34 replies to this topic

[jabowery]

Neurodegenerative diseases have various pathways -- all resulting in massive neuron death.  One approach to treating these diseases is to tailor therapy to the ultimate causes (silence the mutant huntingtin gene in the case of HD for example).  Other approaches target proximate causes, such as neuron death itself.  

 

Clearly the Longecity community is not oriented toward the highly specialized treatments of ultimate causes as that gets into gene therapies.

 

What are the common pathways of neurodegeneration, up to and including neuron death itself, that are amenable to the approaches being pursued by the Longecity community?

 

 

[xks201]

A hormone deficiency (even sometimes showing as in range) will cause neurodegeneration faster than anything. 

[jabowery]

A hormone deficiency (even sometimes showing as in range) will cause neurodegeneration faster than anything. 

 

Out of all of the doctors and HD specialists I've encountered over the last decade not one has recommended hormone therapy.  The Wikipedia page on estrogen and neurodegenerative diseases is poorly written -- I'd say 80% or more of it is not about estrogen's relationship to neurodegenerative diseases per se but rather could be composed by lifting introductory text from the articles on estrogen and from each of the articles on neurodegenerative diseases respectively. (Perhaps it is because the vast majority of edits are by one Wikipedia author.)

 

A search on huntington's and 'hormone replacement therapy' yields nothing about HD on the first page of results.

 

Bizarre.

 

Do you have cites for how one would go about obtaining proper treatment for a neurodegenerative disease with hormone therapy?

Edited by jabowery, 01 August 2014 - 11:21 PM.

[xks201]

What declines with age? Hormones. Why do older people succumb to more disease? Less hormones. Not many docs have worked on the problem but I know you are smarter than to think because wikipedia doesn't have an article it isn't true. Reference what Nemo wrote in the dihexa thread.
http://m.sfgate.com/...r-s-4291696.php


Take her temp I guarantee it is below 98.0 which means probably she is hypothyroid too.
http://hypothyroidmo...eimers-disease/

if doctors know all the answers please remind me what doctors have done for the progression of her disease ? I hate most doctors because they are ignorant pieces of crap.
Also, do you know what a neurosteroid is? Many hormones are neurosteroids.

[jabowery]

Sorry if I came off as terse but your original response was terse so I assumed, I think reasonably, it would be straight-forward to find the information to which you referred (ie: Wikipedia page and first page google results etc.).  

 

PS:  I understand only too well the problem with "doctors" when it comes to what pathologists call "zebras" (ie rare conditions). 

 

What declines with age? Hormones. Why do older people succumb to more disease? Less hormones. Not many docs have worked on the problem but I know you are smarter than to think because wikipedia doesn't have an article it isn't true. Reference what Nemo wrote in the dihexa thread.
http://m.sfgate.com/...r-s-4291696.php


Take her temp I guarantee it is below 98.0 which means probably she is hypothyroid too.
http://hypothyroidmo...eimers-disease/

if doctors know all the answers please remind me what doctors have done for the progression of her disease ? I hate most doctors because they are ignorant pieces of crap.
Also, do you know what a neurosteroid is? Many hormones are neurosteroids.

 

Edited by jabowery, 02 August 2014 - 12:12 AM.

[xks201]

No problem I'm pissed at doctors for not connecting the dots. Not you. This is relatively new research going on and unfortunately it takes 2 to 4 decades to implement some things after they are discovered. Not only that but there are drug companies donating to med schools making sure common sense hormone therapy takes the back seat to drug therapy in their curriculum. It is quite a joke. Before 1950 for example heart attacks were so rare that when one happened the entire hospital came to observe. We have a lot of endocrine disrupting chemicals sprayed on our crops and everywhere now.

[medicineman]

No problem I'm pissed at doctors for not connecting the dots. Not you. This is relatively new research going on and unfortunately it takes 2 to 4 decades to implement some things after they are discovered. Not only that but there are drug companies donating to med schools making sure common sense hormone therapy takes the back seat to drug therapy in their curriculum. It is quite a joke. Before 1950 for example heart attacks were so rare that when one happened the entire hospital came to observe. We have a lot of endocrine disrupting chemicals sprayed on our crops and everywhere now.

Many other things are implicated. Pollution, lack of micronutrients (creatine, minerals), overload of unneeded nutrients, progressive loss of endogenous anti-oxidants, metabolic garbage, genetic malfunction leading to over/under expression of certain genes, insulin resistance etc. I am sure reduction in hormone levels are associated with disease, and most probably hastens degenerative diseases, but it isn't alone, or any more special than the rest. I think anyways, correct me if I'm mistaken

[jabowery]

What declines with age? Hormones. Why do older people succumb to more disease? Less hormones. Not many docs have worked on the problem but I know you are smarter than to think because wikipedia doesn't have an article it isn't true. Reference what Nemo wrote in the dihexa thread.
http://m.sfgate.com/...r-s-4291696.php

 

I believe "Accelerated Cell Aging in Female APOE-ε4 Carriers: Implications for Hormone Therapy Use" is the academic article cited by the sfgate article on estrogen therapy for Alzheimers.  

 

So the common pathway here is that neurodegenerative diseases are diseases of aging and although they differ in ultimate causality (ie: specific genes or gene complexes) their severity and onset is aggravated by other aspects of normal aging such a hormone deficiency.

 

The recommended course of action is to basically take a print out of the aforelinked article to a doctor and see if they're read it.  If not, get another doctor.  If they read it, see if they will try to measure hormone levels to see if they are consistent with the deficiency described in the article.  If not, get another doctor.  If they measure the hormone levels and find them deficient, and don't treat the hormone deficiency, get another doctor.

 

Does that about sum it up?

Edited by jabowery, 02 August 2014 - 12:36 AM.

[jabowery]

Many other things are implicated. Pollution, lack of micronutrients (creatine, minerals), overload of unneeded nutrients, progressive loss of endogenous anti-oxidants, metabolic garbage, genetic malfunction leading to over/under expression of certain genes, insulin resistance etc. I am sure reduction in hormone levels are associated with disease, and most probably hastens degenerative diseases, but it isn't alone, or any more special than the rest. I think anyways, correct me if I'm mistaken

 

 

When you get into a scatter-shot model like this, it a more tractable approach is looking where all paths converge:  Neuron death.

 

What protects against neuron death?

 

Phoenicis in the dihexa thread mentioned NAD+ and possibly taking Nicotinamide Riboside.

Edited by jabowery, 02 August 2014 - 12:41 AM.

[Major Legend]

I think the "natural" form of degeneration comes from hormonal decline, general oxidation, aging DNA.

 

But perhaps we should discuss chronic inflammation as a possible central preventable cause for almost all neurological disorders, there is some evidence (which I should really attached but don't have enough time), that people taking NSAIDS regularly have a reduced risk to developing dementia and so on.

 

(oh here it is :http://www.scienceda...0505162913.htm)

 

so not eating inflammatory foods may already be a big step, and epigenetics such as curcurmin and so on.

 

neural degeneration is also constantly happening and countered by neurogenesis, of which can independently controlled to an extent by brain exercise, diet supplementation of fats, and epigenetics again. The brain needs cholesterol for building new neuronal connections, so eating stuff like eggs is pretty mucha a must.

 

I think the hugest issue is neurodegeneration is that its not easily recognised until its too late, nobody can really feel the effects of neurotoxicity. The ample cognitive reserve in most younger people, mean problems don't become obvious till 60+.

 

I think the BIGGEST CHALLENGE is that most counter treatments have no visible effects until DECADES later, which doesn't really give incentive for people to adopt preventative measures. Most people can barely put themselves forward a few days, let alone decades, people implement ideas but get disappointed when instant results don't happen over night, so thats why I think the prevailing focus here is on the immediate side.

