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Published on: January 7, 2014
Age-related severity of dopaminergic neurodegeneration to MPTP neurotoxicity causes motor dysfunction in C57BL/6 mice
Satoshi Ohashi1, Atsushi Mori, Naoki Kurihara
1Research Unit for Neurological Diseases, Second Institute of New Drug Discovery, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan.
Abstract:
This study investigated the influence of advancing age on dopaminergic neuronal degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication from the perspective concerning the relationship between dopaminergic function and behavioral features. Young (10 weeks) and older (14-15 months) C57BL/6 mice were treated with one to four injections of MPTP (20 mg/kg at 2h intervals). Although young mice showed no mortality in either MPTP treatment, older mice exhibited mortality from only two injections of MPTP during the experimental period. An extensive dopaminergic cell loss was found in both the striatum and substantia nigra of older mice given one and two injections of MPTP with marked decrease in striatal dopamine (DA) levels, but not young mice. We also found a behavioral change in the tail suspension test associated with the extent of decrease in striatal DA levels in MPTP-treated older mice, but not in young mice. These results clearly present age-related vulnerability to MPTP neurotoxicity in C57BL/6 mice and strongly support our previous report showing that there is a critical threshold level of the decrement in striatal DA contents causing motor dysfunction in this mouse model of Parkinson's disease.
Insights
Older mice are more vulnerable to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity, showing significant dopaminergic neuron loss and motor deficits. Age impacts MPTP
Area of Science:
- Neuroscience
- Toxicology
- Aging Research
Background:
- Advancing age influences susceptibility to neurotoxins.
- 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a common neurotoxin used to model Parkinson's disease.
- Dopaminergic system integrity is crucial for motor function.
Purpose of the Study:
- To investigate age-dependent vulnerability to MPTP-induced neurotoxicity.
- To examine the relationship between dopaminergic function and behavioral changes in aging mice.
- To determine the impact of age on MPTP's effects on dopaminergic neurons.
Main Methods:
- Young (10 weeks) and older (14-15 months) C57BL/6 mice were administered varying doses of MPTP (20 mg/kg).
- Mortality rates, dopaminergic cell loss (striatum and substantia nigra), and striatal dopamine levels were assessed.
- Behavioral changes were evaluated using the tail suspension test.
Main Results:
- Older mice exhibited higher mortality rates following MPTP exposure compared to young mice.
- MPTP treatment caused significant dopaminergic cell loss and reduced striatal dopamine levels in older mice, but not young mice.
- A correlation was observed between decreased striatal dopamine and behavioral impairments in older mice.
Conclusions:
- Aging increases susceptibility to MPTP neurotoxicity in C57BL/6 mice.
- Age-related vulnerability to MPTP is linked to dopaminergic neuron degeneration and motor dysfunction.
- A critical threshold of striatal dopamine depletion underlies motor deficits in this Parkinson's disease model.
