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dna methylation/epigenetics


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Excellent point. It seems that gene expression - particularly gene silencing - is very much part of 'malfunction' (disorder/disease). It is known that stressors (diet, environment - physical and emotional, sleep, outlook, drug use, etc...) can silence genes. Once silenced, then the body dose not fully function and one becomes susceptible to breakdown. Likewise, to some extent, changing how we live and react can reawaken a silenced gene. But mankind is a long way from charting exact correlations and how to fix a specifiy expression. Peptide research has been the most technically useful.

Epigenetic_mechanisms.jpg

As an example of how gene expression is involved: by the time a person is in their 20s, 90% of their genes are silenced. This is because they were used to construct (develop) a human being and are no longer needed since you are now grown. However, as a person ages, needed genes get silenced and we break down - this is where 'gene therapy' would be useful.

HPPD is complex since it is a group of symptoms and very individualistic - in essence it is multiple 'diseases' under one roof. Thus medication response varies widely. Still, there are definate patterns and if these were more specifically catagorized, it would be helpful for treatment.

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looks like research already exists: http://www.google.co.uk/search?sourceid=chrome&ie=UTF-8&q=lsd+gene+expression

from first google search link:

Results to date show that LSD induces expression changes in a relatively small but important collection of genes. Many of these genes influence the way neurons change physically to alter functional abilities in the brain. At least one of the genes is involved in the process of growth and differentiation of various cell types, and has been shown to be necessary for memory consolidation. A common theme of many of the genes regulated by LSD is the process of synaptic plasticity. The genes that LSD affects may thus play an important role in learning and the storage of memories.

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this details the genes that are upregulated http://deoxy.org/wiki/Acid_Genes and is a precis of this study: http://www.nature.com/npp/journal/v26/n5/full/1395848a.html

It specifically mentions hppd as being possibly caused by upregulation of krox 20 and arc genes. This study would be a good starting point to begin a new study looking at the effect on hppders of interventions that modify these gene expressions (if any exist.)

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An epigenetic or altered regulation of genes is an excellent line of reasoning. This would be consistent with the absence of predictable onset, the non dose-dependent linear/etc relationship with symptom severity, the sudden on and off of symptoms, and the individuals who have similar symptoms but do not associate them with hallucinogens often report antibiotics, specifically those with activity as inhibitors or altering DNA/RNA replication. Hallucinogens have responses including affecting receptor trafficking, desensitization (basis for repeated use/no reponse), ability to alter signaling pathways. Nichols has a great review, and discusses the changes in neuronal function based on the influence of gene expression. The proposed idea is long-term expression changes help to explain why we have long-term adverse effects. If the HPPD population were particularly sensitive to gene expression changes an alteration from the acute changes (part of LSD's mechanism of action) resulted in semi/permanent change.

Alterations in GABAA(A) receptor expression/function are often considered a major contribution to some neurological and psychiatric diseases. Considering the VAST array of components for producing all possible implicated subtypes of receptors are not only molecularly heterogeneous but they are obviously regulated both at the transcriptional and post-transcriptional level and this adds up to an almost limitless combinations of interactions at the molecular, cellular, and systemic level that could affect HPPD.

In GABA(A) alone think proteins associated with the receptor: RACK1, GAP34, GCIq-R, PKC, GRIF-1, GABARAP,

Here is a good list of possible areas to look at: (citations after section, this list is a copy/paste for time-saving)

GABAA receptor subtypes: In addition to the elucidation of GABAA receptor stoichiometry, which will be essential to understand the mechanism of channel gating and allosteric modulation, a major open question related to

GABAA receptor subtypes is the role of their subunit composition for determining their functional properties in vivo. This question will need to be resolved both at the level of single-channel properties and at the level of synapse physiology.

GABAA receptor postsynaptic clustering: Four major questions await answers in this field. First, it remains unknown how the interaction of GABAA receptors with proteins of the postsynaptic specialization and their regu- lation by post-translational modification determines GABAergic synaptic function and pharmacology. In other words, how different is the function of GABAA receptors in a heterologous expression system compared with a synaptic context? Second, the nature of the interaction between GABAA receptors and gephyrin needs to be elucidated. Is it mediated by an additional protein(s) or are both GABAA receptors and gephyrin stabilized and clustered by the cytoskeleton? Third, the identification of the ‘‘general’’ and ‘‘synapse-specific’’ clustering signals will be a major advance for elucidating how receptors and signaling pro- teins are sorted to the appropriate synapses. Finally, the role of the DPC in GABAergic synapses remains hypothetical. In addition to possible functions in relation to synaptic stabilization, a role in signal transduction also represents an attractive possibility, especially in analogy with the neuromuscular junction.

