Autoradiography of l–Methyl–4–phenyl–l,2,3,6–tetrahydropyridine (MPTP): Uptake in the Monoaminergic Pathways and in Melanin Containing Tissues

Abstract

A recently discovered neurotoxic compound, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, has been found to cause a parkinsonian-like syndrome in man and monkey, but not in laboratory animals such as rat, mouse and guinea pig. MPTP seems to selectively destroy the melanin containing dopaminergic cells in pars compacta of substantia nigra. Lower mammalian species do not have melanin in these cells, which indicates that the presence of neuromelanin may be of importance for the development of MPTP-induced lesions. By means of whole-body autoradiography of 3H-MPTP in mice, accumulation and retention was observed in the dopaminergic pathways, in locus caeruleus and in structures in the medulla oblongata and spinal cord. A high uptake was also seen in melanin-containing tissues such as in the eyes of pigmented mice. MPTP has earlier been found to have high affinity in vitro for dopamine melanin, which is similar to the pigment in substantia nigra. The typical features of the MPTP-induced neurotoxicity with destruction of pigmented nerve cells and development of parkinsonism may be to to accumulation and retention of MPTP and its metabolites in these cells. In species with pigmented nerve cells, such as man and monkey, the accumulation may be much more pronounced because of the melanin affinity of MPTP and its metabolites.

Pargyline‐Sensitive selective accumulation of a radiolabeled MPTP analog in the primate cerebral cortex and basal ganglia

“…Although the liver, kidneys, and brain contained the highest levels of radioactivity at the end of the scintigraphic study, a progressive accumulation of radioactivity was observed within the eyes over the course of the imaging study. Accumulation within this organ was evident within 50 min postinjection; such accumulation has been reported by other groups using radiolabeled MPTP in the monkey (Hartvig et al, 1986) and is presumed to reflect high retinal MA0 activity and trapping of metabolites by melanin-containing dopaminergic neurons of the retina (D'Amato et al, 1987;Lyden et al, 1985). In contrast to the rodent heart, which maintains levels of [ 1251]MHTP-derived radioactivity comparable to those of the brain (Efange et al, 1989), very little radioactivity was retained in the monkey heart.…”

“…However, the selective dopaminergic neurotoxicity of MPTP may be partially explained by the regional distribution of MPP in vivo. Following the administration of radiolabeled MPTP to rodents, high concentrations of radioactivity were found within the caudate-putamen, nucleus accumbens, and locus coeruleus (Lyden et al, 1985;Lyden-Sokolowski et al, 1988). These areas of the brain are known to contain the highest concentrations of catecholamine uptake sites (Javitch et al, 198513).…”

The function of melanin or six blind people examine an elephant

“…The substance was ultimately purified and demonstrated to bind to melanin (25). The substance produces Parkinson-like symptoms in animals but only in those species that contain high levels of neuromelanin in the substantia nigra (26). It also preferentially kills melanoma cells containing high levels of melanins (27).…”

Tracking extranigral degeneration in animal models of Parkinson’s disease: quest for effective therapeutic strategies

“…Additionally, decreased concentration of corticotropin-releasing factor, found in PD patients, was also recorded in amygdala and paraventricular nucleus of hypothalamus in MPTP-treated rats (Huang and Lee 1995). Significant loss of DA and 5-hydroxytryptamine (serotonin) was recorded in amygdala along with striatum, (Lyden et al 1985) Altered glucose metabolism in spinal cord (Schwartzman and Alexander 1985) Presence of MPTP metabolizing system in spinal cord (Samantaray et al 2008b) Neurodegeneration in cervical and lumbar spinal cord neurons (Samantaray et al 2008a,b) Upregulation of calpain expression and activity in spinal neural cells (Ray et al 2000;Chera et al 2002Chera et al , 2004 Acupuncture at GB34 and LR3 acupoints altered gene expression in cervical spinal cord (Choi et al 2011) Alpha-synuclein pathology and astrogliosis with progressive loss of locomotor function (Neumann et al 2002) Extensive immunoreactivity for insoluble phosphorylated on serine 129 isoform of alpha-synuclein and ubiquitin, associated with caspase 9 activation in spinal cord of end-stage symptomatic A30P mice. Parkin deficiency mitigated neuritic pathology in end-stage symptomatic A30P mice (Fournier et al 2009) Dopamine transporter knock-out Epidural electrical stimulation of dorsal column in spinal cord restored locomotion (Fuentes et al 2009(Fuentes et al , 2010…”