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Manganese Pathway Linked to Motor Deficits

By Eddy Ball
October 2006

a hand holding test tubes over a centrifuge
(Photo courtesy of Steve McCaw)

In an NIEHS-funded study published by the journal Experimental Neurology, an interdisciplinary team of researchers at the Johns Hopkins Bloomberg School of Public Health and Thomas Jefferson University presented a novel explanation for the neurological impact of chronic exposure to manganese. Medical science has known for decades that manganese exposure produces motor deficits that are similar to those found in early stages of Parkinson's Disease (PD) and are usually irreversible. The researchers used a combination of assessment methods to determine, for what they believe is the first time, the effects of manganese on dopamine (DA) release in the brains of non-human primates.

Study results may have implications in the ongoing debate about chronic exposures to ambient levels of manganese, including inhalant exposures of manganese from the combustion of gasoline containing the octane enhancer methylcyclopentadienyl manganese tricarbonyl (MMT). Identifying the mechanism of manganese on DA release may also help scientists develop effective interventions for the manganese-induced condition, also known as manganism, which does not damage neurons in the same way as PD and produces a distinct symptom cluster that differs in several ways from PD.

Researchers established baseline imaging values, behavior ratings, general activity patterns and fine motor skills assessments in a group of young adult male research macaques. The team then started a regimen of injecting the primates with small doses of manganese sulfate based on body weight once each week over a period of 39 to 40 weeks. Three additional animals that did not receive injections or experimental procedures served as a comparison group for post-mortem brain analysis. Researchers monitored behavior, activity and fine motor performance of injected animals regularly during exposures and used a modified rating assessment based on a Parkinson's symptom rating scale developed for non-human primates.

After initiation of manganese administration, the primates underwent the same imaging studies as at baseline. The team studied in vivo DA release in response to an amphetamine challenge, dopamine receptors and dopamine transporters to assess the effects of manganese on DA neuron function. Following euthanasia the researchers examined the animals' brains and measured blood and brain tissue levels of manganese, iron, copper and zinc. They performed post-mortem analysis of dopaminergic neuronal markers to confirm the in vivo findings.

According to the study, exposure to manganese produced a distinct increase in scores of motor deficits corresponding with a progressive decline of in vivo DA release measured in the brain's striatum. Concentrations of brain manganese and copper increased significantly, but researchers found no significant effects on iron or zinc concentrations. The manganese-induced decrease in DA release was present despite the fact that dopamine transporter levels were not changed, indicating an intact but dysfunctional nigrostriatal dopamine system.

In addition to discovering physical and behavioral evidence of the distinct set of symptoms of manganese exposure, the researchers also determined whole blood manganese concentrations. Results were found to be within the upper range of concentrations reported in children or adults in previous studies of environmental exposures. This finding raises new questions about the harmful effects of exposure to manganese such as those from the combustion of MMT-containing gasoline that is approved for use in such countries as Canada and South Africa. Largely because of this possibility, the U. S. Environmental Protection Agency continues to call for long-term animal testing to more accurately define the risk.

Manganism produces early symptoms of behavioral, psychiatric and memory disturbances. Patients then develop motor symptoms, including action tremor, abnormalities in walking and motion instability. The most effective early therapy for PD, L-dopa, has not been found to be effective. Understanding the response of the dopamine system to manganese may consequently help scientists develop an effective intervention.

Citation: Guilarte TR, Chen MK, McGlothan JL, Verina T, Wong DF, Zhou Y, Alexander M, Rohde CA, Syversen T, Decamp E, Koser AJ, Fritz S, Gonczi H, Anderson DW, Schneider JS. 2006. Nigrostriatal dopamine system dysfunction and subtle motor deficits in manganese-exposed non-human primates. Exp Neurol on-line early release doi:10.1016/j.expneurol.2006.06.015.



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