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Nitric oxide synthase inhibition and MPTP-induced toxicity in the common marmoset
G M Mackenzie1, M J Jackson, P Jenner
1Neurodegenerative Diseases Research Centre, King's College London, United Kingdom.
Abstract:
Nitric oxide, produced following activation of N-methyl-D-aspartate (NMDA) receptors, may be involved in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity since NMDA receptor antagonists have been shown to prevent MPTP induced nigral cell loss in primates. Common marmosets were treated with either saline or MPTP or L-NGnitro arginine methyl ester (L-NAME) or MPTP and L-NAME. MPTP-treated common marmosets showed motor deficits including bradykinesia, rigidity, and tremor accompanied by a marked loss of tyrosine hydroxylase-immunoreactive neurones in the substantia nigra pars compacta and of [3H]-mazindol binding in the caudate-putamen. MPTP treatment also caused an increase in glial fibrillary acidic protein (GFAP) staining in the substantia nigra compared to controls. However, MPTP treatment did not alter the number of constitutive nitric oxide synthase-immunoreactive neurones in the caudate-putamen. Furthermore, neurones or glial cells immunoreactive for inducible nitric oxide synthase were not observed in the substantia nigra pars compacta following MPTP treatment. L-NAME treatment alone did not produce any behavioural changes in marmosets and did not alter the number of tyrosine hydroxylase-immunoreactive cells in the substantia nigra pars compacta, the number of constitutive nitric oxide synthase-immunoreactive neurones or [3H]-mazindol binding in the caudate-putamen compared to saline-treated control animals. Furthermore, L-NAME did not affect the motor deficits, loss of tyrosine hydroxylase-immunoreactive neurones in the substantia nigra pars compacta, loss of [3H]-mazindol binding in the caudate-putamen, or the increase in GFAP staining in the substantia nigra induced by MPTP treatment of common marmosets. The failure of L-NAME to protect against MPTP-induced toxicity in the marmoset suggests that nitric oxide does not play a major role in such toxicity and casts doubt over the involvement of the NMDA:nitric oxide system in neurodegeneration in MPTP-treated primates.
Insights
Nitric oxide does not appear to play a significant role in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity. Studies show L-NG-nitro arginine methyl ester (L-NAME) did not prevent MPTP-induced neurodegeneration or motor deficits in marmosets.
Area of Science:
- Neuroscience
- Toxicology
- Pharmacology
Background:
- Nitric oxide (NO), produced via N-methyl-D-aspartate (NMDA) receptor activation, is hypothesized to contribute to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity.
- NMDA receptor antagonists have previously shown protective effects against MPTP-induced neuronal loss in primate substantia nigra.
Purpose of the Study:
- To investigate the role of nitric oxide in MPTP-induced neurotoxicity and associated motor deficits in common marmosets.
- To determine if inhibiting nitric oxide synthesis with L-NG-nitro arginine methyl ester (L-NAME) can prevent MPTP-induced damage.
Main Methods:
- Common marmosets were administered saline, MPTP, L-NAME, or a combination of MPTP and L-NAME.
- Behavioral assessments evaluated motor deficits (bradykinesia, rigidity, tremor).
- Post-mortem analyses quantified tyrosine hydroxylase-immunoreactive neurons in the substantia nigra and [3H]-mazindol binding in the caudate-putamen, alongside glial fibrillary acidic protein (GFAP) staining.
Main Results:
- MPTP treatment induced significant motor deficits, loss of dopaminergic neurons in the substantia nigra, and reduced [3H]-mazindol binding in the caudate-putamen.
- MPTP also increased GFAP staining in the substantia nigra, indicating neuroinflammation.
- L-NAME administration alone did not cause behavioral or cellular changes and crucially failed to prevent any of the MPTP-induced motor deficits, neuronal loss, or neurochemical alterations.
Conclusions:
- The findings suggest that nitric oxide does not play a major role in MPTP-induced neurotoxicity in common marmosets.
- This challenges the proposed involvement of the NMDA:nitric oxide pathway in MPTP-mediated neurodegeneration in primates.