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Motor Neurons Pathology After Chronic Exposure to MPTP in Mice
Giorgio Vivacqua1,2, Francesca Biagioni3, Carla L Busceti3
1Department of Anatomy, Histology, Forensic Medicine and Locomotor Sciences, Via A. Borelli 50, 00161, Rome, Italy.
Abstract:
The neurotoxin 1-methyl,4-phenyl-1,2,3,6-tetrahydropiridine (MPTP) is widely used to produce experimental parkinsonism in rodents and primates. Among different administration protocols, continuous or chronic exposure to small amounts of MPTP is reported to better mimic cell pathology reminiscent of Parkinson's disease (PD). Catecholamine neurons are the most sensitive to MPTP neurotoxicity; however, recent studies have found that MPTP alters the fine anatomy of the spinal cord including motor neurons, thus overlapping again with the spinal cord involvement documented in PD. In the present study, we demonstrate that chronic exposure to low amounts of MPTP (10 mg/kg daily, × 21 days) significantly reduces motor neurons in the ventral lumbar spinal cord while increasing α-synuclein immune-staining within the ventral horn. Spinal cord involvement in MPTP-treated mice extends to Calbindin D28 KDa immune-reactive neurons other than motor neurons within lamina VII. These results were obtained in the absence of significant reduction of dopaminergic cell bodies in the Substantia Nigra pars compacta, while a slight decrease was documented in striatal tyrosine hydroxylase immune-staining. Thus, the present study highlights neuropathological similarities between dopaminergic neurons and spinal motor neurons and supports the pathological involvement of spinal cord in PD and experimental MPTP-induced parkinsonism. Remarkably, the toxic threshold for motor neurons appears to be lower compared with nigral dopaminergic neurons following a chronic pattern of MPTP intoxication. This sharply contrasts with previous studies showing that MPTP intoxication produces comparable neuronal loss within spinal cord and Substantia Nigra.
Insights
Chronic low-dose MPTP exposure in mice reduces spinal cord motor neurons and increases alpha-synuclein, mimicking Parkinson's disease pathology. This occurs even without significant loss of dopaminergic neurons, suggesting a lower toxic threshold for spinal motor neurons.
Area of Science:
- Neuroscience
- Toxicology
- Pathology
Background:
- 1-methyl,4-phenyl-1,2,3,6-tetrahydropiridine (MPTP) is a neurotoxin used to model Parkinson's disease (PD).
- Chronic MPTP exposure better mimics PD pathology than acute exposure.
- While catecholamine neurons are known targets, MPTP's spinal cord effects, including motor neuron alterations, are increasingly recognized in PD.
Purpose of the Study:
- To investigate the effects of chronic low-dose MPTP on spinal cord motor neurons and alpha-synuclein.
- To compare spinal cord pathology with dopaminergic neuron changes in MPTP-treated mice.
- To determine the relative toxic thresholds of spinal motor neurons versus nigral dopaminergic neurons.
Main Methods:
- Mice were administered MPTP (10 mg/kg daily for 21 days).
- Quantification of motor neurons in the ventral lumbar spinal cord.
- Assessment of alpha-synuclein and Calbindin D28 KDa immune-staining in the spinal cord.
- Evaluation of dopaminergic cell bodies in the Substantia Nigra and tyrosine hydroxylase in the striatum.
Main Results:
- Chronic low-dose MPTP significantly reduced spinal cord motor neurons.
- Increased alpha-synuclein immune-staining was observed in the ventral horn.
- MPTP affected other spinal neurons (Calbindin D28 KDa positive) and caused slight striatal dopaminergic changes, but minimal nigral dopaminergic neuron loss.
- The toxic threshold for spinal motor neurons appeared lower than for nigral dopaminergic neurons.
Conclusions:
- Chronic low-dose MPTP induces spinal cord pathology, including motor neuron loss and alpha-synuclein accumulation, mirroring PD.
- Spinal cord involvement in PD and MPTP-induced parkinsonism is supported by these findings.
- Motor neurons in the spinal cord may be more vulnerable to chronic MPTP intoxication than nigral dopaminergic neurons.
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