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What are some CRF1 antagonists?

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#61 farshad

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Posted 09 August 2018 - 05:49 PM

Antipsychotic drugs inhibit the human corticotropin-releasing-hormone

 

It has been found that chlorpromazine (0.1-5.0 microM), haloperidol (0.5-5.0 microM), clozapine (1.0-5.0 microM), thioridazine (1.0-5.0 microM), promazine (5.0 and 10 microM), risperidone (5.0 and 10.0 microM), and raclopride (only at the highest used concentrations, ie 30 and 100 microM) present in culture medium for 5 days inhibited the CRH-CAT activity.Sulpiride and remoxipride had no effect. Since CRH gene activity is most potently enhanced by cAMP/protein kinase A pathway, the effect of antipsychotics on the forskolin-induced CRH-CAT activity was determined. Chlorpromazine (1.0-5.0 microM), haloperidol (1.0-5.0 microM), clozapine (1.0-5.0 microM), thioridazine (3.0 and 5.0 microM), and raclopride (30 and 100 microM), but not promazine, sulpiride, risperidone, and remoxipride, inhibited the forskolin-stimulated CRH gene promoter activity. A possible involvement of protein kinases in chlorpromazine and clozapine inhibitory action on CRH activity was also investigated. It was found that wortmannin (0.01 and 0.02 microM), an inhibitor of phosphatidylinositol 3-kinase (PI3-K), significantly attenuated the inhibitory effect of chlorpromazine and clozapine on CRH gene promoter activity. In line with these results, a Western blot study showed that these drugs increased phospho-Ser-473 Akt level, had no effect on total Akt, and decreased glycogen synthase kinase-3beta level. Additionally, we found that clozapine decreased protein kinase C (PKC) level and that its action on CRH activity was attenuated by PKC activator (TPA, 0.1 microM). The obtained results indicate that inhibition of CRH gene promoter activity by some antipsychotic drugs may be a molecular mechanism responsible for their inhibitory action on HPA axis activity. Clozapine and chlorpromazine action on CRH activity operates mainly through activation of the PI3-K/Akt pathway. Moreover, PKC-mediated pathway seems to be involved in clozapine action on CRH gene activity.



#62 farshad

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Posted 11 August 2018 - 04:20 PM

yeah gonna try either of these 4:

 

 

Valproate   decreased CRH release in rats, whereas lamotrigine  stabilized ACTH/cortisol secretion. Moreover, felbamate was found to inhibit stress-induced corticosterone release in mice.
https://www.ncbi.nlm...pubmed/19205363

valproic acid(Valproate)  can decrease CRF1 binding in the amygdala and hypothalamus.
https://scholarworks....=honors_theses

Carbamazepine  has been shown to inhibit hypothalamic CRH secretion in vitro.
https://www.research....thy_volunteers


Edited by farshad, 11 August 2018 - 04:30 PM.


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#63 farshad

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Posted 13 August 2018 - 11:20 PM

wow im such a F#cking dumbass.. I thought CRH stand for = cortisol releasing hormone , it doesent ,it means Corticotropin-releasing hormone. 

 

cortisol and corticotropin isnt the same thing is it?

 

cortisol = steroid hormone 

 

corticotropin (releasing hormone) = 41 amino acid peptide hormone 

trough Corticotropin-releasing hormone receptor 1 (CRHR1) which  is a protein increases anxiety.

 

they are produced in different places .

 

in that case, Lamictal & felbamate wont work .

 

 

only 2 options: carbamazepine or valproate.

 

 


Edited by farshad, 13 August 2018 - 11:21 PM.

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#64 farshad

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Posted 15 August 2018 - 03:35 AM

is crh created only in the  Paraventricular nucleus of hypothalamus? this study:https://www.ncbi.nlm...ubmed/19467289 says = In conclusion, two widely used atypical antipsychotics, 

olanzapine and quetiapine are able to acutely reduce the release of CRH from isolated rat hypothalami and hippocampi.
 

