Effects of manganese oxide on monkeys as revealed by a combined neurochemical, histological and neurophysiological evaluation

Abstract

Four monkeys were exposed to a total of 8 g each of manganese as oxide by repetitive subcutaneous injections during 5 months, after which they were left for 1 week to 6 months before they were sacrificed. All animals developed hyperactive behaviour after about 2 months. About 5 months after the start of the exposure the animals became hypoactive with an unsteady gait, and subsequently an action tremor appeared in some of the animals. The animals lost power in both upper and lower limbs and the movements of the hands and feet were very clumsy. The serum content of manganese rose 10-40 times during the exposure time and the content in brain was generally increased more than 10 times, with the highest content found in globus pallidus and putamen. The observed neurochemical effects were also largest in globus pallidus and putamen. In these regions there was a considerable depletion of dopamine and 3,4-dihydroxyphenylacetic acid, while the homovanillic acid content remained almost unchanged. A severe neuronal cell loss was observed in globus pallidus but not in other regions. This is in accordance with results from the most recent neuropathological study of a human suffering from chronic manganese poisoning [Yamada et al. (1986) Acta Neuropathol 70: 273-278] where globus pallidus was devoid of neuronal cells while the content of pigmented cells in substantia nigra was normal. Our data suggest a reduction in number of dopaminergic nerve terminals, as the activity of the dopamine synthesizing enzyme DOPA-decarboxylase was also lowered.(ABSTRACT TRUNCATED AT 250 WORDS)

Mapping of functional brain activity in freely behaving rats during voluntary running using manganese-enhanced MRI: Implication for longitudinal studies

“…In particular, the effect of manganese on motor function has been reliably reproduced in different animals and experimental paradigms; this effect is apparent across a wide range of doses, different routes of administration and chemical species of manganese (Calabresi et al, 2001;Dodd et al, 2005;Mohammad and Faris, 2006;Nam and Kim, 2008;Newland and Weiss, 1992;Normandin et al, 2004). Manganese treatment typically results in decreased motor activity or disturbances in motor coordination, although a manganese-induced hyperactivity has also been reported (Calabresi et al, 2001;Eriksson et al, 1987). The effects are usually reversible, dose-dependent and often remain long after the end of manganese administration.…”

“…Although the mechanisms underlying manganese neurotoxicity remain unclear, experimental evidence exists that manganese may affect dopaminergic and cholinergic neuromodulatory systems, which may lead to various cognitive and neurological disorders including motor dysfunction (Calabresi et al, 2001;Eriksson et al, 1987;Nam and Kim, 2008;Newland and Weiss, 1992;Olanow et al, 1996). Taking this into account, a successful application of MEMRI technique for longitudinal studies, particularly involving behaving animals, critically depends on the manganese administration regimen that does not or minimally compromise homeostatic capacity, while achieving MRI-detectable cumulative concentration of Mn 2+ in the brain.…”

Adequacy and Consistency of Animal Studies to Evaluate the Neurotoxicity of Chronic Low-Level Manganese Exposure in Humans

“…Due to the limited number of non-human primate studies of manganese neurotoxicity and the fact that results are mostly reported for individual animals, attempts to draw general observations from this dataset are necessarily tentative. The most consistent outcomes produced by manganese exposure are a decrease in striatal dopamine and a deleterious effect on globus pallidus integrity, variously characterized as damaged globus pallidus (Mella 1924), loss of pallidal neurons (Eriksson et al 1987b;Pentschew et al 1963), gliosis (Shinotoh et al 1995), proliferation of Alzhemimer Type II astrocytes (Pentschew et al 1963), and decreased globus pallidus dopamine content (Bird et al 1984).…”

Imaging neuronal pathways with 52Mn PET: Toxicity evaluation in rats

“…The basal ganglia, and the dopaminergic neurons in particular, are most vulnerable to manganese (Eriksson et al, 1992, Stanwood et al, 2009, Sriram et al, 2010. As a result, motor extrapyramidal symptoms, resembling those of Parkinson's disease patients, are a common manifestation in humans (Huang et al, 1998, Tuschl et al, 2013 as well as in experimental animals (Eriksson et al, 1987, Olanow et al, 1996. Consequently, Mn 2+ doses used in MEMRI studies must be carefully evaluated, M A N U S C R I P T…”