hpa-axis and MS disease progression research

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hpa-axis and MS disease progression research

Postby CaliReader » Sun Dec 30, 2012 3:41 pm

Hi folks,

Greetings from California. I hope everyone had a good holiday.

Since diagnosis, I've been researching, looking for possible measures to take. The most complex but interesting material I found so far is contained in articles I found related to the endocrine system and excess cortisol produced in MS. I'm looking for help understanding what this means for us and fighting the disease.

Apparently, at least to MS researchers, it is common knowledge that the hypothalamo-pituitary-adrenocortical axis, a major endocrine system process, changes in people with MS. This results in too much of the stress hormone cortisol.

Is this issue somehow dealt with by the usual treatments? Has anyone asked an endocrinologist about it? Are there tests or treatments? The only thing I can find in the usual sources is advice to reduce stress.

Here are the research abstracts I found. The links are to PubMed. I'm hoping this might be useful. Thanks very much for any response.

Cynthia

Hypothalamo-pituitary-adrenal axis activity predicts disease progression in multiple sclerosis.
http://www.ncbi.nlm.nih.gov/pubmed/15935481

Fatigue and regulation of the hypothalamo-pituitary-adrenal axis in multiple sclerosis.
http://www.ncbi.nlm.nih.gov/pubmed/15710856

Dysregulation of the hypothalamo-pituitary-adrenal axis is related to the clinical course of MS
http://www.ncbi.nlm.nih.gov/pubmed/10489039

Impaired hypothalamic-pituitary-adrenal axis activity in patients with multiple sclerosis.
http://www.ncbi.nlm.nih.gov/pubmed/19064876

Stress and hypothalamic-pituitary-adrenal axis function in experimental autoimmune encephalomyelitis and multiple sclerosis
http://www.ncbi.nlm.nih.gov/pubmed/17602841

Stress regulation in multiple sclerosis: current issues and concepts.
http://www.ncbi.nlm.nih.gov/pubmed/17439878

The role of stress-response systems for the pathogenesis and progression of MS.
http://www.ncbi.nlm.nih.gov/pubmed/16214415
conclusion: hyperactivity of the HPA axis has been linked to neurodegeneration and increased disability.

Neuropsychiatric manifestations of depression in multiple sclerosis: neuroinflammatory, neuroendocrine, and neurotrophic mechanisms in the pathogenesis of immune-mediated depression
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181849/
HPA is linked to depression
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Re: hpa-axis and MS disease progression research

Postby Anonymoose » Sun Dec 30, 2012 5:21 pm

Hi Calireader,

I'm currently obsessed with hpa axis dysregulation in MS too. However, I am more concerned with aldosterone's influence than cortisol's at the moment. I'm starting an aldosterone blocker in January and after my neurologist and I decide whether or not it's working, I'll start looking into ways to correct hpa axis dysregulation. Some possibilities for correction include vagus nerve stimulation and vagus nerve decompression. I'm sure I'll probably start working with an endocrinologist too.

You can find info and related links (some of the one's you posted! lol) in threads in CCSVI and general forums. From what i gather, there aren't many others interested in hpa axis dysregulation here. It's good to have a co-obsessor!

Welcome!

oh...I think dexamethasone can inhibit cortisol production...in normal people anyway. St. John's Wort might do it too but with MS damage hanging over your head, I'm not sure you want to depend on a maybe...
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Re: hpa-axis and MS disease progression research

Postby CaliReader » Mon Dec 31, 2012 8:34 am

Thanks for the welcome Anonymoose. Thanks also for the feedback and advice.
I won't say I'm glad to be here, but I am extremely grateful for the people here and the excellent set of resources compiled on this board.

