Question on PSP and melatonin

This topic is for information and sharing exchanges between PSP and CBD patients.

Moderators: Moderator, phpBB2 - Administrators

Question on PSP and melatonin

Postby Mack » Wed Dec 02, 2009 1:34 am

I have a friend whose father has PSP and I promised I would take a look into it for him. I've been going over the pubmed medical database trying to see what causes this disease and current treatments, why it differs from Alzheimer's and Parkinsons, the biochemical pathways that are believed to cause it and the thing that I keep coming back to is that it seems to me that all of the above could be explained by a deficiency of melatonin. My reasons for this include indactions from pubmed research papers that:

Melatonin reduces cdk5 expression which has been shown to be upregulated in PSP

Melatonin prevents tau hyperphosphorylation

PSP shows signs of exidative stress in neurons in different parts of the brain. Melatonin acts as an antioxidant

Inhibition of PP2A induces tau hyperphosphorylation- PP2A is inhibted by oxidative stress.

Mitcochrondrial complex 1 oxidative damage has been shown in PSP- melatonin protects this complex from oxidative stress.

Oxidised products of dopamine promote tau polymerization and are neurotoxic

Deliberate suppression of melatonin in mice resulted in spatial memory impairment and tau hyperphosphorylation

There's other complicated chemical relationships I haven't got my head fully around yet such as PKA, calcium, cAMP, cdk5, DARPP32 and GSK-3beta and it's surely can't be that simple but what I would like to know is if anyone here has tried melatonin and seen any reduction of symptoms or if there is a test that would show melatonin levels as being low or non-existant in this disease? I couldn't find any reference that this compound has been trialled in PSP.

I believe it has been or is being trialled in Alzheimers and Parkinsons with signs of some improvement but those diseases have differences to PSP so aren't a true test whether it would be of assistance.

As a further note my friend's father suffered a head trauma in a car accident many years ago. I was wondering if this may be of significance to any other sufferer of PSP as a possible trigger.

Regards to you all,

Mack
Mack
 
Posts: 6
Joined: Wed Dec 02, 2009 1:06 am

Postby Robin » Wed Dec 02, 2009 2:32 am

Mack,

My dad took melatonin to help with sleep. We saw no benefit to his sleep (or anything else) so we stopped it.

I'm aware of no clinical trials of melatonin in AD or PD where the goal is to slow disease progression. It's widely used for treatment of sleep disorders.

Certainly head trauma increases one's risk of a host of diseases (including PD) but I don't think PSP is included in that list.

Good luck,
Robin
Robin
 
Posts: 3840
Joined: Fri Feb 20, 2004 2:32 am
Location: USA - Northern CA

Postby Mack » Wed Dec 02, 2009 6:31 pm

Robin, can I ask what dosage you tried? And for how long you used it for? I know people use extremely small doses for sleep- less than 1-3mg in most cases but if there was melatonin depletion in the brain perhaps a trial of very high doses might be worthwhile even if only to reduce excessive oxidative damage occuring. I'm not yet aware that even high doses have toxicity.

Experimental pinealectomy causes scoliosis in chickens and rats and while you can never trust animal results to match people, is there any indication that scoliosis or other joint/skeletal problems occurs in PSP?

Even if there is another cause for the oxidative stress driving this disease my hope is that if Melatonin restores anti-oxidant levels in the brain to proper levels, further damage won't occur or will be slowed. but I found this from Feb 2009 on AD research interesting:

"Most patients with Alzheimer's disease (AD) present decreased levels of melatonin, a day-night rhythm-related hormone. To investigate the role of melatonin deficiency in AD, we used constant illumination to interrupt melatonin metabolism and measured some of the AD-like alterations in rats. Concomitant with decreased serum melatonin, the rats developed spatial memory deficits, tau hyperphosphorylation at multiple sites, activation of glycogen synthase kinase-3 and protein kinase A, as well as suppression of protein phosphatase-1. Prominent oxidative damage and organelle lesions, demonstrated by increased expression of endoplasmic reticulum (ER) stress-related proteins including BiP/GRP78 and CHOP/GADD153, decreased number of rough ER and free ribosome, thinner synapses, and increased superoxide dismutase and monoamine oxidase were also observed in the light exposed rats. Simultaneous supplement of melatonin partially arrested the behavioral and molecular impairments. It is suggested that melatonin deficiency may be an upstream effector responsible for the AD-like behavioral and molecular pathologies with ER stress-involved mechanisms."

