 100 micrometers); panel B (scale bar is 10 micrometers) shows a higher power image of TH-ir neurons in control and MPTP-treated mid-gestational fetuses. The lack of effect of MPTP exposure on TH-ir in young monkeys is illustrated in panel C (scale bar is 100 micrometers). TH-ir produces a brown stain, thionin staining is blue.

Figure 3

MPTP exposure induced a loss of TH-ir neurons and an increase in Nissl-stained neurons without TH-ir in the SNpc. Data derives from 3 control and 3 MPTP-exposed samples from each development stage. * indicates a significant MPTP-induced change from controls of that age. See text for details of statistical analyses.

Figure 4

MPTP-induced loss of striatal DA and HVA concentrations in adult monkeys. DA and HVA concentrations were measured in subregions of the striatum from 4 control and 4 MPTP-treated animals. Abbreviations: dCD, dorsal caudate nucleus; dPT, dorsal putamen; vCD, ventral caudate nucleus; vPT, ventral putamen. * indicates a statistically significant difference compared to the control value for that region. See text for details of statistical analyses.

Figure 5

Effect of MPTP on striatal DA and HVA concentrations in young monkeys. No loss of DA concentration, but a decrease in HVA concentration, was found in striatum from 4 control and 5 MPTP-treated young monkeys. Note that the Y-axes have different scale to those in Figure 4, as young monkeys have lower levels of striatal DA and HVA than adults. Abbreviations: dCD, dorsal caudate nucleus; dPT, dorsal putamen; vCD, ventral caudate nucleus; vPT, ventral putamen. * indicates a statistically significant difference compared to the control value for that region. See text for details of statistical analyses.

Figure 6

MPP+ accumulation in brain following MPTP injection depended on region and age. * indicates brain regions in which significantly more MPP+ was retained in the adult compared with the young monkey at 24 hours following MPTP injection. Bars with different lower case letters indicate regions in the adult brain that contained significantly different levels of MPP+. See text for details of statistical analyses. Bars with different upper case letters indicate regions in the young monkey brain that contained significantly different levels of MPP+. Data derived from 3 adult and 3 young monkeys. Abbreviations: CCx, cingulate cortex; dCD, dorsal caudate nucleus; DLPFC, dorsolateral prefrontal cortex; Nigra, substantia nigra; OccCx, occipital cortex; vPT, ventral putamen.

Figure 7

Greater expression of mRNA UPC2 in SN of young monkeys relative to adults. Data are adjusted for expression of mRNA GAPDH, and derive from samples taken from 3 adults and 5 young monkeys. * indicates a significant different from adult levels. See text for details of statistical analyses.