I thought CRH was created in the PVN only and there were CRF1/CRF2 receptors all over the brain in which the CRH activates, But now I find out the hippocampus can create its own CRH? or am I understanding it wrong.

''CRF1/CRF2 are activated through the binding of CRF/CRH(Corticotropin-releasing hormone)''

 

hypothalamus-> stress -> CRH->CRHR1/CRHR2 & by blocking CRH = less CRHR1/CRHR2

 

 

Usually if you have and overactive receptor in these hormones (corticotropins, thyrotropins, etc), the ligand will be downregulated through a negative feedback loop. It really depends on why your CRHR1 is hyperactive : is it auto-immune with activating antibodies? In that case, you will usually see decreased CRH but increased CRHR1 because the body is trying to downregulate the hormone from the top, but you're overstimulating the CRHR1 without its ligand. You can also have Gain of Function mutations where the receptor is always active, regardless of ligand. In that case too, there will be less CRH because of the negative feedback loop. To lower CRHR1 levels you need to completely inhibit it, but also take synthetic ACTH and other produced by the pituitary to avoid a feedback loop. Then, without being constantly stimulated, the pituitary should naturally downregulate CRHR1 levels.

And high CRHR1 surface expression is definitely not the same as CRHR1 activity levels.  if your problem is at the level of the receptor, you will have low levels of CRH, both in the case of an auto-immune disease and hypermorphic mutation. It's actually one of the ways to detect these cases in blood tests. And crh tumor can be detected with the help if a full MRI-Scan.

 



#65 farshad

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Posted 16 August 2018 - 07:37 AM

ok heres the ultimate fear extinction stack ive come up with lemme know your thoughts:

 

tribulus - possible reduce crh

st johns worth - reduce crh by 20%

ginkgo biloba - slows down crh secretion

 

memantine - alpha  7 antagonist (alpha 7 nicotinic receptor controls amygdala activity but memantine is weak need a stronger one but it has a long half life) alternative BNC-210 or somth if you can get it.

5a-dhp / progesterone / pregnenolone - precursor to allopregnenolone potent modulator of gaba-a which inhibits crh

Vorinostat/ black seed oil/sodium butyrate etc - HDAC inhibitors decrease fear a lot

valproic acid (depakote) - decrease CRF1 binding in the amygdala and hypothalamus.

marijuana or synthetic cb1 drugs -CB1 agonists decrease anxiety

Antalarmin or Pexacerfont or astressin b - Antagonist on CRF1 and CRH(ie both crf1/crf2)

 

add on this:

 

Memantine - NMDA antagonist

carbazeminepine - sodium channel blocker (reduces glutatmine exitoary neruontransmitter)



#66 farshad

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Posted 19 August 2018 - 10:12 AM

1. full body MRI scan (detect any CRH tumors)
2. dexamethasone crh test (can find out what is causing high CRH/CRF1) (edit) I imagine CRH  would rise in adrenal suppression (for which you would use a short synacthen test)
3. auto-immune disease and hypermorphic mutation CRH or CRF1  blood tests


Edited by farshad, 19 August 2018 - 11:08 AM.


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#67 farshad

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Posted 19 August 2018 - 09:23 PM

It was found that imipramine, amitryptyline, desipramine, fluoxetine, and mianserin, present in the culture medium for 5 days, in a concentration-dependent manner inhibited basal hCRH gene promoter activity in undifferentiated Neuro-2A cells, while other drugs under study (citalopram, tianeptine, moclobemide, venlafaxine, reboxetine, mirtazapine, and milnacipram) were inactive. In the differentiated cells, all examined antidepressants, except moclobemide (no effect) and tianeptine (increase), inhibited hCRH gene transcription. 

 

https://www.ncbi.nlm...pubmed/14735130

 

 

 

the structure of carbamazepine is similar to imipramine and chlorpromazine,.

