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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline

« Drug Companies In Great Britain: Ease Up, Won't You? | Main | Outcomes, Expensive Outcomes »

December 5, 2013

Parkinson's From the Environment?

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Posted by Derek

I've been meaning to link to this piece by Lauren Wolf in C&E News on the connections between Parkinson's disease and environmental exposure to mitochondrial toxins. (PDF version available here). Links between environmental toxins and disease are drawn all the time, of course, sometimes with very good reason, but often when there seems to be little evidence. In this case, though, since we have the incontrovertible example of MPTP to work from, things have to be taken seriously. Wolf's article is long, detailed, and covers a lot of ground.

The conclusion seems to be that some people may well be genetically more susceptible to such exposures. A lot of people with Parkinson's have never really had much pesticide exposure, and a lot of people who've worked with pesticides never show any signs of Parkinson's. But there could well be a vulnerable population that bridges these two.

Comments (17) + TrackBacks (0) | Category: The Central Nervous System | Toxicology


COMMENTS

1. Greg on December 5, 2013 3:07 PM writes...

I know that the VA considers Agent Orange (herbicide, not pesticide, but still) to be a cause of Parkinson's.

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2. Pennpenn on December 5, 2013 5:35 PM writes...

Seems logical. I mean, there's no reason to beleive that there isn't going to be a variability in predisposition or resistance to certain effects based on genetics.

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3. Lane Simonian on December 5, 2013 5:58 PM writes...

Yes, susceptibility is the key. It can be genetic susceptibility or it can be one factor combining with another factor pushing someone over the threshold. Many neurological diseases are caused by peroxynitrites. Peroxynitrite-mediated damage includes nitration, oxidation, lipid peroxidation, and DNA stand breakage leading to inflammation, vascular dysfunction, mitochondrial dysfunction, and the death of neurons.

MPP+ (mentioned in the article) is likely a neurotoxin because it produces peroxynitrites. Other environmental toxins that produce peroxynitrites include but are not limited to mercury, aluminum fluoride, diesel fumes, and bisphenols. Non-environmental factors that increase peroxynitrite levels are high glucose levels, high sodium levels, low density lipids, Down syndrome, bisphosphonate osteoporosis drugs (such as Fosamax), and stress (including from excessive exercise).

Glutathione is the body's principal scavenger of peroxynitrites. If for genetic reasons its supply is low or if it is depleted by one or more factors that increase the formation of peroxynitrites, the result can be neurological damage. Natural and/or synthetic peroxynitrite scavengers can likely be used to treat many neurological diseases.

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4. SteveM on December 5, 2013 9:59 PM writes...

I grew up in a very Catholic area with large families. My grade school classes were huge. I remember just a few kids retrospectively who probably had ADHD. And one guy in high school who may have been autistic.

Parenthetically and rhetorically, so where did the ADHD and autism epidemics come from?

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5. Tom on December 6, 2013 8:26 AM writes...

Doesn't it seem entirely irresponsible to use the term 'pesticides' in this context? Really, it's been one (or even just a few) chemicals that have been at least loosely or tenuously linked to causing disease. Yet, because MPTP has shown a link - surely all pesticides, fungicides, insecticides... etc - MUST cause Parkinson's. That's some good science, and scientific reporting right there.

In all the stories I have read about this, there has been very little effort to emphasize that the problem is specifically a strikingly small number of chemicals, instead of explicitly fingering the suspects. The analogy would read that "Scientists discover link between prescription drugs and heart attacks," - nevermind all the nuances of Vioxx. Drugs cause heart attacks.

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6. I'm sure he got tenure on December 6, 2013 9:03 AM writes...

"Neurologist Ali H. Rajput of the University of Saskatchewan and his team surveyed approximately 20 early-onset Parkinson’s patients—those diagnosed under the age of 40—living in the province. Rajput’s team found that early in life, the patients spent 92% of their time in a rural environment".

Um, sample bias?

http://en.wikipedia.org/wiki/Saskatchewan

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7. Eric C. on December 6, 2013 10:12 AM writes...

#6: Based on the abstract, this seems to have been a case-control study without, um, controls. And that gets published how?

So, anyone have full-text access to this? My library can only find it on paper. . . .

