a new view of PD
 

1: Rev Neurosci. 2008;19(4-5):245-316.

Parkinson's disease as a neuroendocrine disorder of circadian function:
dopamine-melatonin imbalance and the visual system in the genesis and progression
of the degenerative process.

Willis GL.

The Bronowski Institute of Behavioural Neuroscience, Neurosciences Section,
Coliban Medical Centre, Kyneton, Victoria, Australia. gwillbro@bigpond.com

For more than 50 years, Parkinson's disease (PD) has been conceptualized as a
product of nigro-striatal dopamine (NSD) system degeneration. In spite of a
growing body of evidence depicting the mammalian brain as an interrelated
complexity of circuitous systems, dopamine (DA) deficiency of the NSD is still
regarded as the main problem, with DA replacement being the purpose of
therapeutic intervention. For at least 191 years circadian involvement in various
aspects of PD, including depression and insomnia, has been recognized as an
integral part of the symptom matrix of PD and yet attempts to elucidate the
involvement of this system is uncharted territory. The present review attempts a
major reorganization of mammalian brain into a coordinated complex involving the
NSD and the retinal hypothalamic tract (RHT) as the primary systems involved in
the retino-diencephalic/mesencephalic-pineal (RDMP) axis. Secondary systems
including the lateral hypothalamus (LH), the area postraema (AP) and the
subthalamic nucleus (STN) also form an integral part of this system as they have
been shown to be either intimately related to the primary systems of the RDMP
axis or have been shown to be significantly involved in the expression and
treatment of PD. A large volume of evidence suggests that the RDMP axis is
activated during the course of PD and during therapeutic intervention. Four types
of neurotoxicity associated with melatonin are identified and the susceptibility
of various parts of the RDMP axis to undergo neuropathological change, the
tendency for melatonin to induce PD-like behavioural toxicity, and the
relationship of this to PD symptomotology are described. This includes adverse
effects of melatonin on motor function, hypotension, the adjuvant use of
benzodiazepines, depression, insomnia, body weight regulation and various
biochemical effects of melatonin administration: all problems currently facing
the proposal to introduce melatonin as an adjuvant. It is suggested further that
traditional DA replacement may well work by exerting its effect upon the
circadian system, rather than simply replacing deficient DA. Activation of the
circadian function by antagonizing melatonin with bright light not only has
therapeutic value in treating the primary symptoms of PD but it shares a common
mechanism with L-dopa in reducing the occurrence of seborrheic dermatitis.
Concepts at the centre of understanding pineal function in PD, including pineal
calcification, melatonin deficiency, symptomatic versus protective features of
melatonin and antioxidative effects, are explained in a counterintuitive context.
Intriguing propositions including the role of the retina in the aetiology of PD
and that the nigra functions as a retina in this disorder are presented with the
intention to provide a new understanding of the underlying compromised function
in PD and to provide new treatment strategies. For the first time, abundant
evidence is presented describing PD as an endocrine disorder of melatonin
hyperplasia. The role of circadian interventive therapies and internal
desynchrony in the aetiology and progression of PD provides a new direction for
understanding the underlying physiology of a disease which is currently in a
state of impasse and provides new hope for those who suffer from its debilitating
effects.


PMID: 19145986 [PubMed - in process]

Rick - this makes a lot of sense to me. It is much closer to my own experience with PD.

Thanks!

for what it's worth....
 

Juan told me - several times - of a study done in Mexico - maybe a couple of decades ago? - in which massive amounts of melatonin were given to PD patients who then showed remarkable improvements in symptoms.

Maybe you can locate that information?

I, for one, am more than ready for a new line of therapeutic intervention.

melatonin is...
 

rick, What exactly is melatonin and what is it's function in lay terms....thank u so much sir..

paula

A lot there to digest
 

But it is heartening to see neuroendocrinology having some bold input.

The way that I read it, melatonin is actually a problem in PD and should be avoided. There had been hints of this for years. An early therapy for PD was sleep deprivation which lowered melatonin production.