 

chronic administration of imipramine to experimental animals significantly decreases CRH messenger RNA levels in the paraventricular nucleus

https://www.ncbi.nlm.../pubmed/9253341

 

'' in vitro sutdies show that procaine is a potent stimulus to hypothalamic CRH release, while carbamazepine, a limbic anticonvulsant effective in the treatment of major affective disorder, inhibits procaine-induced in vitro CRH.''
'Carbamazepine has been shown to inhibit hypothalamic CRH secretion in vitro.''
 
carbamazepine and impiramine similar both inhibit CRH , pros carbamazepine easier to get and longer half life ,less side effects,.  is not well known for  using against anxiety tho..
 
 CRHR1 has to accept CRH, CRHR1/CRHR2 are just receptors CRH works trough, same with GABA and GABA A and B.
 

Edited by farshad, 19 August 2018 - 09:37 PM.


#68 farshad

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Posted 23 August 2018 - 12:03 PM

so I bought the astressin-b hairspray by DS laboratories it is supposed to block CRH but it is topical you spray it on your head hair, I don't think it is working, it says spray 6x times and rub it in , I did but I feel nothing.

 

here is the description on it:

 

''first treatment powered by astressin-b''

An advanced hair boosting agent, spectral,f7 is a breaktrough formula that incorporates astressin-b, a powerful peptide to aid in stopping stress related hair loss



#69 farshad

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Posted 24 August 2018 - 02:01 PM

carbamazepine, desipramine/imipramine,valproic acid,xanax etc and most Antipsychotic drugs inhibit CRH
 
 
 
1. carbamazepine
2. desipramine/imipramine
3. valproic acid
 

Edited by farshad, 24 August 2018 - 02:01 PM.


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#70 farshad

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Posted 24 August 2018 - 09:22 PM

Quercetin   blocks CRF release 

https://www.ncbi.nlm...pubmed/20447436

 

diazepam also.



#71 farshad

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Posted 24 August 2018 - 10:49 PM

 It was found that   amitryptylinefluoxetine(prozac), and mianserin, present in the culture medium for 5 days, in a concentration-dependent manner inhibited basal hCRH gene promoter activity in undifferentiated Neuro-2A cells.

 

1. carbamazepine
2. desipramine/imipramine
3. valproic acid

Edited by farshad, 24 August 2018 - 10:50 PM.


#72 farshad

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Posted 25 August 2018 - 12:11 PM

CRH gene encodes a member of the corticotropin-releasing factor family. The encoded preproprotein is proteolytically processed to generate the mature neuropeptide hormone. In response to stress, this hormone is secreted by the paraventricular nucleus (PVN) of the hypothalamus, binds to corticotropin releasing hormone receptors and stimulates the release of adrenocorticotropic hormone from the pituitary gland. Marked reduction in this protein has been observed in association with Alzheimer's disease. Autosomal recessive hypothalamic corticotropin deficiency has multiple and potentially fatal metabolic consequences including hypoglycemia and hepatitis. In addition to production in the hypothalamus, this protein is also synthesized in peripheral tissues, such as T lymphocytes, and is highly expressed in the placenta. In the placenta it is a marker that determines the length of gestation and the timing of parturition and delivery. A rapid increase in circulating levels of the hormone occurs at the onset of parturition, suggesting that, in addition to its metabolic functions, this protein may act as a trigger for parturition.

Edited by farshad, 25 August 2018 - 12:11 PM.


#73 farshad

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Posted 25 August 2018 - 06:38 PM

Cortisol/Glucocorticoids inhibit CRH production in the hypothalamus. However, in the amygdala – a brain region involved in the behavioral stress response – cortisol increases CRH, leading to anxiety and fear [R].

 

in this case, negative feedback loop won't work..

 

Chronic stress increases CRH receptors in the PVN, which makes you even more susceptible to the harmful effects of stress ®. 

Early life stress causes heightened neuronal activity in response to stress-induced CRH release.   With repeated exposure to stress, you’ll continue to hyper-secrete CRH. Over time, CRH receptors in the anterior pituitary will become down-regulated, producing depression and anxiety symptoms ®.

 

I think long-term stress decreases CRH.