The above all arose just from supressing melatonin by continual illumination. and what resulted seems similar to the same kind of dysregulation that occurs in PSP, more so than AD as I think that involves amyloid deposits and possible abnormal metal accumation in the brain driving the oxidative damage in that case..

My thinking on the car accident was that it might have either damaged the pineal gland or its regulation by the circadian biological clock perhaps causing its atrophy, calcification or inability to release melatonin in response to darkness. There is some evidence that even whiplash injuries can cause this without the physical destruction of the gland.

I intend to suggest to my friend that his father's doctors should check if possible the functioning of the pineal gland and/or brain melatonin levels. I also will tell him that if he is on parkinson type medication such as levodopa he should be aware that this might exhaust cellular glutathione antioxidant levels and he should supplement with some form of cysteine to ensure this is replaced. There is also a US based doctor organisation that claims dopamine precursors used for parkinsonian type drugs can also deplete serotonin in the brain because both use a similar biochemical pathway but I don't know yet if this claim is correct or not or whether their solution- to supplement with additional serotonin precursors such as 5-HTP under a doctor's supervision works. If they are right though then parkinson medications after a period of use would increase oxidative stress and also reduce serotonin levels which are the precursor for melatonin.

Acetyl l carnitine and co-enzyme q10 were two other things that I thought could be of assistance becaue of their protection and enhancement of he mitochondria which seem damaged in PSP but I need to spend more time going through the medical database to see if there is evidence they would actually help.

Regards

Mack
Mack
 
Posts: 6
Joined: Wed Dec 02, 2009 1:06 am

Postby Robin » Wed Dec 02, 2009 9:12 pm

Mack,

We used Trader Joe's melatonin mints. I think they are 1/2mg each. Usual dose was 4 to 6 mints, so 2-3mg. We probably tried this for 2-4 weeks.

There was a guy named Ron Ritch who cared for his wife with PSP. He died himself a few months ago. He was also convinced that anti-oxidants were the solution. You might find some relevant info on his website (which is still live), pspinformation.com. He posted a lot about this on the PSPinformation Yahoo!Group but the search function hasn't worked there for quite some time so I don't think your efforts there would pan out.

I've never heard of scoliosis or other joint/skeletal problems occurring in PSP.

The current thinking as to a cause of PSP is that it's a "variable combination of genetic, environmental, oxidative stress, and inflammatory factors." ("Unraveling progressive supranuclear palsy: from the bedside back to the bench. PubMed ID#18267262)

As you may know, CoQ10 is being studied by the (American) NIH for its neuroprotective benefits in PD. The leader of that research until he died was Dr. Schults from UCSD; most of the key articles published thus far are with him as the lead author.

Good luck,
Robin
Robin
 
Posts: 3840
Joined: Fri Feb 20, 2004 2:32 am
Location: USA - Northern CA

Postby Mack » Wed Dec 02, 2009 11:02 pm

Thanks very much Robin! I will look into all those references especially what was tried with antioxidants.

I was thinking of massive doses of melatonin, say 70mg plus, taken every day before bed to mimic natural production for as long as it takes to flood the brain and neurons with it. It is apparently a small molecule so can function as an antioxidant inside the cells where others may not reach, aside from its interesting biochemical interactions which I am still trying to unravel.

It just seems to me to interact in all the right places so as to to shut down phosphorylated tau formation. I don't know if a good effect would show up obviously- if it worked perhaps it would simply stop further neuronal damage.