I become more and more convinced that the endocrine system is the Big Dog here and not the nervous. The latter has a very limited number of factors to account for a large number of symptoms. "OK, ya got dopamine. What else?"

The endocrine system, however, has hormone squirting out of everything but the ears. Cortisol, epinephrine, insulin, estrogen, testosterone, and a half-dozen more. And every one of them has receptors in the brain. You can explain a lot of non-motor symptoms with that kind of toolkit.

The heartening thing to me is that with a rich, complex collection of causes there are a rich, complex set of opportunities to intervene.

bingo!
 

"The heartening thing to me is that with a rich, complex collection of causes there are a rich, complex set of opportunities to intervene. " ~ reverett123

Thanks Rick.

"The heartening thing to me is that with a rich, complex collection of causes there are a rich, complex set of opportunities to intervene. "

its true, but it is also a problem when you dont know what you are looking for. Current description of PD seems similar to ten blind men describing an elephant they are touching, each has a part of the elephant but no one has a complete picture (this is an Indian story, there must be an equivalent one here!).

girija

A bit confusing !
 

I takt melatonin mainly to help in sleeping .. now Rick raises doubts about the wisdom of it !
The article he presented is technically beyond me but on google I found a lot of articles which say that melatonin is good fo PD .
Example :
Jefferson Researchers Show Melatonin’s Potential Benefits In Preventing Parkinson's Damage
ScienceDaily (Oct. 25, 1999) — Melatonin could be a key to someday understanding how to treat Parkinson’s disease. Scientists at Jefferson Medical College have shown in the laboratory and in test animals that melatonin is effective in preventing a particular type of brain cell damage similar to that found in Parkinson’s.

DEAR PAULA -melatonin answer
 

MONTMORENCY CHERRIES CONTAIN MELATONIN -natural sleep aid
the cicadian rythmn is highly important because of R.E.M. sleep
this deep sleep repairs the brain ---this my own wording from all 16 years of research - from my natural approach to regain health
*no link to my brain"
however;
an article found here:

Cherries Found to Be a Natural Sleep Aid
by Jo Hartley, citizen journalist
See all articles by this author
Email this author


(NaturalNews) There is a tart cherry called Montmorency that contains a significant level of melatonin and hence is helpful as a natural sleep aid. The University Of Texas Health Science Center in San Antonio recently discovered these properties in the tart cherry.

Melatonin was discovered in 1958 by a dermatologist named Aaron Lerner at Yale University.

Melatonin is a natural hormone that is produced in the pineal gland located at the base of the brain. It triggers sleepiness during night hours. Melatonin production can be disrupted because of staying up at night utilizing artificial light. Melatonin has been found to decrease with age. This is why elderly people often have trouble sleeping or staying asleep at night. Stress can also cause melatonin levels to drop thus causing poor sleep and insomnia.

What Foods Contain Melatonin?

Melatonin is most plentiful in tart cherries, especially the Montmorency variety.

http://www.naturalnews.com/025210.html

I recently started taking Melatonin as well but it is contraindicated for PD?

I didn't mean to shake anyone's tree
 

I was more interested in the opening of the endocrine doorway. There are a huge number of studies that say melatonin is safe and helpful in PD. Against that you have a lone researcher, Dr. Willis, saying "Not so fast." The thing that gives me pause is that the reaction seems to have been to ignore him rather than to challenge his findings which involve the problem of an imbalance in the ratios of melatonin and dopamine. I don't know enough yet to take a position. But the man has a pretty good record of publications and he is not beating around the bush-

1: Physiol Behav. 1999 Jul;66(5):785-95.

A therapeutic role for melatonin antagonism in experimental models of
Parkinson's disease.

Willis GL, Armstrong SM.

The Bronowski Institute of Behavioural Neuroscience, Coliban Medical Centre,
Kyneton, Victoria, Australia.

