In VivoEvidence of Increased nNOS Activity in Acute MPTP Neurotoxicity: A Functional Pharmacological MRI Study

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.

Aberrant astrocytes impair vascular reactivity in Huntington disease

“…For FAIR MRI, the derivation of the CBF maps was according to our previous study . The VR was assessed using the level of CBF increase induced by carbogen switched from air in the region of interest.…”

“…For data acquisition and quantification of MRI (3D ΔR 2 ‐mMRA, BOLD MRI, and FAIR), drawing of regions of interest was performed using identical standard operating procedures …”

“…For FAIR MRI, the derivation of the CBF maps was according to our previous study. 31 The VR was assessed using the level of CBF increase induced by carbogen switched from air in the region of interest. Under the air-inhaling condition, the CBF was defined as the basal level, whereas the VR level was defined as the CBF increase divided by the basal level expressed as a percentage.…”

Systematic literature review on Parkinson's disease and Childhood Leukaemia and mode of actions for pesticides

“…The major reported key events reported in the investigated studies comprise JNK activation Xia et al, 2001) and activation of NMDA receptors with subsequent increase in the intracellular Ca 2+ concentration (Siow et al, 2013). The inhibition of complex I activity (especially in the striatum and substantia nigra) (Dauer et al, 2002;Richardson et al, 2007) and mitochondrial dysfunction such as inhibition of mitochondrial respiration, mitochondrial enzyme deficiency and swollen mitochondria (Yang et al, 2009) have been demonstrated.…”

“…to intrathecal application. Rat (Hung et al, 2014;Siow et al, 2013), cat (Aznavour et al, 2012), and zebrafish (Sallinen et al, 2009) have also been used to study MPTP neurotoxicity but less frequent than mice and monkeys.…”