Aldosterone also looks interesting. I'm hoping an endocrinologist will give me the basics of the HPA axis and what treatments might be available if any. It looks like an avenue of research that has not been addressed by neurology.
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Re: hpa-axis and MS disease progression research

Postby Anonymoose » Wed Mar 06, 2013 8:33 am

I finally gathered the audacity to intrude upon the time/mind of the head of a MS research program. I didn't want to waste too much of his time so I just blurted a few things in an email and asked that he think about the possibility that aldosterone/hpa-axis dysregulation drive the development and progression of MS. Then I quickly hit send before I could come to my senses and delete everything.

His response was that he agreed the hpa-axis abnormalities may be involved in the "activation of the attack sequence." He said he would think about it but couldn't promise to redirect his research.

Wow. That was much more of a response than I ever expected...more than my own neurologist's. Maybe there is something to this idea...or maybe he was just kindly blowing me off. :P

Anyway, that's that. I don't think I'll have the guts to do that again so I hope he really does think about it...and issues a report that tells me if I'm barking up the wrong tree or not.
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Re: hpa-axis and MS disease progression research

Postby jimmylegs » Wed Mar 06, 2013 9:14 am

reminds me of what my neuro said about elevated uric acid, anon. i didn't get it at the time but it does make sense now (as one of many consequences of poor nutrient status, zinc in particular).

this was interesting:

Enhancement of social isolation-induced aggressive behavior of young mice by zinc deficiency. (2008)
http://www.ncbi.nlm.nih.gov/pubmed/18374363
Abstract
Neuropsychological behavior via activation of the hypothalamic-pituitary-adrenal (HPA) axis was analyzed using young mice fed a zinc-deficient diet for 2 weeks. Serum corticosterone concentration was significantly increased after 2-week zinc deprivation, whereas zinc concentration in the brain was not decreased. In the resident-intruder test, the rate of mice that exhibited aggressive behavior to the total mice was significantly higher in isolated zinc-deficient mice than in isolated control mice. The duration of aggressive behavior was more in isolated zinc-deficient mice. These results indicate that aggressive behavior of young mice elicited by social isolation is enhanced by zinc deficiency. On the other hand, social isolation-induced aggressive behavior was enhanced in isolated pair-fed mice with food restriction that can activate the HPA axis. Serum corticosterone concentration was also significantly higher in isolated zinc-deficient mice. To see the effect of the increased serum corticosterone on behavioral abnormality, neurotransmitter concentrations in brain tissue were checked. The concentrations of glutamate and GABA in brain tissue were significantly higher in both grouped and isolated zinc-deficient mice. Furthermore, the concentration of extracellular glutamate in the amygdala before the resident-intruder test was significantly higher in isolated zinc-deficient (aggressive) mice and the higher concentration was maintained during the test. The changes in neurotransmitter homeostasis, probably via the increase in serum corticosterone, seem to be linked to aggressive behavior elicited by social isolation in zinc deficiency
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Re: hpa-axis and MS disease progression research

Postby Anonymoose » Wed Mar 06, 2013 10:56 am

jimmylegs wrote:reminds me of what my neuro said about elevated uric acid, anon. i didn't get it at the time but it does make sense now (as one of many consequences of poor nutrient status, zinc in particular).

this was interesting:

Enhancement of social isolation-induced aggressive behavior of young mice by zinc deficiency. (2008)
http://www.ncbi.nlm.nih.gov/pubmed/18374363
Abstract
Neuropsychological behavior via activation of the hypothalamic-pituitary-adrenal (HPA) axis was analyzed using young mice fed a zinc-deficient diet for 2 weeks. Serum corticosterone concentration was significantly increased after 2-week zinc deprivation, whereas zinc concentration in the brain was not decreased. In the resident-intruder test, the rate of mice that exhibited aggressive behavior to the total mice was significantly higher in isolated zinc-deficient mice than in isolated control mice. The duration of aggressive behavior was more in isolated zinc-deficient mice. These results indicate that aggressive behavior of young mice elicited by social isolation is enhanced by zinc deficiency. On the other hand, social isolation-induced aggressive behavior was enhanced in isolated pair-fed mice with food restriction that can activate the HPA axis. Serum corticosterone concentration was also significantly higher in isolated zinc-deficient mice. To see the effect of the increased serum corticosterone on behavioral abnormality, neurotransmitter concentrations in brain tissue were checked. The concentrations of glutamate and GABA in brain tissue were significantly higher in both grouped and isolated zinc-deficient mice. Furthermore, the concentration of extracellular glutamate in the amygdala before the resident-intruder test was significantly higher in isolated zinc-deficient (aggressive) mice and the higher concentration was maintained during the test. The changes in neurotransmitter homeostasis, probably via the increase in serum corticosterone, seem to be linked to aggressive behavior elicited by social isolation in zinc deficiency