To determine the effects of endogenous and exogenous melatonin on experimental
models of Parkinson's disease (PD), Sprague-Dawley rats were exposed to
intracerebroventricular implants of slow release melatonin, pinealectomy (PX),
or constant light (LL) and then injected with central 6-hydroxydopamine (6-OHDA)
or i.p. 1-methyl-4-phenyl,1-1,2,3,6-tetrahydropyridine (MPTP). The resulting
impairment of motor function and related behavioural impairment were exacerbated
by melatonin implantation, while PX and exposure to LL significantly reduced the
severity of experimental PD. These results are consistent with previous work
highlighting the importance of aberrant amine production in neurological disease
and demonstrate that treatments that reduce endogenous melatonin bioavailability
can ameliorate experimental PD. Furthermore, these findings illustrate that
melatonin is not the universal remedy that it is currently claimed to be, and
may pose considerable problems in neurological diseases characterised by
dopamine degeneration.

PMID: 10405106 [PubMed - indexed for MEDLINE]

and


1: Drug News Perspect. 2005 Sep;18(7):437-44.

The role of ML-23 and other melatonin analogues in the treatment and management
of Parkinson's disease.

Willis GL.

Bronowski Institute of Behavioural Neuroscience, Coliban Medical Centre,
Victoria, Australia. gwillbro@nex.net.au

Contemporary theory regarding the cause and treatment of neuropsychiatric disease
strongly suggests that as the human body ages it gradually loses the intrinsic
safeguards that protect it from oxidative damage. Melatonin is one hormone that
serves this function in that it possesses antioxidative properties in the
mammalian body and brain. Melatonin has been shown to prevent the progressive
degeneration produced by neurotoxins employed in experimental models to mimic the
degenerative events in various neuropsychiatric disease states. There are an
abundance of models for numerous disease states demonstrating that melatonin can
inhibit oxidative stress and by such a mechanism it is presumed to exert a
therapeutic effect. While a similar scenario has been revealed with in vitro work
relating specifically to Parkinson's disease, clinical work with melatonin in
this disorder demonstrates that it is devoid of any remarkable therapeutic
effects. More recent preclinical and clinical work has reliably demonstrated that
melatonin in fact may be without therapeutic efficacy and may even worsen the
condition. On this pretense, attempts to reduce the bioavailability of melatonin
using a melatonin receptor antagonist have been found to completely restore
behavioral and regulatory function in the presence of chronically reduced levels
of dopamine, without producing side effects commonly seen with traditional
dopamine replacement therapy. The unavoidable conclusion from this work suggests
that within the dynamic framework of the mammalian brain, hormones may play a
duel, and possibly ambivalent, role in homeostasis and in the etiology of
disease. Such a position requires a reevaluation of the etiology, the role of
dopamine, the neurochemical characteristics of Parkinson's disease and the
validity of the models employed....


PMID: 16362083 [PubMed - indexed for MEDLINE]

Melatonin
 

Melatonin is produced by the pineal gland. It is probably more a question of what is the pineal gland since melatonin is its messenger. The PG is a central part of the time-keeping system of our bodies and seems to be regulated by light by way of signals from the retina. When the retina sees light the PG stops making melatonin and resumes in the dark.

But, like much of the endocrine system, we just don't know. Until relatively recently it was considered to be one of those "vestigal organs" that we seemed to have several of.

girija
 

One of my favorite stories! I find it particularly appropriate for matters of religion as it is such a good illustration that two minds reaching different conclusions may both be right. And it is certainly applicable to our knowledge of PD. We have a dozen possible causes and they may all be correct, just incomplete.

:eek: wow!

I wonder if sleeping with a bright light on would be a natural melatonin antagonist?

Been there, tried that.
 

Inconclusive. I would like to know how it affects someone at the start of the PD Experience before the meds get us so screwed up. Also, I intend to look into the light therapy research a bit more.

Light Therapy
 

Like many pwp, I had a long history of depression before DX. I noticed it was seasonal "SAD" and purchased an official "light box" for treatment. The light box worked great. What I liked the most was that the light therapy works within a few days if it in fact is going to work. Light "burns off" melatonin very quickly and it would seen that the greater problem is light exposure or contamination "burning off" available melatonin when one is supposed to be sleeping.

So where does that leave us heavy computer users who spend hours of our night time in front of a screen? :D

Pineal gland.........
 