 

For example most people including myself, don't bother titrating with drugs, but there is a high likelyhood in my opinion that microdosing over a long period of time (titrating up and titrating down), makes alot more sense than they way we are currently taking drugs. Kind of like an extended release, yet the way we go about it is swallow the largest dose and see if anything changed in the next few hours. Unfortunately this leaves weeds out workable solutions that may take a longer period of time, especially the lifespan occurrence of inflammation.

 

I certainly second that doctors are too secluded into their elitist bubble, there is too much restriction and a lack of interest in novel use of mediciness, its a completely irony that they are the gate keepers to powerful medicinal intervention yet are often the ones most reluctant to use these interventions unless big pharma tells them to.

 

I also think there is a discussion to be had that, neuronal degeneration MAY not be an eventuality of ageing itself, but rather an accumulation of bad diet and lack of brain exercise (sedentary physically and mentally lifestyle) over long periods of time, of course we don't know that as the cohort of people putting in preventative methods aren't old enough yet to see the effects of their efforts.

Edited by Major Legend, 02 August 2014 - 01:21 AM.

[Phoenicis]

Hi James,

 

I am very sorry to hear about your wife, the fact that you are here and looking for ways to slow or stop the progression of HD is awesome. I was moved by your story and decided to do some research on therapies for HD. I suffer from a much less serious serious inherited disease called psoriasis and hope that gene therapies become more available soon; obviously starting with serious disorders like HD. I certainly hope that you are able to find the best treatments for Jan, you seem like a sharp fellow!

 

I am not qualified to give medical advice and would like to remind anyone reading that it is their own responsibility to seek independent medical advice before taking any of the bellow mentioned substances. This does not constitute medical advice.

 

As you mentioned, Huntington's Disease (HD) is an inherited neurodegenerative disorder thought be caused by a CAG repeat expansion in the huntingtin gene, leading to polyglutamine expansion in the huntingtin protein [1]. The exact mechanism by which the mutant huntingtin causes HD remain illusive, but it is known that abnormalities in gene transcription, as well as mitochondrial function are involved and that these are accompanied by increases in oxidative damage. [1]

 

Targets for limiting degeneration = energy metabolism, inflammation, oxidative damage [1]

 

At this point therapies are being aimed at limiting the degenerative process, as you mentioned curing this disease will likely require gene therapy. In mouse models of HD small interfering RNA has however shown some promise for directly targeting the HD gene and its protein products [28][29].

 

Here are some of the methods under investigation for slowing degeneration:

 

Metabolic:

Evidence exists for a link between impaired metabolism and the pathogenesis of HD. Low expression of Peroxisome proliferator- activated receptor (PPAR) gamma coactivator PCG-1 alpha, is implicated in the mitochondrial dysfunction and oxidative damage in HD.[1][8] Haplotypes in the gene encoding HD PCG-1alpha influence the onset of HD, the mutant mHtt interferes with transcription of PCG-1aplha, leading to decreases of it and its targets, as well as BDNF[1]. This results in defective energy metabolism, antioxidant defence and ROS accumulation, leading to mitochondrial damage.[1] mHtt also disrupts the mitochondrial fission/fusion process, resulting in increased fission and vesicular transport interference.[1] This all results in decreased ATP production at nerve terminals and neuron death. [1]

 

Pharmacologic treatment with CoQ10, creatine, bezafibrate and nicotinamide increase PCG-1alpha and should improve neuron survival [1][9]. Thiazolidinediones, such as pioglitazone, have been used to increase PPARs and PCG-1 alpha and are neuroprotective in mouse models of HD. [1][10][11]. In mouse models of HD, pan-ppar agonist bezafibrate improved rotarod performance and survival also increased stratial atrophy and atrophy of stratial medium spiny neurons. [12] It also increased mitochondrial number and reduced malondialdehyde (MDA) in the stratium.[12]

 

NAD+ and the Sirtuins

Activation of SIRT1 results in the deacetylation of PGC-1alpha and increases activity[1]. Increased expression of SIRT1 has shown neuroprotective benefits in mouse models for HD and deficiency promotes the HD phenotype.[1][13][14].

 

Since sirtuins are NAD+ dependant deacetylases [13], one approach of activating them is by andminister NAD+ precursors. These include nicotinamide (Nam), nicotinic acid (NA), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). This also has the advantage of activating both SIRT1 and SIRT3, the latter induces superoxide dismutase 2 and mitochondrial reduced glutathione. [1] Increase Glutathione peroxidase expression has been shown to have neuroprotective effects in animal models of HD [1][23].

 

For further reading on the sirtuins and NAD+ in neurodegeneration and aging see [24], [25], [26], [27].

 

The Precursors

Nicotinamide, which is regular vitamin b3, may not be the best method for raising SIRT1 levels because at high doses it is inhibited by NAD+ in a negative feedback mechanism.[18] It has also been shown to inhibit SIRT1 at high concentrations and the rate limiting enzyme for its synthesis into NAD+ (NAMPT) declines with age [26]. That said, nicotinamide has been shown to increase BDNF and PCG-1 alpha in mouse models of HD.[19]

 

Nicotinamide mononucleotide has been used to increase NAD+ levels and aerobic metabolism in mice[17]. It is degraded into NR before it can enter cells[20] and NMN also seems to be less efficiently synthesized into NAD+ than NA or NR in muscle and liver tissues [16].

 

Nicotinamide riboside should 'in theory' be the most easily utilized by neurons because they are inefficient at de novo and salvage NAD+ synthesis [15]. However chronic NR administration failed to raise NAD+ levels significantly in the brain, which may be due to lower expression of Nrk2, which is responsible for NR metabolism into NAD+ [16].

 

Nicotinic acid has shown a 200 fold greater efficacy than Nam in raising NAD+ levels in glial cells.[15]. The rate limiting enzyme in NA biosynthesis to NAD+ is NAPRT, this enzyme is not inhibited by an NAD+ negative feedback bottleneck like NAMPT for Nam is [22]. Glial cells likely play a prominent role in supplying NAD+ to neurons.[15] Astrocytes (glial cells) outnumber neurons 5 fold and tile the entire central nervous system [21] Astrocystes can readily synthesize NAD+ from precursors like NA and Nam and transport NAD+ across the plasma membrane directly via the adenosine receptor P2XY7R [15]. Using precursors like NA gives the glia control of biosynthesis or restriction of NAD+. [15] It has shown efficacy in the treatment of pellagric dimentia and schizophrenia and increases brain NAD+ levels just 20 min after being injected into the brain.[15]

 

NA therefore seems like a promising NAD+ precursor and could possibly work in the brain. NR showed some disappointing results in the brain and is also more expensive than NA, costing close to $49.00 for 30 x 250mg, whereas NA cost about $5.00 for 100 x 250mg.

 

Oxidative Damage

CoQ10 – works within the electron transport chain and is a scavenger of free radicals. [1] It blocks 3-nitropropionic acid (3-NP) mediated striatal lesions and blocks DNA and lipid oxidation.[1] In a clinical trial for HD patients (CARE-HD), 600mg/day CoQ10 and ramacemide slowed progression of the disease.[6] A second clinical trial (2CARE) is currently underway using 2,400 mg /day doses, after an earlier study (Pre2care) showed that plasma CoQ10 levels plateau at levels above this dose [7].

 

MitoQ is a form of coenzyme Q linked to triphosphonium ions, this modification allows it to selectively accumulate within the mitochondria. [1]

 

SS31 and SS20 are novel peptide antioxidants which bind to the inner mitochondria and have been shown to be neuroprotective in mice [1] [2] [3].

