Alzheimer's, Parkinson's, MS, Depression and Bipolar Disorder All Linked To Metal Toxicity

Metal toxicants entering the part of the brain that deals with stress and panic have been linked to disorders dealing with the central nervous system. Increasing evidence indicates that damage to the locus ceruleus (LC), is present in a wide range of neurodegenerative diseases including demyelinating and psychiatric disorders. 



There are a growing number of Clinicians and Scientists who are convinced that excitotoxins and heavy metals play a critical role in the development of several neurological disorders, including migraines, seizures, infections, abnormal neural development, certain endocrine disorders, specific types of obesity, and especially the neurodegenerative diseases; a group of diseases which includes: ALS, Parkinson's disease,Alzheimer's disease, Huntington's disease, and olivopontocerebellar degeneration.

The locus ceruleus (LC) is a nucleus in the pons (part of the brainstem) involved with physiological responses to stress and panic. It is the principal site for brain synthesis of the hormone and neurotransmitter norepinephrine (noradrenaline).
It has been known for many years that toxicants (i.e., poisons that are put into the environment or human body by human activity) that block the uptake of noradrenaline can damage the LC of experimental animals.

The recent finding that a metal toxicant, inorganic mercury, selectively enters the cytoplasm of human LC neuron has prompted researchers to investigate how these toxicants cause many of these CNS disorders.


The Locus Ceruleus Is Upregulated By Stress

An increased output of noradrenaline from the LC can be elicited by a wide range of acute and chronic stressors, in particular those that are physical (e.g., pain), psychological (e.g., anxiety), or social (e.g., isolation). Chronic stressors can keep noradrenergic neurons in a highly active state permanently. Stressors can increase the uptake of circulating toxicants that use neurotransmitter transporters to enter LC neurons.

Stress has been implicated in the onset or relapse of a number of neurodegenerative, demyelinating and psychiatric conditions. The increased activity of the LC during stress, with a concomitant increase in neurotransmitter release and re-uptake, encourage circulating toxicants to enter the terminal axons of LC neurons.
Studies indicating which elements of the LC-Toxicant hypothesis relate to particular CNS disorders.

CNS Regions Are Innervated By The Locus Ceruleus
About 70% of all CNS noradrenaline comes from the LC innervate in particular CNS regions that are involved in Alzheimer’s disease (hippocampus, neocortex, basal forebrain), amyotrophic lateral sclerosis (brain stem and spinal motor neurons), and mood disorders (amygdala). The substantia nigra, which is damaged in Parkinson’s disease, also receives innervation from the LC.
The normal human brain contains about 32,000 LC neurons and is estimated to contain capillaries with a total length of 640 kilometres. This means that, on average, each LC neuron is responsible for innervating 20 meters of capillaries. No other neuronal system has such widespread contact with circulating blood.

Noradrenaline plays an important part in maintaining the integrity of the blood-brain barrier and in responding to stressors by increasing cerebral blood flow. With their large exposure to the blood circulation, LC neurons could take up toxicants even if they were at low levels in the blood.
Noradrenaline also suppresses inflammation, mostly because of its affects on microglia, which have a high expression of adrenoreceptors. Inflammation would be further increased if a permeable blood-brain barrier, caused by noradrenaline depletion, allowed inflammatory cells to enter the CNS. 


The Locus Ceruleus Has Been Shown To Be Damaged In Neurodegenerative, Demyelinating, and Psychiatric Disorders
A man who injected himself intravenously with metallic mercury had mercury staining in the cytoplasm of about 70% of his LC neurons. This individual committed suicide a few months after the mercury injection, so mercury uptake by the LC may have been aided by stress-induced upregulation of the LC neurons. This is the first time that a metal toxicant has been found to be able to enter the human LC selectively.

Neuromelanin, a dark pigment produced neurons in the LC, increases during aging and may influence cell function. Neuromelanin could initially play a protective role by chelating certain circulating metal toxicants such as mercury and lead and when production is inhibited could dramatically affect uptake.

Recent reviews have highlighted the extent of LC damage in neurodegenerative, demyelinating, and psychiatric disorders.
The LC-Toxicant hypothesis can explain a number of puzzling features of neurodegenerative, demyelinating and psychiatric disorders, which are grouped below under the term “neurodegenerative disorders”.
One agent that enters neurons at an early age and cause damage later in life is a heavy metal, since metal toxicants persists within human neurons for many years.


CNS and Neurogenerative Disorders

In Parkinson’s disease, cell loss is more severe in the LC than in the substantia nigra. This fits with suggestions based on animal experiments that in Parkinson’s disease LC damage occurs first, and that the noradrenaline-deficient substantia nigra is then more susceptible to toxic insults.

The topographical distribution of cell loss in the LC varies in Alzheimer’s disease, Parkinson’s disease and depression. he type of pathology differs as well, with LC cell loss in Alzheimer’s disease and Parkinson’s disease, gliosis in multiple sclerosis, and neuronal shrinkage in amyotrophic lateral sclerosis. These topographical and pathological differences suggest that toxicants affect LC neurons in different ways.

Genetic variation is unlikely to account for the variations in incidence of neurodegenerative disorders that have been described between city and country living, or for increases or decreases of disease incidence over time. Here environmental factors are more likely. The LC would be subjected to different toxicants in the city versus the country, and would be exposed to different levels of pollutants over time. Geographic differences in toxicant exposure could interact with other environmental factors in a disorder such as multiple sclerosis, where a reduction in sunlight and vitamin D levels at increased latitudes has been implicated.

Herbicides, pesticides, vaccinations, medications and industrial exposures may be the most effective approach likely to define groups with known exposures to certain toxicants and then look for genetic variants (either single nucleotide, copy number, or epigenetic) in the biological pathways that normally protect individuals from these toxicants. An analysis could then be undertaken to see if these genetic variants are more common in people within these defined groups who have neurodegenerative disorders.

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