Woo Woo things to think about........http://www.crystalinks.com/thirdeyepineal.html

enlightening
 

lindy, you asked where does that leave heavy nighttime computer users?

perhaps not as bad as we could be? Or, conversely,since melatonin is also recommended to help with sleep, perhaps we are harming ourselves.

i'm guessing it's one or the other...:p


ibby - that's an interesting page about the pineal gland. And just to top it off, remember it was Edgar Cayce who said PD started in the glands.

i could wonder out loud/speculate about a lot of things here...about light and following it...especially regarding a gland that has mythical background ...even being called the soul. But i can't, so I won't.

maybe someday we can include other means of healing in our discussions and gain knowledge and experience about the signs and capabilities that are never used or realized. This pineal gland discussion led us to a page that was completely unexpected yet fits in to my life [in that its' history is tied to a place outside the real world] as I seek more of a spiritual realm. And this part of us [ comtemplating our own mortality] is completely normal - many of us are in the age "zone".

I think it's fascinating. Rick, you are a busy guy - see what you have produced today? i'm picturing a scene from A River Runs Through It...of course it includes Brad Pitt and a fish. I'd rather do that than meditate...no focus. lol

Thanks ibby - more connections to think about. It's gorgeous today in Florida...in the 80s. I need to go out and turn off my melatonin.

paula

This one is a little more understandable
 

1: Cell Mol Neurobiol. 2001 Dec;21(6):605-16.

Melatonin-dopamine interactions: from basic neurochemistry to a clinical setting.

Zisapel N.

Department of Neurobiochemistry, Tel Aviv University, Israel.
navazis@post.tau.ac.il

To review the interaction between melatonin and the dopaminergic system in the
hypothalamus and striatum and its potential clinical use in dopamine-related
disorders in the central nervous system. Medline-based search on
melatonin-dopamine interactions in mammals. Melatonin. the hormone produced by
the pineal gland at night. influences circadian and seasonal rhythms, most
notably the sleep-wake cycle and seasonal reproduction. The neurochemical basis
of these activities is not understood yet. Inhibition of dopamine release by
melatonin has been demonstrated in specific areas of the mammalian central
nervous system (hypothalamus, hippocampus, medulla-pons, and retina).
Antidopaminergic activities of melatonin have been demonstrated in the striatum.
Dopaminergic transmission has a pivotal role in circadian entrainment of the
fetus, in coordination of body movement and reproduction. Recent findings
indicate that melatonin may modulate dopaminergic pathways involved in movement
disorders in humans. In Parkinson patients melatonin may, on the one hand,
exacerbate symptoms (because of its putative interference with dopamine release)
and, on the other, protect against neurodegeneration (by virtue of its
antioxidant properties and its effects on mitochondrial activity). Melatonin
appears to be effective in the treatment of tardive dyskinesia. a severe movement
disorder associated with long-term blockade of the postsynaptic dopamine D2
receptor by antipsychotic drugs in schizophrenic patients. The interaction of
melatonin with the dopaminergic system may play a significant role in the
nonphotic and photic entrainment of the biological clock as well as in the
fine-tuning of motor coordination in the striatum. These interactions and the
antioxidant nature of melatonin may be beneficial in the treatment of
dopamine-related disorders.

PMID: 12043836 [PubMed - indexed for MEDLINE]

Please excuse my total ignorance, but I'm enticed by you "Current Blend". Is this just an all over feel good blend or have you specifically picked each one for Parkinsons? Thanks, I find your post very interesting!

my "blend"
 

These are the things that I have tried and/or researched enough to attempt to take regularly. It is up-to-date at the moment but slips from time to time.

sorry
 

I just realized that I didn't answer your question. They are all PD oriented. The ALA-ALC-Carnosine combination boosts mitochondrial function and fights glycation. The B-vitamins pop up in the nervous system every time you turn around. Ginseng and gingko help with stress damage and the former is a top adaptogen. Turmeric does so many things that I won't try to list them all. Fish oil is anti-inflammatory and provides one of the primary building blocks of brain tissue.

Thank you! You have been most helpful...