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Age-related susceptibility to MPTP-induced neurotoxicity in mice
S F Ali1, S N David, G D Newport
1Division of Neurotoxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079-9502.
Abstract:
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is known to cause neurotoxicity in rodents and nonhuman primates. In this study the ontogeny of MPTP-induced DA depletion and formation of reactive oxygen species (ROS) were evaluated in mouse striatum. C57/B6N mice were injected four times with 0 or 10 mg/kg MPTP (i.p.) at two-hour intervals on either postnatal day 23, at about 7 months of age, and at one year of age. Animals were sacrificed 1, 2, 4, 8, 12, 24, 48 and 72 hours after the last dose. Brains were rapidly removed and striata were dissected for neurochemical analysis. Dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured by HPLC/EC. ROS formation was measured by a fluorescence probe, 2',7'-dichlorofluorescein-diacetate (DCFH-DA). MPTP produced a slight but significant decrease of DA only 4 hours post dosing on PND 23. DOPAC and HVA levels decreased up to 4 and 8 hours post dosing respectively and returned to control values thereafter. At 7 months of age, MPTP produced a 50-65% decrease of DA and its metabolites (DOPAC and HVA) in striatum 24 hours post dosing. In one year old mice, MPTP produced an 80% decrease of DA and 60-80% decrease of DOPAC and HVA in striatum. In contrast, ROS formation in striatum was not significantly increased by MPTP treatment at any age but was decreased at 1 hour only in PND 23 and 7 month old mice. These studies suggest that MPTP-induced neurotoxicity is age-dependent in the mouse.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
MPTP neurotoxicity in mice is age-dependent, with older mice showing greater dopamine depletion. Reactive oxygen species (ROS) levels were not significantly increased by MPTP, suggesting a complex neurotoxic mechanism.
Area of Science:
- Neuroscience
- Toxicology
- Pharmacology
Background:
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a known neurotoxin.
- MPTP induces Parkinsonism-like symptoms in animal models.
- The ontogeny of MPTP's effects on dopamine depletion and reactive oxygen species (ROS) formation is not fully understood.
Purpose of the Study:
- To evaluate the age-dependent effects of MPTP on dopamine (DA) depletion.
- To assess the impact of MPTP on reactive oxygen species (ROS) formation in the mouse striatum across different ages.
- To elucidate the developmental trajectory of MPTP neurotoxicity.
Main Methods:
- C57/B6N mice were administered MPTP (10 mg/kg) or saline four times at 2-hour intervals on postnatal day 23, at 7 months, and at 1 year of age.
- Striata were dissected at various time points post-injection for neurochemical analysis.
- Dopamine and its metabolites (DOPAC, HVA) were measured using HPLC/EC; ROS formation was assessed with the DCFH-DA probe.
Main Results:
- MPTP caused a slight DA decrease in young mice (PND 23) but significant depletion (50-80%) in adult and aged mice.
- Dopamine metabolite levels (DOPAC, HVA) mirrored DA depletion, with greater reductions in older mice.
- MPTP did not significantly increase ROS formation at any age; a decrease was observed at 1 hour post-injection in younger mice.
Conclusions:
- MPTP-induced neurotoxicity, specifically dopamine depletion in the striatum, is significantly age-dependent in mice.
- The lack of increased ROS formation suggests that oxidative stress may not be the primary mechanism of MPTP neurotoxicity across all ages.
- These findings highlight the importance of age as a factor in MPTP neurotoxicity studies.
