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Published on: July 22, 2014
In vivo evidence of increased nNOS activity in acute MPTP neurotoxicity: a functional pharmacological MRI study
Tiing Yee Siow1, Chiao-Chi V Chen, Nina Wan
1Institute of Biomedical Sciences, Academia Sinica, 128 Section 2, Academia Road, Nankang, Taipei 11529, Taiwan ; Department of Medical Imaging and Intervention, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan 33302, Taiwan.
Abstract:
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin commonly used to produce an animal model of Parkinson's disease. Previous studies have suggested a critical role for neuronal nitric oxide (NO) synthase- (nNOS-) derived NO in the pathogenesis of MPTP. However, NO activity is difficult to assess in vivo due to its extremely short biological half-life, and so in vivo evidence of NO involvement in MPTP neurotoxicity remains scarce. In the present study, we utilized flow-sensitive alternating inversion recovery sequences, in vivo localized proton magnetic resonance spectroscopy, and diffusion-weighted imaging to, respectively, assess the hemodynamics, metabolism, and cytotoxicity induced by MPTP. The role of NO in MPTP toxicity was clarified further by administering a selective nNOS inhibitor, 7-nitroindazole (7-NI), intraperitoneally to some of the experimental animals prior to MPTP challenge. The transient increase in cerebral blood flow (CBF) in the cortex and striatum induced by systemic injection of MPTP was completely prevented by pretreatment with 7-NI. We provide the first in vivo evidence of increased nNOS activity in acute MPTP-induced neurotoxicity. Although the observed CBF change may be independent of the toxicogenesis of MPTP, this transient hyperperfusion state may serve as an early indicator of neuroinflammation.
Insights
This study provides the first in vivo evidence that neuronal nitric oxide synthase (nNOS) activity increases during MPTP-induced neurotoxicity. Inhibiting nNOS prevented changes in cerebral blood flow, suggesting NO
Area of Science:
- Neuroscience
- Toxicology
- Biochemistry
Background:
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin used to model Parkinson's disease.
- Neuronal nitric oxide (NO) synthase (nNOS)-derived NO is implicated in MPTP pathogenesis, but in vivo evidence is limited due to NO's short half-life.
Purpose of the Study:
- To investigate the in vivo role of NO in MPTP neurotoxicity.
- To assess MPTP-induced changes in hemodynamics, metabolism, and cytotoxicity.
- To determine if nNOS inhibition affects MPTP-induced effects.
Main Methods:
- Utilized flow-sensitive alternating inversion recovery (FAIR) sequences, in vivo localized proton magnetic resonance spectroscopy (MRS), and diffusion-weighted imaging (DWI).
- Administered MPTP to experimental animals.
- Pretreated animals with a selective nNOS inhibitor, 7-nitroindazole (7-NI), before MPTP challenge.
Main Results:
- MPTP induced a transient increase in cerebral blood flow (CBF) in the cortex and striatum.
- Pretreatment with 7-NI completely prevented the MPTP-induced CBF increase.
- Demonstrated the first in vivo evidence of increased nNOS activity in acute MPTP neurotoxicity.
Conclusions:
- This study provides the first in vivo evidence of increased nNOS activity in acute MPTP neurotoxicity.
- The observed transient hyperperfusion may be an early indicator of neuroinflammation, though potentially independent of MPTP's toxicogenesis.