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8. ClutchChemist on December 6, 2013 10:19 AM writes...

The article quotes a paper that says "Men who were exposed to paraquat and who had nonfunctional glutathione S-transferase were 11 times more likely to have Parkinson’s disease than nonexposed men who had functional enzymes." Why wouldn't you compare exposed men with the nonfunctional enzyme to exposed men with a functional enzyme to see if the enzyme is really wahts making the difference?

Also, the enzyme in question "...is responsible for cleansing cells of foreign substances such as pesticides and protecting against oxidative stress." I might be wrong, but missing an enzyme that protects against oxidative stress has got to cause more suceptibilty to a LOT more environmental chemicals than just pesticides, right?

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9. Lane Simonian on December 6, 2013 10:54 AM writes...

Glutathione S-transferase is a critical enzyme because it conjugates glutathione to environmental toxins. Without it, peroxynitrite levels can increase leading to greater neurological damage.

The question of how much exposure to environmental toxins would be needed to trigger Parkinson's would likely fall upon epidemiologists. Severe exposure to one toxic or less intense exposure to multiple toxins may produce the same result.

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10. dave w on December 6, 2013 4:54 PM writes...

#4... it seems likely that the "autism epidemic" may be a case of "diagnostic substitution" as much as an increase of the prevalence of the characteristic itself: many kids who are presently being described as "autistic" would have historically been in some category such as "mental retardation", "behavior problem", "atypical development", etc. - it is only in relatively recent years that autism, as such, has become (for example) something for which "Special Education" programs provide specific assistance: give folks a category and they will use it!

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11. metaphysician on December 7, 2013 10:29 AM writes...

Okay, a question for the room: I've always assumed #9's babble about peroxynitrite is voodoo. Am I correct in assuming that, or is peroxynitrite an actual substance at least?

( this question is specifically *not* asked of you, #9, as obviously the fact in question is your trustworthiness )

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12. Lane Simonian on December 7, 2013 11:36 AM writes...

I am going to provide a link and then try to step out of the way.

Pal Pacher, Joseph S. Beckham, and Lucas Liaudet, Nitric oxide and Peroxynitrite in Health and Disease.

72 pages of text with 1478 references.

Please someone read it and critique it. If they are correct, it critically changes the way we treat neurological diseases. If they are partially incorrect, it is important to know where and why.

This too was recommended to me. The Kegg Pathway --Alzheimer's disease (ONOO- peroxynitrite right bottom of chart).

Again, I am looking for constructive input. I can understand and evaluate most of this, but not all of this. It is not that I don't appreciate the input of chemists, but I would particularly like the expert analysis of a biologist or a biochemist.

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13. Mike C on December 8, 2013 1:23 PM writes...

#12:"but I would particularly like the expert analysis of a biologist or a biochemist. "

Would expert analysis that disagreed with your opinion affect the quantity of your peroxynitrite posts in the slightest? Google pegs them at 203 and counting.

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14. Lane Simonian on December 8, 2013 2:10 PM writes...

Yes, such analysis would. If the damage attributed to peroxynitrites does not actually occur in the human body then I would need to look elsewhere for the causes of neurodegenerative diseases (just as those who assert that amyloid plaques and hyperphosphorylated tau proteins are the cause of Alzheimer's disease might have to look elsewhere as well).

If the damage attributed to peroxynitrites does actually occur in the human body then I am extremely interested in input as to which peroxynitrite scavengers--either synthetic or from natural products--work the best.

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15. simpl on December 9, 2013 6:19 AM writes...

I remember hearing in the '80s from a GP in a steel town that iron vapour increased the number of Parkinsonism patients that he saw. I can find a few papers confirming some environmental effect, but it doesn't seem to have echoed in the public understanding as yet.

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16. TX raven on December 9, 2013 7:03 AM writes...

I hear some folks talking about "reactive nitrogen species". Is the meaning of that the same than "peroxynitrate"?
I am more familiar with "reactive oxygen species"...

Permalink to Comment

17. Lane Simonian on December 9, 2013 11:18 AM writes...

Yes, peroxynitrite is one of the reactive nitrogen species.

Permalink to Comment

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