 

Ways of activating the nuclear factor erythroid 2 related factor 2 / antioxidant response element (Nrf2/ARE) transcriptional pathway are also under investigation [1]. This mediates the expression of the antioxidant enzymes hemeoxygenase 1, NADPH-oxidoreductase, heat shock proteins, as well as enzymes that produce glutathione.[1] 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO)-methylamide was investigated for this purpose and did yield some positive results [2]. CDDO-methylamide and CDDO-trifluoroethylamide improved motor function in a mouse model of Hd [4] Dimethylfumarate, had some positive results in phase III clinical trials for multiple sclerosis and is approved for clinical use. [5]

 

Good luck with your research, what is your rational for using Dihexa?

 

 

[1] Chandra et al., Prospects for Neuroprotective Therapies in Prodromal Huntington’s Disease, Movement Disorders, Vol. 29, No. 3, 2014.

 

[2] Yang L, Zhao K, Calingasan NY, Luo G, Szeto HH, Beal MF. Mitochondria targeted peptides protect against 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine neurotoxicity. Antioxid Redox Signal 2009;11:2095-2104.

 

[3] Petri S, Kiaei M, Damiano M, et al. Cell-permeable peptide antioxidants as a novel therapeutic approach in a mouse model of amyo- trophic lateral sclerosis. J Neurochem 2006;98:1141-1148.

 

[4] Stack C, Ho D, Wille E, et al. Triterpenoids CDDO-ethyl amide and CDDO-trifluoroethyl amide improve the behavioral phenotype and brain pathology in a transgenic mouse model of Huntington’s disease. Free Radic Biol Med 2010;49:147-158.

 

[5] Ellrichmann G, Petrasch-Parwez E, Lee DH, et al. Efficacy of fumaric acid esters in the R6/2 and YAC128 models of Hunting- ton’’s disease. PloS One 2011;6:e16172.

 

[6] Huntington Study G. A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease. Neurol- ogy 2001;57:397-404.

Huntington’s disease: the issue of inter- mediate and reduced penetrance alleles. J Med Genet 2001;38:E12.

 

[7] Huntington Study Group Pre2CARE Investigators, Hyson HC, Kieburtz K, et al. Safety and tolerability of high-dosage coenzyme Q10 in Huntington’s disease and healthy subjects. Mov Disord 2010;25:1924-1928.

 

[8] Johri A, Chandra A, Flint Beal M. PGC-1alpha, mitochondrial dys- function, and Huntington’s disease. Free Radic Biol Med 2013;62: 37-46.

 

[9] Maat-Kievit A, Losekoot M, Van Den Boer-Van Den Berg H, et al. New problems in testing for

 

[10] Chiang MC, Chern Y, Huang RN. PPARgamma rescue of the mitochondrial dysfunction in Huntington’s disease. Neurobiol Dis 2012;45:322-328

 

[11] Jin YN, Hwang WY, Jo C, Johnson GV. Metabolic state deter- mines sensitivity to cellular stress in Huntington disease: normal- ization by activation of PPARgamma. PloS One 2012;7:e30406.

 

[12] Johri A, Calingasan NY, Hennessey TM, et al. Pharmacologic acti- vation of mitochondrial biogenesis exerts widespread beneficial effects in a transgenic mouse model of Huntington’s disease. Human Mol Genet 2012;21:1124-1137.

 

[13] Jiang M, Wang J, Fu J, et al. Neuroprotective role of Sirt1 in mammalian models of Huntington’s disease through activation of multiple Sirt1 targets. Nat Med 2012;18:153-158.

 

[14] Jeong H, Cohen DE, Cui L, et al. Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway. Nat Med 2012;18:159-165.

 

[15] Penberthy et al., The Importance of NAD in Multiple Sclerosis, Curr Pharm Des. PMC Mar 5, 2009.

 

[16] Canto et al., The NAD+ Precursor Nicotinamide Riboside Enhances Oxidative Metabolism and Protects against High-Fat Diet-Induced Obesity, Cell Metabolism 2012, Volume 15, Issue 6, p838–847.

 

[17] Sinclair et al., Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging, Cell 2013 155, Issue 7, p1624–1638.

 

[18] Bitterman et al., Inhibition of Silencing and Accelerated Aging by Nicotinamide, a Putative Negative Regulator of Yeast Sir2 and Human SIRT1, The Journal of Biological Chemistry 2002, 277, 45099-45107.

 

[19] Hathorn T, Snyder-Keller A, Messer A. Nicotinamide improves motor deficits and upregulates PGC-1alpha and BDNF gene expression in a mouse model of Huntington’s disease. Neurobiol Dis 2011;41:43-50.

 

[20] Nikiforov et al., Pathways and subcellular compartmentation of NAD biosynthesis in human cells: from entry of extracellular precursors to mitochondrial NAD generation, J Biol Chem. 2011 Jun 17;286(24):21767-78.

 

[21] Vinters et al., Astrocytes: Biology and Pathology, Acta Neuropathol. 2010 119(1): 7-35.

 

[22] Hara et al., Elevation of Cellular NAD Levels by Nicotinic Acid and Involvement of Nicotinic Acid Phosphoribosyltransferase in Human Cells, J. Biol. Chem. 2007, 282:24574-24582.

 

[23] Mason RP, Casu M, Butler N, et al. Glutathione peroxidase activ- ity is neuroprotective in models of Huntington’s disease. Nat Genet 2013;45:1249-1254.

 

[24] Wiley et al., NAD+ controls neural stem cell fate in the aging brain, The EMBO JournalVolume 33, Issue 12, pages 1289–1291, 17 June 2014.

 

[25] Guarente et al., Sirtuin deacetylases in neurodegenerative diseases of aging, Cell Research (2013) 23:746–758. 21 May 2013

 

[26] Imai et al., NAD+ and sirtuins in aging and disease, Volume 24, Trends in Cell Biology, Issue 8, August 2014, Pages 464–471

 

[27] Herskovitis et al., SIRT1 in Neurodevelopment and Brain Senescence, Neuron Volume 81, Issue 3, 5 February 2014, Pages 471–483

 

[28] Pfister EL, Zamore PD. Huntington’s disease: silencing a brutal killer. Exp Neurol 2009;220:226-229.

 

[29] Godinho BM, Ogier JR, Darcy R, O’Driscoll CM, Cryan JF. Self- assembling modified b-cyclodextrin nanoparticles as neuronal siRNA delivery vectors: focus on Huntington’s disease. Mol Pharm 2013;10:640-649.

Edited by Phoenicis, 02 August 2014 - 10:19 PM.

[Phoenicis]

This recent study does seem to redeem NR's efficacy in the brain, but I have not read the full text and do not know just how effective it is compared to NA. 

[jabowery]

...

I think the BIGGEST CHALLENGE is that most counter treatments have no visible effects until DECADES later, which doesn't really give incentive for people to adopt preventative measures. Most people can barely put themselves forward a few days, let alone decades, people implement ideas but get disappointed when instant results don't happen over night, so thats why I think the prevailing focus here is on the immediate side.

 

Although the rat lifespan is vastly shorter than human, the speed with which dihexa restores, not only gait but, water maze performance is empirical evidence that for some of the major aspects of neurodegeneration, we're talking far less than the human equivalent of decades for restoration.

[jabowery]

Wow, that's a lot to digest but I'll do so over the next few days as I get time for it.  Thanks, Phoenicis.

 

As for my rationale for encouraging my wife to use Dihexa*:

 

From a theoretic standpoint:

 

The well-documented loss of BDNF during the progression of HD has caused people in the HD community go to extraordinary lengths -- usually with vigorous exercise regimens involving the better part of their waking hours -- to stimulate BDNF production.

 

From an empirical standpoint:

 

The restoration of cognitive (water maze) and motor (gait) neural function in rats over a matter of weeks with dihexa aligns with the loss of those functions in HD.  The empirical evidence for exercise-stimulated BDNF to mitigate HD's degeneration is controversial at best and was actually pronounced more or less debunked at the last major HD conference.  

