Environmental Toxins and the Brain

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Environmental Health Perspectives v.104, n.8 Aug96

http://www.mindfully.org/Health/Brain-Toxins.htm

 

For years scientists have suspected that the environment plays a role in

neurodegenerative diseases such as Alzheimer's disease, Parkinson's

disease, multiple sclerosis, and dementia. Only recently have scientists

begun to investigate the complex relationship between environmental

toxins and the chronic death of neurons, the cells that serve as

information transmitters and processors in the brain.

 

Two NIEHS researchers, Jean Harry and Jau-Shyong Hong, hope their work

will shed light on the mechanisms that trigger neuroimmune

responses--eventually killing neurons--in the central nervous system.

Ultimately, they hope to uncover drug therapies that could one day slow

the progression of neurodegenerative diseases.

 

Scientists theorize that environmental exposures have a latent effect on

the brain, causing a noticeable degeneration only years later. " The

nervous system is great in compensation, " says Harry, a

neurotoxicologist. After a stroke, for example, the victim's surviving

neurons sprout and make new connections, striving to keep the brain in

balance. As the system ages, however, it gradually forfeits the ability

to compensate, and an accelerated aging process may begin. " You may have

been exposed to something when you were five years old, " Harry says.

" Basically, the whole process sort of [catches] up with you. "

 

Rogue Brain Cells

Hong and his colleagues in the neuropharmacology section of the

Laboratory of Toxicology at the NIEHS have set out to bolster the theory

that microglia--brain cells that somehow become activated by neurotoxins

or other injuries--kill neurons in the brain. According to Hong, the

microglia play a critical surveillance role during the resting stage,

just as immune cells do in the peripheral nervous system.

 

However, when the brain is injured--either through adverse environmental

exposure, a viral or bacterial infection, trauma, or stroke--these

sentinel cells launch an out-of-control rampage in the brain. Suddenly

transformed from loyal bodyguards into overactive destroyers, they kill

the very neurons they were intended to protect. Hong likens the process

to misuse or overuse of a beneficial drug. Too much of a good thing, he

says, can be very harmful. " When [these cells] work too hard, they not

only kill the foreign invader, they also kill the neurons, " he explains.

 

 

Hong's experiments studying reactive gliosis have used an in vitro cell

culture system. Such a model is necessary, he contends, to reveal

molecular pathways involved in this process. Hong's experiments have

supported the theory that overactive microglia kill neurons, and that,

in contrast, astroglia (large neuroglial cells also known as astrocytes)

produce proteins known to promote neuronal growth or survival, which may

help to preserve the neurons under attack by inflammatory cells. To

further complicate an already complex relationship, microglia are known

to release mitogens that activate astroglia, while astroglia produce

growth factors that stimulate microgliosis.

 

Hong's work has also focused on how opioid peptides may modulate the

microglia's function. His research team has sought to discover the

effects of endogenous opioid peptides on the production of

pro-inflammatory cytokines by microglia cells, as well as their possible

relationship to toxin-induced neurodegeneration. " We found opioid

peptides have a very important effect on microglial function, " Hong

says. " They potentially could be used as a therapy for the neuroimmune

system. " Hong explains that opioid peptides tend to dampen the activity

of the microglia, helping to prevent the aberrant activation that

destroys neurons. According to Hong, information generated from this

line of research raises the possibility that inhibition of either

deleterious microglial activation or the production of specific

microglial-derived neurotoxins could provide therapeutic interventions

for neurodegenerative diseases.

 

Hong's group has also collaborated with a researcher at Duke University

Medical Center to examine the role of opioid peptides on the interaction

between HIV and microglia. An envelope protein of HIV--gp120--has been

shown to activate the microglia, which means that, in an AIDS patient,

not only are lymphocytes being destroyed, but brain cells are being

destroyed as well. " More than 50% of AIDS patients eventually suffer

from AIDS dementia complex, " Hong says.

 

Triggers of Neurodegeneration

Harry, who heads the neurotoxicology group at the NIEHS, suspects that

specific patterns of neurodegeneration may be due to neuronal-glia

signaling interactions. During the past few years, research on the

nervous system has shown that resident cells in the central nervous

system can produce cytokines the same way cells in the peripheral

nervous system do. These cells can react to injury by initiating a

cytokine response, which has been shown to be associated with tissue

damage. Injury or inflammation appear to be the precursors of this

immune-like response, which could trigger a number of neurodegenerative

processes in the brain. Harry's research focuses on understanding the

signaling processes associated with this inflammatory response and their

role in nervous system damage following exposure to environmental

agents.

 

According to Harry, an important mechanism associated with brain injury

is the cytokine inflammatory response. Inflammation at the site of

injury, she says, spurs the microglia to release a number of factors,

creating a cytokine network that may play a major role in

immunologically mediated neurodegenerative diseases. Astroglia produce

other growth factors and support the neurons by regulating the neuronal

growth and function of microglia.

