Effect of MPTP on Serotonergic Neuronal Systems and Mitochondrial Complex I Activity in the Living Brain: A PET Study on Conscious Rhesus Monkeys

Abstract

The objective of the present PET study was to compare the effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on serotonergic neuronal systems and mitochondrial complex I (MC-I) activity with that of dopamine in conscious rhesus monkeys (Macaca mulatta). Methods: A Parkinson disease monkey model was prepared by repeated administration of MPTP. For the PET measurements, normal and MPTP-treated conscious monkeys received an intravenous injection of 11 C-DASB for serotonin transporter, 18 F-MPPF for serotonin 1A receptor, 11 C-PE2I for dopamine transporter, 11 C-6MemTyr for dopamine synthesis, 11 C-raclopride for dopamine D 2 receptor, or 18 F-BCPP-EF for MC-I. Serotonin and dopamine parameters were calculated using time-activity curves in the cerebellum as the input function. The total distribution volume of 18 F-BCPP-EF was assessed using Logan plot graphical analysis with metabolite-corrected plasma as the input function. Results: MPTPinduced diffuse reductions in MC-I activity were observed throughout the brain, except the cerebellum. Significant reductions in the presynaptic dopamine parameters-dopamine transporter and dopamine synthesis-were detected in the striatum and substantia nigra pars compacta of MPTP-treated monkeys, whereas no significant differences in postsynaptic dopamine D 2 receptor binding were observed. Serotonin transporter binding was reduced by MPTP not only in striatal regions but also in extrastriatal regions. In contrast, serotonin 1A receptor binding was unaffected by MPTP anywhere in the brain. In the cortex, the reduction of serotonin transporter binding correlated with that of MC-I. Conclusion: The results obtained by multiparametric PET measurements in a Parkinson disease monkey model demonstrated that chronic MPTP treatment induced reductions not only in the dopaminergic system in the nigrostriatal pathway but also in serotonin transporter in the cortical and subcortical regions. These results suggest that the neurotoxicity of MPTP is not exclusive to the nigrostriatal pathway, as predicted from MC-I damage in the extrastriatal regions of the brain.

Perimenopause and emergence of an Alzheimer’s bioenergetic phenotype in brain and periphery

“…Other measures of mitochondrial function, such as metabolomic studies in blood and/or CSF, are of interest as they would allow measurement of lactate, pyruvate, and related metabolites in the perimenopause to menopause transition. Likewise, novel PET tracers for mitochondrial activity are currently being tested in animals, including primates, for possible application in humans[ 48 ].…”

PET Imaging of Mitochondrial Function in the Living Brain

“…MRI was performed on each monkey using a 3.0 T MR imager (Singna Excite HDxt 3.0 T, GE Healthcare) using a 3D spoiled gradient echo (SPGR) sequence under pentobarbital anesthesia. To avoid anesthetic effects on brain function as well as PET probe kinetics, PET scans were conducted under conscious condition using high-resolution animal PET scanners (SHR-7700 and 38,000, Hamamatsu Photonics) as reported previously [11][12][13][14].…”

“…[ 11 C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile ([ 11 C]DASB) [50] 5-HT 1A receptor (5-HT 1A R) binding using 4-(2′-methoxyphenyl)-1-[2′-(N-2″-pyridinyl)-p-[ 18 F]fluoro-benzamido]ethylpiperazine ([ 18 F]MPPF)[51] in parallel with DA parameters for presynaptic DA synthesis (DAS) using 6-[ 11 C]methyl-m-tyrosine ([ 11 C]6MemTyr)[52,53], DA transporter (DAT) using[ 11 C]N-(3-iodoprop-2E-enyl)-2β-carbomethoxy-3β-(4-methyl-phenyl) nortropane ([ 11 C]PE2I)[54], postsynaptic DA D 2 R using [ 11 C]Raclopride, and MC-I activity using [ 18 F]BCPP-EF in the living brains of MPTP-treated monkeys[13].…”

Animal Model of Parkinson Disease: Neuroinflammation and Apoptosis in the 6-Hydroxydopamine-Induced Model

“…The most commonly used neurotoxins are: (a) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [9], which is converted to 1-methyl-4-phenylpyridinium (MPP+) by monoamine oxidase (MAO-B), (b) 6-hydroxydopamine (6-OHDA) [6,10], (c) herbicides such as paraquat or rotenone [11] and (d) metals (manganese, iron) [12]. MPTP crosses the blood-brain barrier (BBB) [13], which in addition to cause damage to the nigrostriatal pathway, causes neuronal loss of the GABAergic neurons [14], catecholaminergic neurons (VTA, locus coeruleus, retrorubral nuclei) [15], reduction of serotonine receptor in the cortical and subcortical regions and reactive gliosis [16]. The toxicity of herbicides and metals is characterized by mitochondrial dysfunction due to peripheral and brain cellular stress [6,17].…”