 

 

 

 

 



#74 farshad

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Posted 26 August 2018 - 01:39 PM

It was found that clomipramine lowers CRH mRNA expression in the PVN by 74%, regardless of stressor conditions. Imagine combining clomipramine with ST johns wort which has been shown to reduce CRH in the PVN by 22%... ... 96% crh reduction

https://www.ncbi.nlm...pubmed/15214866

 

Trimipramine ,desipramine & clomipramine is made from imipramine.

 

  Mirtazapine is an inhibitor of the release of corticotropin-releasing hormone (CRH) from CRH-containing neurons (33) .(didn't work for me, so I assume mianserin wouldn't work either)

Prozaz didn't work either.

I assume amitriptyline wont work either becuase of the similar mechanism to mianserin on CRH and  since mianserin is similar to mirtazapine.

 

 

 

choices boil down to:

 

1. carbamazepin

2. clomipramine  or imipramine

3. valproate/valpoic acid

 

 

 

(edit) hmmm...:  8 wk of daily imipramine treatment (5 mg/kg, i.p.) in rats decreased corticotropin-releasing hormone (CRH) mRNA levels by 37% in the paraventricular nucleus (PVN) of the hypothalamus .

 

only 37% by imipramine... clomipramine 74%.. better choice by far.


Edited by farshad, 26 August 2018 - 02:08 PM.


#75 Caravaggio

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Posted 27 August 2018 - 07:37 AM

I think the St. John's Wort works because it lowers cortisol and ethinyl estradiol.

 

Phytother Res. 2005 Oct;19(10):901-6.

Effects of St John's wort (Hypericum perforatum L.) extract on plasma androgen concentrations in healthy men and women: a pilot study.
Donovan JL, DeVane CL, Lewis JG, Wang JS, Ruan Y, Chavin KD, Markowitz JS.

https://www.ncbi.nlm...pubmed/16261523

 

High IL-1β and TNF-α can cause a rise in CRH, both cytokines which would point to an inflammation.

 

Also low testosterone itself can cause anxiety.

 

Could you provide all your hormonal results here? FSH, LH, Estradiol, total testosterone, free testosterone, DHT, DHEA, SBHG, cortisol, HGH, prolactin, ACTH.



#76 farshad

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Posted 27 August 2018 - 10:11 AM

I think the St. John's Wort works because it lowers cortisol and ethinyl estradiol.

 

https://www.ncbi.nlm...pubmed/16261523

 

High IL-1β and TNF-α can cause a rise in CRH, both cytokines which would point to an inflammation.

 

Also low testosterone itself can cause anxiety.

 

Could you provide all your hormonal results here? FSH, LH, Estradiol, total testosterone, free testosterone, DHT, DHEA, SBHG, cortisol, HGH, prolactin, ACTH.

 

 I don't have those but iv'e had multiple blood tests and my results came back normal according to my doctor.

at this point im sure I know what is causing my anxiety it is high CRH-CRHR1 signaling, not sure the cause but doesen't matter that would take forever to figure out im just looking for a solution and I think im gonna go with clomipramine + st johns wort.

the study says clomipramine lowers Expression ,     im guessing thats the same as activity or levels? same thing. anyhow im gonna try and get clomipramine out for OCD.



#77 farshad

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Posted 27 August 2018 - 08:06 PM

Lofepramine ''prodrug'' of imipramine so chances are it inhibits crh.



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#78 farshad

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Posted 28 August 2018 - 10:57 AM

btw seroquel didn't work for me either for som reason. I would stick to the meds on comment #74 or #69 for reducing crh.



#79 farshad

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Posted 04 September 2018 - 01:26 PM

would clomipramine work in reducing CRH in these cases? as it has been shown to lower CRH mRNA expression in the PVN.

CRH-secreting tumor , An increase in CRH gene dose (a gene duplication), from increased CRH mRNA or protein expression, or CRH constitutive protein activity.

Obviously it would work in the case of increased mRNA but what about the other 4 possible causes?

 



#80 farshad

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Posted 05 September 2018 - 06:22 PM

constitutive protein activity -  "Constitutive" activity means that the regulation of the enzyme's activity is gone, it's been mutated or something to allow it to always be active.

