[Conductor71]

Hi,

I have not been able to let these two anecdotal experiences of PWP rest.

** As early as the 70's PWP have reported improvements during in flight travel.
**More recently, MJF tells the world in an interview that his symptoms improved to point of not needing meds during a stay in the mountains of Bhutan.

I have been wondering if hypoxia, or reduction in oxygen, helps us somehow and why? The research points to a big yes, so makes you wonder if PD has a vascular component which is overlooked. Results are quite interesting. There is a new hypothesis out there that PD, ALS, AD may start with oxygen transcription factors know as Hypoxia Inducible Factors (HIF-1a). Generally speaking they regulate release of oxygen from blood stream into our cells. All of our cells.

I could list different ways this hypothesis explains many seemingly trivialities in PD but would take too long. The gist of it is, we underexpress HIF-1a (note cancer is now thought due to over expression of this). In PWP, this underexpression is linked to excess iron accumulation, unchecked Reactive Oxygen Species, resulting in cell loss. This explains BOTH the loss of Dopamine and Norepinephrine because these specialized areas are high in neuromelanin which is a known iron regulator. These cells are the main losses in PD, so iron homeostasis and metabolism must be key to the pathology of PD. The big questions left are what is the role of alpha-synuclein clumping, where do prions fit in, and why is our immune system triggered? Oh, and the biggie- why isn't iron being cleared out like it should?

Here is what hits home for many of us:

Hypoxia-inducible factor (HIF) plays an important role in cell survival by regulating iron, antioxidant defense, and mitochondrial function.

Pharmacological inhibitors of the iron-dependent enzyme class prolyl hydroxylases (PHD), which target α subunits of HIF proteins for degradation, have recently been demonstrated to alleviate neurodegeneration associated with stroke and hypoxic-ischemic injuries. Here we report that inhibition of PHD by 3,4-dihydroxybenzoate (DHB) protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigral dopaminergic cell loss and up-regulates HIF-1α within these neurons

That DHB is an iron chelator. In fact there are numerous studies popping up showing iron chelation resulting in an increase in HIF-1a and...

A more recent study finds that placing cells in a mildly hypoxic state thus inducing HIF-1a promotes the change from neuronal stem cell to dopamine cells.

Iron chelation resulted in protection of dopa cells but also in their restoration. In fact when treated prior to inducing the MPTP model of PD, this treatment completely reversed the loss.


Key Sources:

Hypoxia Inducible Factor-1 as a Target for Neurodegenerative Diseases
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3213300/

[vlhperry]

Excellant resource. Good post (thread)!

My problem is I always have low oxygen levels in blood. So low I sleep with a C-PAP machine. I have oxigen damage in my brain. 2 mutations in Parkin gene and Fdopa scan showed moderately severe loss of dopamine uptake.

Dianna

[reverett123]

Long before PD I had noticed that I was a very shallow breather when at rest (e.g. when beginning a nap or sitting quietly). I wonder if a state of self-induced hypoxia might be diagnostic?
-Rick

[lurkingforacure]

Great post, Laura, thank you. From wiki:

"Research at UCSF indicates that clioquinol appears to block the genetic action of Huntington's disease in mice and in cell culture.[10]

Recent animal studies have shown that clioquinol can reverse the progression of Alzheimer's, Parkinson's and Huntington's diseases. According to Dr. Siegfried Hekimi and colleagues at McGill's Department of Biology, clioquinol acts directly on a protein called Clk-1, often informally called “clock-1,” and might slow down the aging process. They theorize that this may explain the apparent ability of the drug to be effective in the above conditions, but warn against individuals experimenting with this drug.[1]"

I noticed that clioquinol is neurotoxic in "large doses", perhaps that is why they warn not to experiment with it.

This sure ties a lot of things together, doesn't it?

[Conductor71]

Originally Posted by Dianna_Wood

Excellant resource. Good post (thread)!

My problem is I always have low oxygen levels in blood. So low I sleep with a C-PAP machine. I have oxigen damage in my brain. 2 mutations in Parkin gene and Fdopa scan showed moderately severe loss of dopamine uptake.

Dianna

Wow! I recall seeing one of the known PD mutations as playing a part in hypoxia, but it was DJ-1. However, I just found this:

Parkin regulates metal transport via proteasomal degradation of the 1B isoforms of divalent metal transporter 1.

Basically says that Parkin anomalies result in dysregulation of metals, namely iron and manganese transport. We know of the link between Manganese exposure and Parkinsonism.

I have read that zinc is being touted now as neuroprotective and a powerful antioxidant in PD; maybe it intervenes with the iron accumulation?

[Conductor71]

Originally Posted by reverett123

Long before PD I had noticed that I was a very shallow breather when at rest (e.g. when beginning a nap or sitting quietly). I wonder if a state of self-induced hypoxia might be diagnostic?
-Rick

Rick,

I did not notice it pre diagnosis, but I sure notice it post. I get super winded just going up and down the basement stairs. Having a little kid, I can take 5 days to catch up on laundry.

Incidentally, have you taken one of those pulmonary tests where you blow into the tube. Mine was so abysmal the doctor wanted to do an EEG test on the spot.
This ties into the fact that our sympathetic something or other in our hearts are affected in PD. Norepinephrine loss is believed to be the culprit here as well as orthostatic hypotension.

Check this out!

The locus coeruleus-norepinephrine network optimizes coupling of cerebral blood volume with oxygen demand.