Regulation of cell-surface expression: The concept that GABAA receptors might shuffle between the cell surface and an intracellular, subsynaptic compartment is new and is largely derived from corresponding findings in the field of glutamate receptor biology. The role of GABAA receptor internalization, its regulation by physiological and pharmacological means, and the fate of internalized recep- tors along the degradation/recycling pathways will require considerable attention to understand how these mechanisms determine the number of receptors available for synaptic transmission at any given time point in a neuron.

Allosteric modulation by neurosteroids: One of the major issues in this field is the site of synthesis of neuro- active steroids in the brain, along with the regulation of their synthesis. Are neurosteroids produced by astrocytes and released in the vicinity of synapses, and are locally synthe- sized neurosteroids playing an important role in the modu- lation of GABAA receptors under physiological conditions? In addition, the function and the subcellular localization of the steroid-sensitive GABAA receptor subtypes, in particular those induced by fluctuating progesterone concentrations, remain largely enigmatic.

GABAergic synaptic plasticity in disease states: The rapid, but long-lasting, alterations in the distribution of GABAA receptors and other markers of GABAergic synapses reviewed in Section 5 raise fundamental issues with regard to their functional significance. In particular, it remains unresolved whether sprouting of GABAergic axons and synaptogenesis occur under pathophysiological situa- tions, for instance in Huntington’s disease or in epilepsy, or whether the apparent increase in the number of GABAA receptor clusters and GABAergic axons merely reflects an up-regulation of these proteins in existing structures. In the field of epilepsy, a key issue will be to clarify the role of the mutations identified in the a1- and g2-subunits for producing the associated syndrome. More generally, the mech- anisms of epileptogenesis and seizure expression in relation to the reorganization of GABAergic circuits and GABAA receptor up-regulation are to be understood. Finally, in stroke and ischemia, the functional significance of the long-lasting reduction of GABAA receptor expression needs to be clarified. Are there homeostatic mechanisms to com- pensate for this alteration of inhibitory function?

(Jean-Marc Fritschy, Ina Bru ̈nig, Formation and plasticity of GABAergic synapses: physiological mechanisms and pathophysiological implications, Pharmacology & Therapeutics 98 (2003) 299–323)

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See the following for LSD action on regulation of 5HT

Buckholtz, N. S., Zhou, D. F., & Freedman, D. X. (1988). Serotonin2 agonist administration down-regulates rat brain serotonin2 receptors. Life Sci 42, 2439 – 2445.

Buckholtz, N. S., Zhou, D. F., Freedman, D. X., & Potter, W. Z. (1990). Lysergic acid diethylamide (LSD) administration selectively downregu- lates serotonin2 receptors in rat brain. Neuropsychopharmacology 3, 137 – 148.

Dave

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David,

This is a VERY interesting discussion and possibility – and especially in light of studies connecting LSD with gene expression.

This would be consistent with the absence of predictable onset, the non dose-dependent linear/etc relationship with symptom severity, the sudden on and off of symptoms, and the individuals who have similar symptoms but do not associate them with hallucinogens often report antibiotics, specifically those with activity as inhibitors or altering DNA/RNA replication.

While genes clearly play a part in disease susceptibility, so does environment. Many report high anxiety states contributing to developing HPPD and the like bucket of symptoms.

For some there is a characteristic deterioration that may go on many weeks. Is this not in the fashion of nerve degeneration?

When looking at Parkinsonism as a model, the primary damage is reportedly synaptic, due to high oxidative stress factors. Again, environment plays a major role in oxidative stress, whether ‘toxic’ or just high metabolic activity.

When looking at Toxic Encephalopathies, particularly with solvents, symptoms also involve primary and secondary demyelination, and even death of distal axons.

All of these models seem valid in explaining breakdowns in nuclei (brain neuronal systems) or, even greater, between them, which produce our symptoms. And none of these would show on medical imaging (except if axonal death was vast). All are ‘stubborn’ to correct (there is yet no anti-LSD pill to reverse LSD – ‘underloading’ does not correct past ‘overloading’).

While life is simpler if problems can be distilled to single factors, we could be looking at multiple types of injury in many cases.

Reversing gene silencing to correct gene expression has to be, handsdown, beneficial. It would be fascinating to see any relief of symptoms from such a method. Are there any such reports?

Any thoughts?

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I have answers such stressxdiathesis model/etc... but, we need to go through the problem with some structure or we will loop ourselves into frenzy. I found this the case writing the text. I would read a new article providing evidence for one small piece, and putting together the puzzle was beyond the scope of my work or I would never have finished. However, we can do this here.

I will set-up sections in the forums to resemble some type of useful structure (perhaps we start at the level of the neurotransmitters and go from there. I have research with anxiety-induced genetic disregulation of multple receptor complexes including loss of inhibitory firing, role of cortical cells in information processing, the related functional anatomical structures...

It begins feeling like Nitrous, you keep on taking in more balloons to get "Closer" to the "Answer" that explains "Everything" and it becomes an addiction and then you have 10 models for HPPD and a headache.