 

*I've informed all of Jan's medical professionals of my ideas and given all of them full opportunity to relate to us their concerns, both medical and ethical.  My starting this thread is an attempt to forestall Jan's using Dihexa for as long as I can, in good conscience, delay it given the rapidity of her degeneration, so as to try other options while the results are coming in from the self-reported human trials here.  In response to you and xks201; last night I started Jan on two over-the-counter supplements: Estroven (despite the fact that I can't take her temperature effectively due to her involuntary ejecting the thermometer) and inositol hexanicotinate based on recommendations here.  These were simply what I found most readily available at Walmart. This will confound my attempt at establishing a clean baseline for beginning Dihexa but if they slow the progression enough, it may be advisable to wait for clinical trials of gene silencing.  I wouldn't be considering Dihexa at all for her were it not for the fact that the delays in human trials for gene silencing have been going on for about 10 years now and during that time she has gone from merely unemployable to requiring 24/7 care.  Much of these delays have been to address concerns that have been known for 10 years to be invalid.  That, combined with some horror stories involving 'professionals' render it difficult for me to relinquish my role as guardian of Jan's interests.  Quite literally, lives have been put in direct jeopardy by some of these 'professionals' due to their arrogance and ignorance and I just do not have the resources to pursue legal remedies nor am I inclined to do so when what is being remedied is loss of life and limb that I could have prevented by using my best judgement supported by ground-truth.

 

Hi James,

 

I am very sorry to hear about your wife, the fact that you are here and looking for ways to slow or stop the progression of HD is awesome. I was moved by your story and decided to do some research on therapies for HD. I suffer from a much less serious serious inherited disease called psoriasis and hope that gene therapies become more available soon; obviously starting with serious disorders like HD. I certainly hope that you are able to find the best treatments for Jan, you seem like a sharp fellow!

 

I am not qualified to give medical advice and would like to remind anyone reading that it is their own responsibility to seek independent medical advice before taking any of the bellow mentioned substances. This does not constitute medical advice.

 

As you mentioned, Huntington's Disease (HD) is an inherited neurodegenerative disorder thought be caused by a CAG repeat expansion in the huntingtin gene, leading to polyglutamine expansion in the huntingtin protein [1]. The exact mechanism by which the mutant huntingtin causes HD remain illusive, but it is known that abnormalities in gene transcription, as well as mitochondrial function are involved and that these are accompanied by increases in oxidative damage. [1]

 

Targets for limiting degeneration = energy metabolism, inflammation, oxidative damage [1]

 

At this point therapies are being aimed at limiting the degenerative process, as you mentioned curing this disease will likely require gene therapy. In mouse models of HD small interfering RNA has however shown some promise for directly targeting the HD gene and its protein products [28][29].

 

Here are some of the methods under investigation for slowing degeneration:

 

Metabolic:

Evidence exists for a link between impaired metabolism and the pathogenesis of HD. Low expression of Peroxisome proliferator- activated receptor (PPAR) gamma coactivator PCG-1 alpha, is implicated in the mitochondrial dysfunction and oxidative damage in HD.[1][8] Haplotypes in the gene encoding HD PCG-1alpha influence the onset of HD, the mutant mHtt interferes with transcription of PCG-1aplha, leading to decreases of it and its targets, as well as BDNF[1]. This results in defective energy metabolism, antioxidant defence and ROS accumulation, leading to mitochondrial damage.[1] mHtt also disrupts the mitochondrial fission/fusion process, resulting in increased fission and vesicular transport interference.[1] This all results in decreased ATP production at nerve terminals and neuron death. [1]

 

Pharmacologic treatment with CoQ10, creatine, bezafibrate and nicotinamide increase PCG-1alpha and should improve neuron survival [1][9]. Thiazolidinediones, such as pioglitazone, have been used to increase PPARs and PCG-1 alpha and are neuroprotective in mouse models of HD. [1][10][11]. In mouse models of HD, pan-ppar agonist bezafibrate improved rotarod performance and survival also increased stratial atrophy and atrophy of stratial medium spiny neurons. [12] It also increased mitochondrial number and reduced malondialdehyde (MDA) in the stratium.[12]

 

NAD+ and the Sirtuins

Activation of SIRT1 results in the deacetylation of PGC-1alpha and increases activity[1]. Increased expression of SIRT1 has shown neuroprotective benefits in mouse models for HD and deficiency promotes the HD phenotype.[1][13][14].

 

Since sirtuins are NAD+ dependant deacetylases [13], one approach of activating them is by andminister NAD+ precursors. These include nicotinamide (Nam), nicotinic acid (NA), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). This also has the advantage of activating both SIRT1 and SIRT3, the latter induces superoxide dismutase 2 and mitochondrial reduced glutathione. [1] Increase Glutathione peroxidase expression has been shown to have neuroprotective effects in animal models of HD [1][23].

 

For further reading on the sirtuins and NAD+ in neurodegeneration and aging see [24], [25], [26], [27].

 

The Precursors

Nicotinamide, which is regular vitamin b3, may not be the best method for raising SIRT1 levels because at high doses it is inhibited by NAD+ in a negative feedback mechanism.[18] It has also been shown to inhibit SIRT1 at high concentrations and the rate limiting enzyme for its synthesis into NAD+ (NAMPT) declines with age [26]. That said, nicotinamide has been shown to increase BDNF and PCG-1 alpha in mouse models of HD.[19]

 

Nicotinamide mononucleotide has been used to increase NAD+ levels and aerobic metabolism in mice[17]. It is degraded into NR before it can enter cells[20] and NMN also seems to be less efficiently synthesized into NAD+ than NA or NR in muscle and liver tissues [16].

 

Nicotinamide riboside should 'in theory' be the most easily utilized by neurons because they are inefficient at de novo and salvage NAD+ synthesis [15]. However chronic NR administration failed to raise NAD+ levels significantly in the brain, which may be due to lower expression of Nrk2, which is responsible for NR metabolism into NAD+ [16].

 

Nicotinic acid has shown a 200 fold greater efficacy than Nam in raising NAD+ levels in glial cells.[15]. The rate limiting enzyme in NA biosynthesis to NAD+ is NAPRT, this enzyme is not inhibited by an NAD+ negative feedback bottleneck like NAMPT for Nam is [22]. Glial cells likely play a prominent role in supplying NAD+ to neurons.[15] Astrocytes (glial cells) outnumber neurons 5 fold and tile the entire central nervous system [21] Astrocystes can readily synthesize NAD+ from precursors like NA and Nam and transport NAD+ across the plasma membrane directly via the adenosine receptor P2XY7R [15]. Using precursors like NA gives the glia control of biosynthesis or restriction of NAD+. [15] It has shown efficacy in the treatment of pellagric dimentia and schizophrenia and increases brain NAD+ levels just 20 min after being injected into the brain.[15]

 

NA therefore seems like a promising NAD+ precursor and could possibly work in the brain. NR showed some disappointing results in the brain and is also more expensive than NA, costing close to $49.00 for 30 x 250mg, whereas NA cost about $5.00 for 100 x 250mg.

 

Oxidative Damage

CoQ10 – works within the electron transport chain and is a scavenger of free radicals. [1] It blocks 3-nitropropionic acid (3-NP) mediated striatal lesions and blocks DNA and lipid oxidation.[1] In a clinical trial for HD patients (CARE-HD), 600mg/day CoQ10 and ramacemide slowed progression of the disease.[6] A second clinical trial (2CARE) is currently underway using 2,400 mg /day doses, after an earlier study (Pre2care) showed that plasma CoQ10 levels plateau at levels above this dose [7].

 

MitoQ is a form of coenzyme Q linked to triphosphonium ions, this modification allows it to selectively accumulate within the mitochondria. [1]

 

SS31 and SS20 are novel peptide antioxidants which bind to the inner mitochondria and have been shown to be neuroprotective in mice [1] [2] [3].