Jimmylegs,
I am cracking up because no matter how many times I read that study, I can't figure out the point you are trying to make. Duurrr. I dug up these studies linking zinc to hippocampus/hpa-axis though. I don't know what to think about zinc supplementation now... :confused:
http://onlinelibrary.wiley.com/doi/10.1 ... 587.x/full
Zinc is concentrated in certain CNS excitatory tracts, especially in hippocampal mossy fibres where it has been suggested to modulate synaptic transmission and plasticity. Using rat mossy fibre synaptosomes depolarized by 4-aminopyridine, we show here that low zinc concentrations restore the membrane potential and reduce glutamate release. Both effects arose from activation of ATP-sensitive potassium channels (KATP), since they were mimicked by the KATP opener diazoxide and antagonized by the KATP blocker tolbutamide. Using recombinant channels expressed in COS-7 cells, we confirmed that micromolar zinc did activate KATP of the type found in hippocampus. We tested the hypothesis that this action of zinc could be beneficial during an ischaemic challenge by using organotypic hippocampal slice cultures. When zinc was applied at micromolar concentrations during a brief anoxic-hypoglycaemic episode, it significantly attenuated the ensuing neuronal death, whereas chelation of endogenous zinc markedly aggravated cell damage. Protective effect of zinc was mediated through KATP, as was shown by using the opener diazoxide and the blocker tolbutamide. Thus, by activating pre-synaptic KATP channels, zinc protects neurones from hyper-excitation, excessive transmitter release and exitotoxicity, and may thus act as an endogenous neuroprotector in conditions such as epilepsy or stroke.

This one seems to conflict with your mouse-agression study. I don't get it.
http://onlinelibrary.wiley.com/doi/10.1 ... ated=false
Abstract
Approximately 10% of total zinc in the brain exists in synaptic vesicles of glutamatergic neurons; however, the function of vesicular zinc is poorly understood. The presynaptic action of zinc against excitatory and inhibitory neurotransmission was studied in rat hippocampus using in vivo microdialysis. When the hippocampal CA3 region was perfused with 10–300 μM ZnCl2, the level of glutamate in the perfusate was decreased, whereas the level of γ-aminobutyric acid (GABA) was increased. Chelation of endogenous zinc with CaEDTA increased the glutamate level in the perfusate but decreased the GABA level, suggesting that zinc released into the synaptic cleft acts differentially on glutamatergic and GABAergic neurons in the CA3 region. The increase of GABA level by zinc was antagonized by 2,3-dioxo-6-nitro-1,2.3,4-tetrahydrobenzo(f)quinoxaline-7-sulphonamide (NBQX), an antagonist of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptors, but not affected by MK801, an antagonist of N-methyl-d-aspartate (NMDA) receptors, and verapamil, a blocker of voltage-dependent calcium channels. The present study suggests that zinc enhances GABA release via potentiation of AMPA/kainate receptors in the CA3 region, followed by a decrease in presynaptic glutamate release in the same region. Zinc seems to be an inhibitory neuromodulator of glutamate release. © 2003 Wiley-Liss, Inc.