I have 15 windows open with documents, so I am going to get up and take a break and return to see what I can put together to start. I have some ideas.

- dk

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This would be consistent with the absence of predictable onset, the non dose-dependent linear/etc relationship with symptom severity, the sudden on and off of symptoms, and the individuals who have similar symptoms but do not associate them with hallucinogens often report antibiotics, specifically those with activity as inhibitors or altering DNA/RNA replication.

Something that may be of interest in this respect - someone over at the visual snow forum managed to cure their VS with a psychedelic - something that you would think more likely to cause it.

I can't remember entirely, but I think he had it since he was born. Right now we don't know if there is a different mechanism behind those who are born with VS, those those who develop it through drugs, those who develop it naturally, and those who develop it in some over way.

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http://www.youtube.com/watch?v=1RfgaolrDn8

A documentary looking at epigenetics in general. It's for a general audience so not much scientific detail but a nice introduction to the subject. The implications of epigenetics are fucking massive - this is what 21st century science is going to be about. Most disturbing implications are that epigenetic changes are heritable, and that they seem to be caused by lots of things that are only now beginning to be investigated if at all (eg everyday common toxins).

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I think a comparative genomic hybridization analysis would go a long way in determining genes involved. It's the same for targeted therapeutics. The genetic profile determines the efficacy and choice of treatment. And yup, methylation patterns are indeed heritable so these facets are quite hardwired. That being said, that means better drugs may be developed without going the circuitous route that things like benzos do, i.e. calming the entire system down rather that up-regulating a gene product (which can be done...good luck to us of Pfizer even thinking about its worth...in time, in time)

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it wouldnt be worth it for pfizer to invest in hppd medicine, but we may be able to piggy-back some research that is more focussed on a more common related condition, like ptsd.

Good point Brendan, there are lots of overlaps with HPPD and the "kosher" brain ailments. I also suspect that we have very different gene expression profiles that give us HPPD, thus the different symptoms and severities. From what I've read over the years, as an example, klonopin works great for lots of sufferers (including me) and does nothing for others. I think HBB was pretty sold on Keppra. Again, targeted therapy is so important for HPPD. The only problem I see with piggy-backing is if a pathway seems to be related when it is actually antagonistic. The poor souls who were prescribed risperadal before it became known to us that it's counterindicated for HPPD!

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Since genes only define weakness, nearly all disease could be prevented with 'healthy' life style. For example, HPPD is mainly from drug abuse. Diabetes and Heart disease is almost entirely preventable. Even cancer can be greatly reduced (1/3 is from smoking, 1/3 is from diet, and a large portion is from pollution). Multiple sclerosis is almost entirely a disease of Western industrialization.

Epigemetocs is important. But changing how humans live is an immediate solution that has been known and available for years. All it takes is personal discipline, political determination and the elimination of business greed - lots of luck!

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  • 3 weeks later...

I don't know too much about gene therapy etc, but it is interesting to note there are some promising early studies with regards to gene therapy in relation to Parkinson's. Athough clearly different from Parkinson's, there is some common ground (at least in some cases), i.e. a lack of dopamine.

One report I read talks about inserting a (harmless, they think!) virus into the brain. The virus contains a gene called GAD. There was an improvement after 6 months of 23.1% compared to the placebo improvement of 12.7%.

The gene 'GAD' stimulates the production of GABA in the subthalamic nucleus, which improves basal ganglia function.

http://www.thelancet...0039-4/abstract

First I heard of GABA having anything to do with Parkinson's.

Clearly I have a lot to learn.

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This is the theory that made the most sense to me back when I was reading up on all of this non-stop. It's either this theory or cell-death that could explain why some people get HPPD and it never goes away. I just think cell death has so many other implications that comes with it that it's hard for me to believe that we've lost so many neurons that our vision has become fucked up.

Cell death certainly does make sense for us past drug users but it doesn't make sense when hearing about people only taking SSRI's or anti-biotics and developing VS or other visuals.

I stay optimisstic that something will come along in the medical community that will help us.

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Cortisol is regulated by GABA. So this is probably overkill. GABA can inhibit CRH production.

[http://www.uams.edu/m2004/Behavioral%20Sciences/Biological%20Determinants/Biology%20of%20Stress/Stress%20text.htm]

But check out this video about RNAi :

http://www.pbs.org/w.../body/rnai.html

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here is also an interesting article:

http://integral-opti...c-marks-on.html

http://www.thaindian..._100217270.html <-------***DAPT***

http://www.ncbi.nlm....les/PMC2631422/

http://pharmrev.aspe...t/60/2/196.full

http://www.emdmillip...ates+of+America

http://en.wikipedia....iki/Apomorphine <--disregard

http://molpharm.aspe.../73/5/1444.full

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