 

Ways of activating the nuclear factor erythroid 2 related factor 2 / antioxidant response element (Nrf2/ARE) transcriptional pathway are also under investigation [1]. This mediates the expression of the antioxidant enzymes hemeoxygenase 1, NADPH-oxidoreductase, heat shock proteins, as well as enzymes that produce glutathione.[1] 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO)-methylamide was investigated for this purpose and did yield some positive results [2]. CDDO-methylamide and CDDO-trifluoroethylamide improved motor function in a mouse model of Hd [4] Dimethylfumarate, had some positive results in phase III clinical trials for multiple sclerosis and is approved for clinical use. [5]

 

Good luck with your research, what is your rational for using Dihexa?

 

 

[1] Chandra et al., Prospects for Neuroprotective Therapies in Prodromal Huntington’s Disease, Movement Disorders, Vol. 29, No. 3, 2014.

 

[2] Yang L, Zhao K, Calingasan NY, Luo G, Szeto HH, Beal MF. Mitochondria targeted peptides protect against 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine neurotoxicity. Antioxid Redox Signal 2009;11:2095-2104.

 

[3] Petri S, Kiaei M, Damiano M, et al. Cell-permeable peptide antioxidants as a novel therapeutic approach in a mouse model of amyo- trophic lateral sclerosis. J Neurochem 2006;98:1141-1148.

 

[4] Stack C, Ho D, Wille E, et al. Triterpenoids CDDO-ethyl amide and CDDO-trifluoroethyl amide improve the behavioral phenotype and brain pathology in a transgenic mouse model of Huntington’s disease. Free Radic Biol Med 2010;49:147-158.

 

[5] Ellrichmann G, Petrasch-Parwez E, Lee DH, et al. Efficacy of fumaric acid esters in the R6/2 and YAC128 models of Hunting- ton’’s disease. PloS One 2011;6:e16172.

 

[6] Huntington Study G. A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease. Neurol- ogy 2001;57:397-404.

Huntington’s disease: the issue of inter- mediate and reduced penetrance alleles. J Med Genet 2001;38:E12.

 

[7] Huntington Study Group Pre2CARE Investigators, Hyson HC, Kieburtz K, et al. Safety and tolerability of high-dosage coenzyme Q10 in Huntington’s disease and healthy subjects. Mov Disord 2010;25:1924-1928.

 

[8] Johri A, Chandra A, Flint Beal M. PGC-1alpha, mitochondrial dys- function, and Huntington’s disease. Free Radic Biol Med 2013;62: 37-46.

 

[9] Maat-Kievit A, Losekoot M, Van Den Boer-Van Den Berg H, et al. New problems in testing for

 

[10] Chiang MC, Chern Y, Huang RN. PPARgamma rescue of the mitochondrial dysfunction in Huntington’s disease. Neurobiol Dis 2012;45:322-328

 

[11] Jin YN, Hwang WY, Jo C, Johnson GV. Metabolic state deter- mines sensitivity to cellular stress in Huntington disease: normal- ization by activation of PPARgamma. PloS One 2012;7:e30406.

 

[12] Johri A, Calingasan NY, Hennessey TM, et al. Pharmacologic acti- vation of mitochondrial biogenesis exerts widespread beneficial effects in a transgenic mouse model of Huntington’s disease. Human Mol Genet 2012;21:1124-1137.

 

[13] Jiang M, Wang J, Fu J, et al. Neuroprotective role of Sirt1 in mammalian models of Huntington’s disease through activation of multiple Sirt1 targets. Nat Med 2012;18:153-158.

 

[14] Jeong H, Cohen DE, Cui L, et al. Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway. Nat Med 2012;18:159-165.

 

[15] Penberthy et al., The Importance of NAD in Multiple Sclerosis, Curr Pharm Des. PMC Mar 5, 2009.

 

[16] Canto et al., The NAD+ Precursor Nicotinamide Riboside Enhances Oxidative Metabolism and Protects against High-Fat Diet-Induced Obesity, Cell Metabolism 2012, Volume 15, Issue 6, p838–847.

 

[17] Sinclair et al., Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging, Cell 2013 155, Issue 7, p1624–1638.

 

[18] Bitterman et al., Inhibition of Silencing and Accelerated Aging by Nicotinamide, a Putative Negative Regulator of Yeast Sir2 and Human SIRT1, The Journal of Biological Chemistry 2002, 277, 45099-45107.

 

[19] Hathorn T, Snyder-Keller A, Messer A. Nicotinamide improves motor deficits and upregulates PGC-1alpha and BDNF gene expression in a mouse model of Huntington’s disease. Neurobiol Dis 2011;41:43-50.

 

[20] Nikiforov et al., Pathways and subcellular compartmentation of NAD biosynthesis in human cells: from entry of extracellular precursors to mitochondrial NAD generation, J Biol Chem. 2011 Jun 17;286(24):21767-78.

 

[21] Vinters et al., Astrocytes: Biology and Pathology, Acta Neuropathol. 2010 119(1): 7-35.

 

[22] Hara et al., Elevation of Cellular NAD Levels by Nicotinic Acid and Involvement of Nicotinic Acid Phosphoribosyltransferase in Human Cells, J. Biol. Chem. 2007, 282:24574-24582.

 

[23] Mason RP, Casu M, Butler N, et al. Glutathione peroxidase activ- ity is neuroprotective in models of Huntington’s disease. Nat Genet 2013;45:1249-1254.

 

[24] Wiley et al., NAD+ controls neural stem cell fate in the aging brain, The EMBO JournalVolume 33, Issue 12, pages 1289–1291, 17 June 2014.

 

[25] Guarente et al., Sirtuin deacetylases in neurodegenerative diseases of aging, Cell Research (2013) 23:746–758. 21 May 2013

 

[26] Imai et al., NAD+ and sirtuins in aging and disease, Volume 24, Trends in Cell Biology, Issue 8, August 2014, Pages 464–471

 

[27] Herskovitis et al., SIRT1 in Neurodevelopment and Brain Senescence, Neuron Volume 81, Issue 3, 5 February 2014, Pages 471–483

 

[28] Pfister EL, Zamore PD. Huntington’s disease: silencing a brutal killer. Exp Neurol 2009;220:226-229.

 

[29] Godinho BM, Ogier JR, Darcy R, O’Driscoll CM, Cryan JF. Self- assembling modified b-cyclodextrin nanoparticles as neuronal siRNA delivery vectors: focus on Huntington’s disease. Mol Pharm 2013;10:640-649.

 

Edited by jabowery, 03 August 2014 - 01:04 AM.

[Phoenicis]

I have read the full text study which led me find this study on Nicotinamide Riboside in Alzheimer's model mice and this study on Nicotinamide, also in Alzheimer's model mice. Both studies found similar positive results including reduced, amyloid-beta, maintained mitochondrial integrity, increased NAD+ SIRT1 activation, improved cognitive function etc.

 

The difference is that the NR dose used was 6 times higher than that used for Nam. For Nicotinic Acid the dose should theoretically be lower than that for Nam because it was found to be 200 fold more effective in glial cells. This is important because as opposed to glial cells, neurons are inefficient at salvage synthesis of Nicotinamide into NAD+, so it must be the glial cells that are doing most of the work.

 

You can follow the discussion in this thread.

Edited by Phoenicis, 03 August 2014 - 12:23 PM.

[jabowery]

The difference is that the NR dose used was 6 times higher than that used for Nam. For Nicotinic Acid the dose should theoretically be lower than that for Nam because it was found to be 200 fold more effective in glial cells. This is important because as opposed to glial cells, neurons are inefficient at salvage synthesis of Nicotinamide into NAD+, so it must be the glial cells that are doing most of the work.

 

You can follow the discussion in this thread.

 

Glial cells!

 

Our last trip to "the HD center for excellence" was, in addition to continue the longitudinal TFC measurements, to get Jan a sleep study so she could be prescribed a drug that would increase her slow wave sleep.