 

Harry and her colleagues have completed several experiments aimed at

identifying the temporal pattern of pro-inflammatory cytokine responses

during chemically induced neurodegeneration. In initial studies, the

researchers examined a prototypic model of neurodegeneration through

systemic administration of the toxic chemical trimethyltin (TMT) into

rats. The TMT caused neuronal necrosis and neurodegeneration in some

cells of the hippocampus, while other cells remained unchanged.

According to Harry, the question of interest is the pattern of

degeneration. " Why do some neurons die while adjacent ones do not? " she

asks. " We found that the microglia cells, which have been linked to most

of the production of cytokines, co-localized with the neurons that were

going to degenerate, " Harry explains. " And they co-localized early,

prior to seeing any necrosis or any indication of neuronal

perturbation. "

 

Harry and her colleagues also observed in those cells an

up-regulation--or increased levels--of the cytokines. " So, the microglia

and the cytokines, because of their co-localization with neurons, may

actually be a driving force in neurodegeneration, " Harry proposes.

 

Harry's team also performed experiments using in vitro cultures of glial

cells (astrocytes, microglia, and oligodendrocytes) to examine the

effects of TMT on morphology and cytokine responses in glia cells alone,

without the contribution of neuronal cells. Their data suggest that TMT

can directly stimulate glial cells without the neuronal signal. Harry

hopes that the in vitro system will allow them to look more closely at

cellular responses, plus allow researchers to pharmacologically

manipulate various glial factors.

 

The team is currently evaluating a mouse model of TMT that produces a

different pattern of hippocampal neuronal damage. The scientists are

finding a concentration of microglia around the degenerating neurons,

again with a concurrent and most likely related up-regulation of

cytokines. These results prompt the question of why the microglia

converge on some neurons and leave others within the same region of the

brain untouched. Harry hopes to do further research with transgenic

animals and genetic mutants to address this question and determine

whether the microglia play a neurotoxic role and the astroglia a

protective one. She also wants to find out if neuronal degeneration is

prevented when pro-inflammatory cytokines, like tumor necrosis factor

alpha, are removed from the equation. In short, Harry says, " We're

trying to find out if the cytokine response is truly responsible for the

neuronal degeneration, or if it augments it, or if it is only an injury

response occurring within a similar time period. "

 

The Next Step

Before embarking on the next level of in vivo research, the team plans

to study an in vitro culture system using the same chemical and

identical cells from the hippocampus. " That will help us identify which

intervention approaches may be successful. Then we can go back in vivo

to confirm whether we can modulate this response, " says Harry.

 

The in vitro approach does have some disadvantages if used without

caution, according to Harry. Because the central nervous system is

protected by a blood-brain barrier--the body's way of keeping unwanted

circulating factors at bay--the brain may be buffered from direct

exposure to certain chemicals. " There are ways the brain gets things

out, that in culture, it can never get away from, " Harry explains. " And

the other thing is, you never know exactly what the brain sees, " she

adds. " If you take a drug or you're exposed to a chemical, it can be

biometabolized to another form. [However], the most important limitation

is the inability to mimic the complex nature of the nervous system in an

isolated in vitro system. "

 

For this reason, Harry doesn't advocate using cultures as an effective

screen for neurotoxicity, arguing that there is no sure way to have all

the systems in place to accurately determine a chemical's toxicity. " We

don't know the mechanisms of toxicity to make sure we cover all the

possibilities, " she concedes. " However, [cultures] do offer a system to

examine specific mechanistic questions. "

 

Like Hong, Harry also hopes for a drug to help stem the tide of

neurodegeneration within the brain. " It's probably one that's already

out there; nothing necessarily new, but one that would work on

modulating the immune response, " she says. " But we'd first have to

confirm that the drug doesn't cause problems in the brain. " Here again,

she explains, culture systems could pose a problem: " We're finding

things that are therapeutic agents that, when given to the person, can

have activity in the culture that you don't necessarily know how to

interpret. "

 

Researchers continue to understand more about neurodegenerative

diseases, and to work steadily toward therapies that could one day

preserve neurons in the brains of people who have begun to experience

symptoms of neurodegeneration. Preservation is the key, because the

cells in the central nervous system can't regenerate like their

counterparts in the peripheral nervous system. The brain comes outfitted

with a finite number of neurons--billions of them. Harry says, " you've

got one shot at getting all of them you need. If anything messes that

up, you can work on a lower balance and you may be fine--until you age. "

 

 

Jennifer Medlin

 

 

 

 

AIM Barleygreen

" Wisdom of the Past, Food of the Future "

 

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