Abstract
Background1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces Parkinson’s disease (PD)-like neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) via its oxidized product, 1-methyl-4-phenylpyridinium (MPP+), which is transported by the dopamine (DA) transporter into DA nerve terminals. DA receptor subtype 3 (D3 receptor) participates in neurotransmitter transport, gene regulation in the DA system, physiological accommodation via G protein-coupled superfamily receptors and other physiological processes in the nervous system. This study investigated the possible correlation between D3 receptors and MPTP-induced neurotoxicity. A series of behavioral experiments and histological analyses were conducted in D3 receptor-deficient mice, using an MPTP-induced model of PD.ResultsAfter the fourth MPTP injection, wild-type animals that received 15 mg/kg per day displayed significant neurotoxin-related bradykinesia. D3 receptor-deficient mice displayed attenuated MPTP-induced locomotor activity changes. Consistent with the behavioral observations, further neurohistological assessment showed that MPTP-induced neuronal damage in the SNpc was reduced in D3 receptor-deficient mice.ConclusionsOur study indicates that the D3 receptor might be an essential molecule in MPTP-induced PD and provides a new molecular mechanism for MPTP neurotoxicity.
Highlights
MPTP targets the basal ganglia and/or the substantia nigra, inducing most of the biochemical, pathological, and clinical features akin to Parkinson’s disease (PD) in both human and non-human primates [1]
No significant behavioral change was observed among the mice that received 5 mg/kg MPTP per injection or the mice injected with an equal volume of saline
Neurohistological assessment Because MPTP may induce PD-like neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and because the above data show that D3 receptor-deficient mice can withstand MPTP neurotoxicity, we evaluated the neurohistological changes in the four cohorts
Summary
MPTP targets the basal ganglia and/or the substantia nigra, inducing most of the biochemical, pathological, and clinical features akin to Parkinson’s disease (PD) in both human and non-human primates [1]. MPTP, which is lipid-soluble, readily penetrates the blood–brain barrier and enters the brain cells. Because it is amphiphilic, it is captured in acidic organelles, mostly lysosomes, of astrocytes [2]. MPTP itself does not appear to be toxic, but its oxidized product, 1-methyl-4-phenylpyridinium (MPP+), is toxic. MPP+appears to support the occurrence of oxidative stress [1,2]
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