Of more value would be a scientific test of pineal function and melatonin release over time or perhaps a test to see if something else is inhibiting its function like an autoimmune antibody. I have read that MRI scans of PSP brains don't show any obvious abnormality. Is that correct?
Mack
 
Posts: 6
Joined: Wed Dec 02, 2009 1:06 am

Postby eplowman » Wed Dec 02, 2009 11:57 pm

Robin,

>>I've never heard of scoliosis or other joint/skeletal problems occurring in PSP<<

In advanced PSP, it apparently can happen. Rose's spine in her final year became S-shaped. I had not noticed that at all until the hospice doctor pointed it out during an exam at the house. Weird and scary. But Rose felt no pain.

ed p.
|My wife of 56 years was Rose b. 1930, dx 1999, symptoms from 1997; d. 06/21/08; PSP-rs autopsy confirmed.
eplowman
 
Posts: 3658
Joined: Tue May 10, 2005 10:22 pm
Location: USA (Northern Va.)

Postby Robin » Thu Dec 03, 2009 1:30 am

Mack,

You said:
"I have read that MRI scans of PSP brains don't show any obvious abnormality. Is that correct?"

T1 sagittal MRIs sometimes show the "hummingbird sign" of PSP.

I think you may find this article of interest:
PubMed #19364361

And you might check out the notes I've posted on some of the recent webinars. In particular the Bordelon webinar may be of interest:
http://forum.psp.org/viewtopic.php?t=8226

Robin
Robin
 
Posts: 3840
Joined: Fri Feb 20, 2004 2:32 am
Location: USA - Northern CA

Melatonin in Parkinson Disease

Postby Mack » Mon Dec 07, 2009 7:43 pm

Have any of you heard of the theory by an Australian researcher called Willis that Parkinson's disease may be caused by excess melatonin- or at least a very high melatonin to dopamine ratio? There seems to be some evidence that in vivo application of melatonin in parkinson's dieases is not helpful whereas it is in Alzheimers and that bright light, pinealectomy and melatonin analogues in animal models improve Parkinson's symptoms.

It is the first time I've come across this suggestion and am interested if the rest of you had heard of it?

Mack
Mack
 
Posts: 6
Joined: Wed Dec 02, 2009 1:06 am

Postby Robin » Mon Dec 07, 2009 8:16 pm

I have not heard of this. As you suggested before, I don't take much stock in animal models of any disease.

If excess melatonin causes PD, why would giving an animal with PD melatonin help the situation?
Robin
 
Posts: 3840
Joined: Fri Feb 20, 2004 2:32 am
Location: USA - Northern CA

Postby Mack » Tue Dec 08, 2009 12:49 am

Here are two of Willis paper abstracts from here:

http://www.ncbi.nlm.nih.gov/pubmed?term ... RVAbstract

As you can see there is a more recent one in 2009 but it has no abstract I can access...

"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 to study this and other neuropsychiatric disorders."

"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."

I think you are right to doubt animal studies and perhaps in vitro studies. I think what he is saying is that there are biochemical feedback circuits involved and simply adding chemicals to cells in test tubes can't hope to model what actually goes on in the human brain, hence conflicting results about melatonin being neuroprotective. Melatonin does appear neuroprotective in AD and I hope it will be in PSP but if he is correct then it contributes to neurotoxicity in PD. Whether Willis has a mechanism for this counterintuitive claim is uncertain but I would think it must necessarily occur through some interaction through the melatonin and dopamine receptors.

The prime suggestion above appears to be that the presence of melatonin and low dopamine is neurotoxic and that dysregulation of melatonin production or the circadian clock creates a high melatonin/dopamine ratio that triggers neuronal death.

Mack
Mack
 
Posts: 6
Joined: Wed Dec 02, 2009 1:06 am

Postby Mack » Tue Dec 08, 2009 12:52 am

Sorry I forgot to respond to your final question. I think the melatonin analogues he used inhibited the action of melatonin at the receptor level without emulating its effect, but this needs clarification.

Regards

Mack
Mack
 
Posts: 6
Joined: Wed Dec 02, 2009 1:06 am


Return to For PSP/CBD Patients Only

Who is online

Users browsing this forum: No registered users and 1 guest