Consider an enzyme: An mRNA molecule is translated to make a protein, which has enzymatic activity on some substrate, and can be regulated.

Expression is a readout for the translation of the mRNA into stable protein. 

 

protein expression - DNA > mRNA > Protein expression(CRH) , it is possible to have low mRNA but high protein expression becuase a single mRNA molecule can stick around and be translated many times. And protein has longer half-life.

 

CRH-gene duplication - gene duplication, if the promoter regions (the DNA that communicates with proteins that tells the mRNA synthesis machinery when and for how long to make that particular gene's mRNA) and/or the enhancer regions (the DNA that adds nuances to what the promoters do) are copied along with the gene, you can predict that the expression of the duplicate will mirror that of the original. If not, maybe the duplicate is just turned off, maybe it picks up signals from promoters/enhances in the new region it gets duplicated into? All options.

Additionally some genes are tightly regulated so that the "dose" of that particular protein doesn't get to high or to low. If this is the case of a gene that gets duplicated, feedback mechanism may kick in and change the total amount of protein that gets made.

 

CRH-Secreting tumor - a tumor secreting a certain substance, if that substance is a protein or peptide, then yes, it has to go through transcription (DNA --> RNA), and translation (RNA--> protein) (fortunately CRH is a Peptide hormone). Since cortisol is not a protein, or peptide, it is a steroid hormone, it is synthesized (by proteins in the cell that did have to follow the DNA --> RNA--> Protein route), from other molecules that the cell takes up. The ability to synthesize these molecules is not unique to tumor cells, although the regulation of the synthesis may be drastically altered.

 


Edited by farshad, 05 September 2018 - 07:21 PM.


#81 farshad

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Posted 05 September 2018 - 08:19 PM

 

 

Corticotropin-releasing hormone (CRH; previously known as corticotropin-releasing factor) is the central regulator of the hypothalamic-pituitary-adrenal (HPA) axis, which is the main organizer of the body’s response to stress.15 Stress induces the hypothalamic production and release of CRH, which then causes the activation of the CRH receptor (CRHR) type 1 (CRHR-1) in the anterior pituitary to stimulate ACTH release, as well as proopiomelanocortin (POMC) expression and processing. 1,2,6 ACTH stimulates the production and secretion of cortisol (humans) or corticosterone (rodents) by the adrenal cortex. These steroids regulate the body’s response to counteract effects of the stressor and suppress the HPA through the negative feedback mechanism. CRH/POMC expression can also be activated by the cytokines interleukin (IL)-1, IL-6 and tumour necrosis factor (TNF)-α, thus involving the immune system in the central regulation of the HPA axis.7 In addition, CRH together with related urocortin (URC) peptides regulate behavioural, autonomic, endocrine, reproductive, cardiovascular, gastrointestinal and metabolic functions both on the central and on the peripheral levels, and CRH has immunosuppressive effects via the HPA.6,812 It is also accepted that peripheral CRH and related peptides have predominantly proinflammatory functions,13,14 and in this way differ from their central immunosuppressive activity.2 However, recent data also suggest that the peripheral CRH may have dual effects: a direct, short-term proinflammatory function and an indirect, remote anti-inflammatory function.1518

 

I think I have finaly solved my issue . St johns wort and clomipramine should do it. in fact clomi should do it alone..strong enuf

 

1 question left is: is it possible for there to be a mutation that causes excess protein activation on its own toward CRHR1 without the need of CRH? I suck at explaining but the answer is probably no.

 

Im currently almost 40 days on st johns worth, it takes 8 weeks for CRH to reduce expression from it so..

 

I have a doctor appointment soon and I will ask for clomipramine which reduces CRH expression way more than st johns wort and faster and stronger.

 

anyhow.. if anyone has any tips or suggestions or anything im forgetting regarding this issue , lemme know.

 


Edited by farshad, 05 September 2018 - 08:22 PM.


#82 farshad

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Posted 05 September 2018 - 10:42 PM

too much crhr1 activity without CRH (possible causes?)