From the abstract:


Given the brain's uniquely high cell density and tissue oxygen levels bordering on hypoxia, the ability to rapidly and precisely match blood flow to constantly changing patterns in neural activity is an essential feature of cerebrovascular regulation. Locus coeruleus-norepinephrine (LC-NE) projections innervate the cerebral vasculature and can mediate vasoconstriction.

These observations show an important role for NE in optimizing neurovascular coupling. As LC neuron loss is prominent in Alzheimer and Parkinson diseases, the diminished ability to couple blood volume to oxygen demand may contribute to their pathogenesis.

[soccertese]

Originally Posted by Conductor71

Hi,

I have not been able to let these two anecdotal experiences of PWP rest.

** As early as the 70's PWP have reported improvements during in flight travel.
**More recently, MJF tells the world in an interview that his symptoms improved to point of not needing meds during a stay in the mountains of Bhutan.

I have been wondering if hypoxia, or reduction in oxygen, helps us somehow and why? The research points to a big yes, so makes you wonder if PD has a vascular component which is overlooked. Results are quite interesting. There is a new hypothesis out there that PD, ALS, AD may start with oxygen transcription factors know as Hypoxia Inducible Factors (HIF-1a). Generally speaking they regulate release of oxygen from blood stream into our cells. All of our cells.

I could list different ways this hypothesis explains many seemingly trivialities in PD but would take too long. The gist of it is, we underexpress HIF-1a (note cancer is now thought due to over expression of this). In PWP, this underexpression is linked to excess iron accumulation, unchecked Reactive Oxygen Species, resulting in cell loss. This explains BOTH the loss of Dopamine and Norepinephrine because these specialized areas are high in neuromelanin which is a known iron regulator. These cells are the main losses in PD, so iron homeostasis and metabolism must be key to the pathology of PD. The big questions left are what is the role of alpha-synuclein clumping, where do prions fit in, and why is our immune system triggered? Oh, and the biggie- why isn't iron being cleared out like it should?

Here is what hits home for many of us:

Hypoxia-inducible factor (HIF) plays an important role in cell survival by regulating iron, antioxidant defense, and mitochondrial function.

Pharmacological inhibitors of the iron-dependent enzyme class prolyl hydroxylases (PHD), which target α subunits of HIF proteins for degradation, have recently been demonstrated to alleviate neurodegeneration associated with stroke and hypoxic-ischemic injuries. Here we report that inhibition of PHD by 3,4-dihydroxybenzoate (DHB) protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigral dopaminergic cell loss and up-regulates HIF-1α within these neurons

That DHB is an iron chelator. In fact there are numerous studies popping up showing iron chelation resulting in an increase in HIF-1a and...

A more recent study finds that placing cells in a mildly hypoxic state thus inducing HIF-1a promotes the change from neuronal stem cell to dopamine cells.

Iron chelation resulted in protection of dopa cells but also in their restoration. In fact when treated prior to inducing the MPTP model of PD, this treatment completely reversed the loss.


Key Sources:

Hypoxia Inducible Factor-1 as a Target for Neurodegenerative Diseases
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3213300/

just to play devil's advocate, it's not oxygen level in the atmosphere that matters, it's oxygen in the blood. the body will compensate by increasing red cell production, capillaries, etc. at low oxygen levels. there's a lot of things going outside the brain that could affect pd, maybe his metabolism slowed down and more pd medicine got to his brain?

[Conductor71]

Originally Posted by soccertese

just to play devil's advocate, it's not oxygen level in the atmosphere that matters, it's oxygen in the blood. the body will compensate by increasing red cell production, capillaries, etc. at low oxygen levels. there's a lot of things going outside the brain that could affect pd, maybe his metabolism slowed down and more pd medicine got to his brain?

Hey Soccertese,

I got hung up on the oxygen level thing because percent of oxygen in pressurized cabin air remains constant at around 21 psi, (not sure of exact number), so I am not exactly clear on how it works - somehow they both result in us taking in less oxygen.

However, I thoroughly research this stuff before I post. Hypoxia Inducible Factor-1a IS triggered by low atmospheric oxygen. This is how we oxygenate our blood, and thus our cells. Our brains are normally in a near hypoxic state and this is why when oxygen supply is cut off, we don't last long. The HIF-1a are genetic constants that respond to low environmental oxygen triggering compensatory measures to keep us alive.

Further, current research shows that putting a person into a slightly hypoxic state is therapeutic. What really clinches this stuff for me is that it fits anecdotal experiences of families with Alzheimer's...a stroke can result in a permanent improvement or reversal of AD symptoms. The key damaging mechanism in stroke is acute hypoxia!

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

The human side of hypoxia-inducible factor

Mechanisms of Action Involved in Ozone Therapy: Is healing induced via a mild oxidative stress?

[GerryW]

"In PWP, this underexpression is linked to excess iron accumulation, unchecked Reactive Oxygen Species, resulting in cell loss. "

I wonder how the donation of blood, especially on a regular basis, affects the symptoms of PD?

[reverett123]

I can't quote a source without a bit of work, but I have always heard that there was a positive relationhip between regular blood donation and reduced symptoms. Break out the darned leeches!!

Sriously, though, that would be an easy thing to test and if causing a short lived drop in something resulted in an improvement of any kind, that would be major news. I can just imagine MJF roling up at the local blood drive driving a Greyhound full of Parkies! The press would eat it up. -rick