 

I wanted to increase Jan's slow wave sleep due to the study Sleep Drives Metabolite Clearance from the Adult Brain that was published last October about the critical role played by the glymphatic system in preventing neurodegeneration.  The drug that most effectively increases slow wave sleep according to her neurologist was Xyrem (patentable version of GHB) but that it can only be prescribed for narcolepsy and only a sleep specialist can diagnose narcolepsy -- his recommendation being the U of IA sleep center's specialist.  Jan had gone from intractable insomnia to hypersomnolence and as a result had gone off all of her sleep meds except Remeron -- primarily serving as an anti-depressant.  Even so when we got to Iowa City, the sleep specialist refused to do a sleep study because Jan was not totally off her sleep meds.  We were never even told that was a prerequisite for a sleep study before he sprung that on us.

 

OK, staying calm, I asked him if he was aware of the discovery of the critical role played by the glymphatic system in preventing neurodegeneration during slow wave sleep.  He said he was not.  So I asked him if he knew of any ways to increase slow wave sleep.  He said that although it is known that slow wave sleep decreases with neurodegeneration, it is not known to cause neurodegeneration.  At this point I was so flabergasted by his imperious ignorance I had to get out of there before I became aggressive or suffered stress hormone damage.  I had the distinct impression from the guy that he saw me as a "drug seeker" -- which most assuredly I was on behalf of Jan -- and that narcolepsy is a gateway diagnosis to highly scheduled drugs, Xyrem being one of the most highly sought after drugs of abuse.  

 

Idiot.

 

Edited by jabowery, 03 August 2014 - 02:55 PM.

[xks201]

If a ppar agonist is needed telmisartan is a good one. Ya jabowery now you see docs are lazy when it comes to new research. Sometimes they are even lazy when it comes to old research. They would rather call you a drug seeker and send you home than be responsible for your wife's disease treatment. Ghb was over the counter and about as cheap as a vitamin before our representatives licensed it to a drug company to sell what was 20 dollars for several thousands to 10k dollars per month under the guise of preventing date rape. Yet, benadryl is still legal. Lol its a joke.

In chronic fatigue they found slow save sleep was constantly interrupted. One could interpret that as a neurodenerative disease. You are smarter than them.

Edited by xks201, 03 August 2014 - 03:14 PM.

[Phoenicis]

In my opinion the problem may be that doctors overwork themselves and don't leave enough time for research. There should be a body to oversee periodic testing of doctors in order to maintain a high level of competency. It does depend on the doctor though, some like a doctor I met at University clinic in Germany, are pioneers in their areas. Another example is Dr Abram Hoffer, who pioneered the treatment of diseases like schizophrenia with nicotinic acid and was at the time mocked. He died in 2009 at the age of 91, and in 2006 predicted that if he lived another 4-5 years, then he would live to see his treatments become more accepted.

 

Now that we are beginning to understand the implications of NAD+ depletion with age and disease, he seems to have been right all along. As ROS accumulate along with DNA damage, NAD+ dependent enzymes like the PARPs become chronically active, trying to fix the damage. This has the unintended consequence of depleting NAD+ even further, leading to a downward spiral of mitochondrial dysfunction, ATP depletion and eventually cell death.

Edited by Phoenicis, 03 August 2014 - 04:06 PM.

[jabowery]

If a ppar agonist is needed telmisartan is a good one. Ya jabowery now you see docs are lazy when it comes to new research. Sometimes they are even lazy when it comes to old research. They would rather call you a drug seeker and send you home than be responsible for your wife's disease treatment. Ghb was over the counter and about as cheap as a vitamin before our representatives licensed it to a drug company to sell what was 20 dollars for several thousands to 10k dollars per month under the guise of preventing date rape. Yet, benadryl is still legal. Lol its a joke.

In chronic fatigue they found slow save sleep was constantly interrupted. One could interpret that as a neurodenerative disease. You are smarter than them.

 

Its becoming quite clear that a common path for all neurodegeneration is loss of slow wave sleep's primary function:  glymphatic system clearing of metabolites such as amyloid proteins.

 

It is also appearing that the _only_ drug that induces slow wave sleep, without almost immediate buildup of tolerance to the drug, is GHB/Xyrem.

 

This whole deal with Xyrem doesn't stink to high heaven just because of the large amount of money that was handed to a strange company that appears to exist for no purpose.  It stinks to high heaven because it has the appearance of a biological attack on the population which is aging, as age reduces slow wave sleep.  

 

I'd really like to know who was behind this -- and no I don't mean who "profited" from it.  This goes so far beyond the piddling amounts of money made in its damage that any intelligence agency, worth of the name, would see it as a national security threat.

Edited by jabowery, 03 August 2014 - 04:07 PM.

[Phoenicis]

The circadian rhythm controls day/night and sleeping patterns and NAD+ dependent deacetylases like SIRT1 regulate it.

 

Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3333-8.

Bellet et al., Pharmacological modulation of circadian rhythms by synthetic activators of the deacetylase SIRT1.

Abstract

Circadian rhythms govern a wide variety of physiological and metabolic functions in many organisms, from prokaryotes to humans. We previously reported that silent information regulator 1 (SIRT1), a NAD(+)-dependent deacetylase, contributes to circadian control. In addition, SIRT1 activity is regulated in a cyclic manner in virtue of the circadian oscillation of the coenzyme NAD(+). Here we used specific SIRT1 activator compounds both in vitro and in vivo. We tested a variety of compounds to show that the activation of SIRT1 alters CLOCK:BMAL1-driven transcription in different systems. Activation of SIRT1 induces repression of circadian gene expression and decreases H3 K9/K14 acetylation at corresponding promoters in a time-specific manner. Specific activation of SIRT1 was demonstrated in vivo using liver-specific SIRT1-deficient mice, where the effect of SIRT1 activator compounds was shown to be dependent on SIRT1. Our findings demonstrate that SIRT1 can fine-tune circadian rhythm and pave the way to the development of pharmacological strategies to address a broad range of therapeutic indications.

→ source (external link)

 

If a ppar agonist is needed telmisartan is a good one. Ya jabowery now you see docs are lazy when it comes to new research. Sometimes they are even lazy when it comes to old research. They would rather call you a drug seeker and send you home than be responsible for your wife's disease treatment. Ghb was over the counter and about as cheap as a vitamin before our representatives licensed it to a drug company to sell what was 20 dollars for several thousands to 10k dollars per month under the guise of preventing date rape. Yet, benadryl is still legal. Lol its a joke.

In chronic fatigue they found slow save sleep was constantly interrupted. One could interpret that as a neurodenerative disease. You are smarter than them.

 

Its becoming quite clear that a common path for all neurodegeneration is loss of slow wave sleep's primary function:  glymphatic system clearing of metabolites such as amyloid proteins.

 

It is also appearing that the _only_ drug that induces slow wave sleep, without almost immediate buildup of tolerance to the drug, is GHB/Xyrem.

 

This whole deal with Xyrem doesn't stink to high heaven just because of the large amount of money that was handed to a strange company that appears to exist for no purpose.  It stinks to high heaven because it has the appearance of a biological attack on the population which is aging, as age reduces slow wave sleep.  

 

I'd really like to know who was behind this -- and no I don't mean who "profited" from it.  This goes so far beyond the piddling amounts of money made in its damage that any intelligence agency, worth of the name, would see it as a national security threat.

 

 

[Major Legend]

Going to go off topic here.

 

I feel bad about hearing about whats happened, I think our "delayed" understanding of effective treatments before the internet has probably made a lot of preventable degenerative illnesses into reality. It doesn't help that the older generation are often extremely skeptical of the internet too.

 

I think this thread is evident of the massive changes needed in the health industry, or somewhat a revolution. Alot of stuff is known to be effective, and then covered up or banned due to monetary interests of large corporations, or rich individuals.