/

high CRH protein expression

 

1.  clomipramine  (decreases CRH mrRNA)

2. carbamazepin (inhibits hypothalamic CRH)  

3. valproate/valpoic acid (decreases CRF1 binding)

 

 

 

 

(1. )clomipramine should decrease the amount of CRH being made, so it clomi doesent work then I dont have a trouble with too much CRH being made.

 

(2. )If I have low mRNA but high CRH protein expression due to lacking enzyme regulating it then carbamazepine should help, it inhibits CRH straight from where it is made.

 

but if still no success..

 

then I obviously have something wrong with just my CRHR1 receptor(s).

 

(3.)and I will try valproate becuase it decreases CRHR1 activity or something . (any better suggestions  for decrease CRHR1 im open )

 

 

 


Edited by farshad, 05 September 2018 - 10:44 PM.


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#83 farshad

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Posted 05 September 2018 - 11:54 PM

just cause clomipramien lowers crh  mRNA production in the pvn doesent mean it will do so wherever the tumor is secreting .. hm 

 

gotta have a full body MRI-Scan just to make sure i keep saying it but delaying it 



#84 farshad

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Posted 06 September 2018 - 12:05 PM

what if you have multiple hypermorphic mutation towards CRH (IE , Increased mRNA CRH production, CRH-gene duplication &  lack the enzyme regulating CRH protein expression) making it overwhelming for your body to regulate so you end up feeling the effects, your body is trying to regulate but it is just too much too fast being made and the body system that make sure everything is regulated/balanced can't keep up.


Edited by farshad, 06 September 2018 - 12:06 PM.


#85 farshad

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Posted 06 September 2018 - 02:44 PM

CRH is not the same as cortisol. CRH is a peptide hormone (so it does have to be transcribed and translated) while cortisol is a steroidal hormone and is synthesized from metabolic precursors.

Hormonal regulation involves lots of different cell types, and signals throughout the body. But yes it is possible that a perfect gene duplication could result in twice as much CRH being made, and additional mutations inhibiting the regulatory and feedback mechanisms would allow for excessive levels of the peptide to circulate in the body.

As far as the location of the overproduction of a hormone and its effect on different parts of the body goes. Steroidal hormones are generally permeable through the blood brain barrier, so the location of their over production won't necessarily protect the body or brain from exposure. Peptide hormones are not freely permeable through the blood brain barrier and need specific transport proteins to get them across. So there could be different effects depending where in the body the excess peptide hormone is being secreted.

 

 

 

(1. )clomipramine should decrease the amount of CRH being made, so it clomi doesent work then I dont have a trouble with too much CRH being made.

 

(2. )If I have low mRNA but high CRH protein expression due to lacking enzyme regulating it then carbamazepine should help, it inhibits CRH straight from where it is made.

 

but if still no success..

 

then I obviously have something wrong with just my CRHR1 receptor(s).

 

(3.)and I will try valproate becuase it decreases CRHR1 activity or something . (any better suggestions  for decrease CRHR1 im open )

+ Full body MRI scan

 

 


Edited by farshad, 06 September 2018 - 02:46 PM.


#86 farshad

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Posted 07 September 2018 - 02:11 AM

bingo!! https://www.psypost....l-anxiety-47544

 

''The researchers focused on the endogenous cannabinoid (endocannabinoid or eCB) system, which include natural lipid signaling molecules that bind to cannabinoid receptors in the brain. Cannabinoid (type 1) receptors control stress-mediating circuits by inhibiting neurotransmitter release — a sort of gating mechanism to keep anxiety in check.

In contrast to the stress-reducing properties of endocannabinoids, a peptide molecule called corticotropin-releasing factor (CRF) activates the stress response and promotes increased sensitivity to stress and anxiety when activated over and over again.''

 

 

 

 

getting closer.