 

The huge barrier to change, and why the healthcare industry is so exploitative is because healthcare is tied to law, which is tied to politics, which is tied to corrupt self serving people. The irony is that the government should be acting in the best interests of people, but it often doesn't when it comes to regulating the free market. 

 

Another great example is finance, another industry tied to law, which is then tier to politics. The finance industry is screwed up not because of the idea of the free market, but because the government has gone and subsidised it in too big to fail theory, eliminating the idea of the free market.

 

Even a bigger irony in this, is free market actually works. The whole reason healthcare is so screwed up is because its so heavily regulated. 

 

Now look at other industries in which steady innovation have been made, like private space travel, software and so on. These are all barely regulated, and when over regulation doesn't exist (meaning corporate lobbyist have no effect on supply and demand), then basically it moves along just fine.

 

Again I make the argument, why shouldn't there be crowdfunding of something like dihexa or NSI? If they can raise millions for a colour changing light bulb...in fact kickstarter bans projects with medical uses exactly because of the fear of the government. 

 

I think healthcare is a sensitive topic because of the ethics involved in it, however in a democratic society where the idea of free speech is promoted. I don't see why we shouldn't be free to do what we want with our treatment options, as long as we understand the disclaimer.

 

I mean if its that big an issue now with exogenous chemicals, what about the future of brain interfaces, cortical implants, bionic implants? Will those be millionaire options because of the legal system again?

[jabowery]

Phoenicis, this appears to be converging on two points of intervention, NAD+ and slow wave sleep, with slow wave sleep being further down-stream in the common paths for neurodegeneration.  

 

NAD+ intervention looks preferable as it seems it may prevent loss of slow wave sleep as well as providing other benefits, but it may be necessary to do some immediate remediation via slow wave sleep enhancement just to clear out the accumulated destructive proteins, and then rely on the upstream NAD+ system for prevention.

 

Emergency remediation to enhance slow wave sleep might then involve these drugs, as well as ordinary measure to improve sleep hygiene:

 

PMC full text:

J Clin Sleep Med. Apr 15, 2009; 5(2 Suppl): S27–S32.

 

Copyright/License ►Request permission to reuse

 

Table 1

Drugs Known to Increase Slow Wave Sleep

Drug

Mechanism of action

Reference

Tiagabine

GAT-1 inhibitor

Mathias et al., 200136

Gaboxadol

Selective extrasynaptic GABAA agonist

Deacon et al., 200721

Gabapentin

α2-δ site on voltage-gated calcium ion channels

Bazil et al., 200537

Pregabalin

α2-δ site on voltage-gated calcium ion channels

Hindmarch et al., 200538

GHB

GABAB/GHB agonist

Pardi et al., 200639

Ritanserin

Partially selective 5HT2A receptor antagonist

Dahlitz et al., 199040

Eplivanserin

Antagonist of Serotonin Two A Receptors (ASTAR)

Hindmarch et al., 200822

Mirtazapine

Multiple receptors, including 5HT2 antagonist

Shen et al., 200641

Olanzapine

Multiple receptors, including 5HT2 antagonist

Sharpley et al., 200542

Trazodone

Multiple receptors, including 5HT2 antagonist

Mendelson, 200543

GABA, γ-aminobutyric acid; GHB, γ-hydroxybutyrate; 5HT, serotonin.

 

As for the NAD+ system, it sounds like nicotinic acid may be preferred. 

 

The circadian rhythm controls day/night and sleeping patterns and NAD+ dependent deacetylases like SIRT1 regulate it.

 

Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3333-8.

Bellet et al., Pharmacological modulation of circadian rhythms by synthetic activators of the deacetylase SIRT1.

Abstract

Circadian rhythms govern a wide variety of physiological and metabolic functions in many organisms, from prokaryotes to humans. We previously reported that silent information regulator 1 (SIRT1), a NAD(+)-dependent deacetylase, contributes to circadian control. In addition, SIRT1 activity is regulated in a cyclic manner in virtue of the circadian oscillation of the coenzyme NAD(+). Here we used specific SIRT1 activator compounds both in vitro and in vivo. We tested a variety of compounds to show that the activation of SIRT1 alters CLOCK:BMAL1-driven transcription in different systems. Activation of SIRT1 induces repression of circadian gene expression and decreases H3 K9/K14 acetylation at corresponding promoters in a time-specific manner. Specific activation of SIRT1 was demonstrated in vivo using liver-specific SIRT1-deficient mice, where the effect of SIRT1 activator compounds was shown to be dependent on SIRT1. Our findings demonstrate that SIRT1 can fine-tune circadian rhythm and pave the way to the development of pharmacological strategies to address a broad range of therapeutic indications.

→ source (external link)

 

If a ppar agonist is needed telmisartan is a good one. Ya jabowery now you see docs are lazy when it comes to new research. Sometimes they are even lazy when it comes to old research. They would rather call you a drug seeker and send you home than be responsible for your wife's disease treatment. Ghb was over the counter and about as cheap as a vitamin before our representatives licensed it to a drug company to sell what was 20 dollars for several thousands to 10k dollars per month under the guise of preventing date rape. Yet, benadryl is still legal. Lol its a joke.

In chronic fatigue they found slow save sleep was constantly interrupted. One could interpret that as a neurodenerative disease. You are smarter than them.

 

Its becoming quite clear that a common path for all neurodegeneration is loss of slow wave sleep's primary function:  glymphatic system clearing of metabolites such as amyloid proteins.

 

It is also appearing that the _only_ drug that induces slow wave sleep, without almost immediate buildup of tolerance to the drug, is GHB/Xyrem.

 

This whole deal with Xyrem doesn't stink to high heaven just because of the large amount of money that was handed to a strange company that appears to exist for no purpose.  It stinks to high heaven because it has the appearance of a biological attack on the population which is aging, as age reduces slow wave sleep.  

 

I'd really like to know who was behind this -- and no I don't mean who "profited" from it.  This goes so far beyond the piddling amounts of money made in its damage that any intelligence agency, worth of the name, would see it as a national security threat.

 

 

 

Edited by jabowery, 03 August 2014 - 05:22 PM.

[xks201]

Many of the drugs in the table will give you a hangover. I suppose gaba is worth a tty. Well said major legend on the free market truth.

[jabowery]

Gamma Aminobutyric Acid as dietary supplement?  How does one get it to cross the blood brain barrier?

Edited by jabowery, 03 August 2014 - 09:23 PM.

[StevesPetRat]

if doctors know all the answers please remind me what doctors have done for the progression of her disease ? I hate most doctors because they are ignorant pieces of crap.

Even so when we got to Iowa City, the sleep specialist refused to do a sleep study because Jan was not totally off her sleep meds. We were never even told that was a prerequisite for a sleep study before he sprung that on us.

OK, staying calm, I asked him if he was aware of the discovery of the critical role played by the glymphatic system in preventing neurodegeneration during slow wave sleep. He said he was not. So I asked him if he knew of any ways to increase slow wave sleep. He said that although it is known that slow wave sleep decreases with neurodegeneration, it is not known to cause neurodegeneration. At this point I was so flabergasted by his imperious ignorance I had to get out of there before I became aggressive or suffered stress hormone damage. I had the distinct impression from the guy that he saw me as a "drug seeker" -- which most assuredly I was on behalf of Jan -- and that narcolepsy is a gateway diagnosis to highly scheduled drugs, Xyrem being one of the most highly sought after drugs of abuse.

Idiot.

I think this thread is evident of the massive changes needed in the health industry, or somewhat a revolution. Alot of stuff is known to be effective, and then covered up or banned due to monetary interests of large corporations, or rich individuals.

Sorry to continue with the O/T ranting, but I totally relate to your experiences. Without going into all the specifics here, I've been having a lot of symptoms more commonly seen in late stage diabetics or post menopausal women (PN, possibly MN, dry eyes/mouth, hypohidrosis, polyuria, polydipsia, arthritis, sudden exercise intolerance, brain fog, you get the idea). Yet all doctors will say is "Hmm, these things happen. Let's get you on something to an age those symptoms." There is absolutely no interest in finding underlying causes; care consists of 100% symptom management.

I live "down the street" from a Theranos (theranos.com) testing center. I could get for $500 (which I would totally tests that would cost $5k from conventional labs and skip a year or more of going through the bullshit "Well let's test this ONE idea I have today, and if it's wrong I'll see you again in 3 months" procedure. Yet I can't find anybody to simply write an order for the tests.

Doctors warn you to stay off the internet. They say it's because people end up worried about some improbable disease or whatever, and probably some idiots do, but for the smart folks it quickly reveals just how ignorant they are. I taught and tutored premeds for a long time, and 90% of them have no intellectual curiosity whatsoever. They want to know the answer, not the principle of inquiry that drives one to the solution. This is to be contacted with engineers and the pure science majors. I would guess the median Longecity member reads more medical journal articles in a week than the median doctor does in a year.

OK, sorry about that. I don't have much to add to the excellent suggestions above, except nobody has mentioned the connection between brain and cardiovascular health. What's good for the heart is typically good for the brain.

[medicineman]

there is going to be a clinical trial using memantine in HD. anecdotal evidence exists(in vitro) and now it's being tested on patients. if you can find the doses or protocols in the trial and maybe you and your wife decide it maybe worth trying? it's used a lot here, quite safe, good information if you search on longecity about memantine.

also a new drug (actually, old and not hard to make) which looks promising is RP103. the company that made this is currently in the spotlight due to a successful clinical trial.

anyhow, it's cysteamine, very simple structure. thought to work via

-inhibiting tissue transglutaminase which are thought to play a role in anchoring the htt protein
-highly neurotrophic
-protects dopaminergic neurons against mptp with low (easily achievable) doses
-maybe an effective anti-depressant
-hepatoprotective


one discouraging thing in the clinical trial was that the improvement didn't result from less htt. the metabolic junk was still there.

anyhow it's worth checking out since it is a very simple molecule. you could probably synthesize it quite easily.

Edited by medicineman, 03 August 2014 - 10:02 PM.

[xks201]

Well take one gram of gaba if you don't believe it affects the nervous system. It will sedate you. There is a huge argument about whether or not it gets in the brain. Even if it doesn't it gets everywhere else effectively lowering the feedback from everywhere else it Is sedating within the body. That is my take on it at least because even in my days of insomnia I could take a gram or two of that and be asleep in no time.

[jabowery]

Well take one gram of gaba if you don't believe it affects the nervous system. It will sedate you. There is a huge argument about whether or not it gets in the brain. Even if it doesn't it gets everywhere else effectively lowering the feedback from everywhere else it Is sedating within the body. That is my take on it at least because even in my days of insomnia I could take a gram or two of that and be asleep in no time.

 

OK, thanks.

 

Perhaps this article points the way, and not only for GABA:

 

http://www.nature.co...full/nn849.html

 

Sniffing neuropeptides: a transnasal approach to the human brain

 

Jan Born¹, Tanja Lange², Werner Kern², Gerard P. McGregor³, Ulrich Bickel⁴ & Horst L. Fehm²

 

Abstract

Neuropeptides act as neuronal messengers in the brain, influencing many neurobehavioral functions¹. Their experimental and therapeutic use in humans has been hampered because, when administered systemically, these compounds do not readily pass the blood–brain barrier, and they evoke potent hormone-like side effects when circulating in the blood^2, 3. We administered three peptides, melanocortin(4–10) (MSH/ACTH(4–10)), vasopressin and insulin, intranasally and found that they achieved direct access to the cerebrospinal fluid (CSF) within 30 minutes, bypassing the bloodstream.

[Phoenicis]

I am not qualified to give medical advice and would like to remind anyone reading that it is their own responsibility to seek independent medical advice before taking any of the bellow mentioned substances. This does not constitute medical advice.

 

It looks like Nicotinic acid reduces pro-inflammatory cytokines like IL-6 [1], which are up-regulated in HD. It increases adiponectin, which has anti-inflammatory properties that may be mediated by overall IL-6 reduction,[2] and may be neuroprotective in rats.[3] Nicotinic acid also upregulates (PPAR) α and PPARγ, possibly by activiating HM74A [4], which could therefore be additional to any later SIRT1 mediated activation.

 

There was also an investigation into "impaired phospholipid-related signal transduction in advanced Huntington’s disease", they found reduced flushing upon topical application of a nicotinic acid derivative (methyl nicotinate). I'm not sure what to make of that, but the researchers did draw parallels to a similar pathogenic impairment in schizophrenia.

 

However HD is complicated and higher levels of adiponectin secretion was found to coincide with a greater degree of motor and functional impairment in HD patients[5]. NA also effects gene expression more dramatically than insulin[6] and has wide ranging effects covering lipid metabolism mediated in part by HM74A.

 

This study on HD also found less NA making it across the BBB than Nicotinamide[7], but I could not find any mention of NAD+ levels in the abstract. That study was later cited in the Multiple Sclerosis study I linked earlier, but the researchers there seem to believe that NA could be superior to Nam in terms of NAD+ production and PPAR elevation. Perhaps research and try and confirm whether NA's effects as an anti-inflammatory, lipolytic agent etc. are going to be beneficial in HD. Maybe then you could decide whether a combination of NA and Nam, or Nam alone would be best.

 

The fact that nicotinamide has so many studies showing it to be neuro-protective is good, it seems more easy to predict. One thing I'm still not sure about is whether it is converted into NAD+ before it gets a chance to inhibit the Sirtuins, which are NAD+ dependent deacetylases. I'm not sure whether the claims that it acts as an inhibitor of the sirtuins (class III HDACi) are relevant in reality. This might all depend on whether NAMPT, the rate limiting enzyme for Nam > NAD+ is active or not. The Alzheimer's mouse model suggests that in mice NAMPT must be working in the brain, but some researchers are finding that it declines with age, or is regulated by the circadian rhythm.

 

[1] http://circ.ahajourn...bstracts/A15978

[2] Kyriazi et al., Effects of Adiponectin in TNF-α, IL-6, and IL-10 Cytokine Production from Coronary Artery Disease Macrophages, Horm Metab Res 2011; 43(8): 537-544.

[3] Qiu et al., Adiponectin protects rat hippocampal neurons against excitotoxicity, Age  2011, Volume 33, Issue 2, pp 155-165.

[4] Riedel et al., Structure-dependent effects of pyridine derivatives on mechanisms of intestinal fatty acid uptake: regulation of nicotinic acid receptor and fatty acid transporter expression, The Journal of Nutritional BiochemistryVolume 25, Issue 7, July 2014, Pages 750–757.

[5] Aziz et al., Leptin secretion rate increases with higher CAG repeat number in Huntington’s disease patients, Clinical Endocrinology 2011 Vol. 73 Issue 2 pp.206-2011.

[6] Choi et al., Widespread effects of nicotinic acid on gene expression in insulin-sensitive tissues: implications for unwanted effects of nicotinic acid treatment, Metabolism Volume 60, Issue 1, January 2011, Pages 134–144.

[7] Hankes et al., Effect of Huntington's and Alzheimer's diseases on the transport of nicotinic acid or nicotinamide across the human blood-brain barrier, :Adv Exp Med Biol. 1991;294:675-8.

Edited by Phoenicis, 04 August 2014 - 07:02 PM.

[Flex]

@ Phoenicis

This could be off topic but nevertheless I wanted to ask, if You accidentally know whether NAM does inhibit Poly(ADP-ribose)-Polymerase 1 (PARP-1)

in a relevant dose. So ca. up to 3 grams daily