#87 farshad

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Posted 07 September 2018 - 12:39 PM

The researchers studied rats that were genetically selected for higher alcohol drinking and also display an anxiety-like phenotype. These rats exhibit a mutation in a gene called Crhr1 that increases CRF (type 1) receptor signaling. (from the study above)

 

hm....... I have a CB1 mutation (leading to low levels of it) but I dont think thats the issue. I also have a mutation in my CRHR1 gene like these rats in the study :(

but CRHR1 can only be activated with CRH right? ...so I wonder how the mutation works, does the DNA just make excess CRH and it goes towards CRHR1 and what about CRHR2 etc? im guessing CRHR2 stays normal.

So it ends up with what ive always thought, I have Excess high CRH-CRHR1 signaling, by inhibiting CRH mRNA basically stop CRH from being made (with clomipiramine hopefully) it will decrease CRHR1.. I hope to god(figure of speech I dont belive in god) im right and this  works.


Edited by farshad, 07 September 2018 - 12:43 PM.


#88 farshad

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Posted 07 September 2018 - 04:05 PM

hypermorphic mutation (increased GENE function = More CRH-CRHR1 signaling)



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#89 farshad

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Posted 10 September 2018 - 06:23 PM

Feedback inhibition is one of the most important function of proteins. Due to feedback inhibition, a cell is able to know whether the amount of a product is enough for its subsistence or there is a lack of the product (or there is too much product). 

''But yes it is possible that a perfect gene duplication could result in twice as much CRH being made, and additional mutations inhibiting the regulatory and feedback mechanisms would allow for excessive levels of the peptide to circulate in the body.''

 

''a regulatory enzyme is an enzyme in a biochemical pathway which, through its responses to the presence of certain other biomolecules, regulates the pathway activity. This is usually done for pathways whose products may be needed in different amounts at different times, such as hormone production. Regulatory enzymes exist at high concentrations (low Vmax) so their activity can be increased or decreased with changes in substrate concentrations.''

 
 
 
For gene duplication, if the promoter regions (the DNA that communicates with proteins that tells the mRNA synthesis machinery when and for how long to make that particular gene's mRNA) and/or the enhancer regions (the DNA that adds nuances to what the promoters do) are copied along with the gene, you can predict that the expression of the duplicate will mirror that of the original. If not, maybe the duplicate is just turned off, maybe it picks up signals from promoters/enhances in the new region it gets duplicated into? All options
 
''some genes are tightly regulated so that the "dose" of that particular protein doesn't get to high or to low. If this is the case of a gene that gets duplicated, feedback mechanism may kick in and change the total amount of protein that gets made.''
 
 
but if you have multiple mutations it will be too much  for your body to regulate.


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#90 farshad

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Posted 11 September 2018 - 09:03 PM

Cortisol/Glucocorticoids inhibit CRH production in the hypothalamus. However, in the amygdala – a brain region involved in the behavioral stress response – cortisol increases CRH, leading to anxiety and fear [R].

 

ok so my theory is.. Im making excess CRH due to multiple mutations (hypermorphic) and since cortisol inhibits CRH if it becomes too much, but according to the study above, cortisol increases CRH in the amygdala which leads to increased CRHR1 receptor activity there. 

 

So too much CRH > cortisol inhibits> but then increases CRH in the amygdala> leading to increased CRHR1 activity there > my 24/7anxiety

 

But dont crhr1 receptors downregulate if it becomes too much? ugh who knows....

 

so either that or..

 

too much CRH being made too much for cortisol to be able to inhibit and lead to dysfunction.

 

either way   the 3  drugs i previously mentioned should help (1 clomipramine 2 carbamazepine 3 valproate which decreases CRHR1 receptors in the amygdala)sodium valproate, a drug known to inhibit CRH production, valproate decreased CRH release , Valproate is a GABA reuptake inhibitor and potentiates the action of GABA, an inhibitory neurotransmitter. In experimental animals, long-term treatment with valproate decreased corticotropin-releasing hormone (CRH) concentrations in the hypothalamic median eminence and reduced CRH mRNA in the hypothalamic paraventricular nucleus (1)I


Edited by farshad, 11 September 2018 - 09:08 PM.






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