http://www.plosone.org/article/info%3Ad ... ne.0055384
Zinc ions highly concentrate in hippocampus and play a key role in modulating spatial learning and memory. At a time when dietary fortification and supplementation of zinc have increased the zinc consuming level especially in the youth, the toxicity of zinc overdose on brain function was underestimated. In the present study, weaning ICR mice were given water supplemented with 15 ppm Zn (low dose), 60 ppm Zn (high dose) or normal lab water for 3 months, the behavior and brain zinc homeostasis were tested. Mice fed high dose of zinc showed hippocampus-dependent memory impairment. Unexpectedly, zinc deficiency, but not zinc overload was observed in hippocampus, especially in the mossy fiber-CA3 pyramid synapse. The expression levels of learning and memory related receptors and synaptic proteins such as NMDA-NR2A, NR2B, AMPA-GluR1, PSD-93 and PSD-95 were significantly decreased in hippocampus, with significant loss of dendritic spines. In keeping with these findings, high dose intake of zinc resulted in decreased hippocampal BDNF level and TrkB neurotrophic signaling. At last, increasing the brain zinc level directly by brain zinc injection induced BDNF expression, which was reversed by zinc chelating in vivo. These results indicate that zinc plays an important role in hippocampus-dependent learning and memory and BDNF expression, high dose supplementation of zinc induces specific zinc deficiency in hippocampus, which further impair learning and memory due to decreased availability of synaptic zinc and BDNF deficit.

http://link.springer.com/article/10.100 ... -y?LI=true
Our results indicated that Zn treatment showed proconvulsant activity and increased BBB permeability, possibly changing prooxidant/antioxidant balance and neuronal excitability during seizures.

http://link.springer.com/article/10.100 ... -9?LI=true
Zinc deficiency causes abnormal glucocorticoid secretion and increases depression-like behavior in animals. Neuropsychological symptoms are observed prior to the decrease in Zn2+ signal in the hippocampus under zinc deficiency. This paper summarizes that hippocampal Zn2+ signaling serves to maintain healthy brain and that glucocorticoid signaling, which is responsive to zinc homeostasis in the living body, is linked to the pathophysiology of depression.
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Re: hpa-axis and MS disease progression research

Postby jimmylegs » Wed Mar 06, 2013 1:30 pm

just that zinc deficiency and hpa dysregulation seem to be linked.

as for the studies you found, i don't pretend to know even a fraction of a fraction of all the ins and outs of zinc biochemistry, and yet i feel comfortable making three statements:

1. zinc deficiency bad (eg serum levels in most of the 'normal' range and below)
2. zinc toxicity bad (eg serum levels in say, the 20s to mid 30s - in umol/L - or higher)
3. optimal zinc good (eg high teens (18-19) and a little higher than serum copper)

wonder what the daily intakes would be in those groups of rats in the study you posted above, if they were converted from parts per million in water, to mg/kg body weight...
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Re: hpa-axis and MS disease progression research

Postby Anonymoose » Thu Mar 07, 2013 4:31 pm

AngII receptor blockers (which correct hpa axis dysregulation) increase production of PEDF, a protein believed to be able to regenerate myelin.

http://www.ncbi.nlm.nih.gov/pubmed/16574788
Angiotensin II type 1 (AT(1)) receptors are expressed within organs of the hypothalamo-pituitary-adrenal (HPA) axis and seem to be important for its stress responsiveness. Secretion of CRH, ACTH, and corticosterone (CORT) is increased by stimulation of AT(1) receptors. In the present study, we tested whether a blockade of the angiotensin II system attenuates the HPA axis reactivity in spontaneously hypertensive rats. Spontaneously hypertensive rats were treated with candesartan (2 mg/kg), ramipril (1 mg/kg), or mibefradil (12 mg/kg) for 5 wk. In addition to baseline levels, CORT and ACTH responses to injection of CRH (100 microg/kg) were monitored over 4 h. mRNA of CRH, proopiomelanocortin, AT(1A), AT(1B), and AT(2) receptors was quantified by real-time PCR. All treatments induced equivalent reductions of blood pressure and had no effect on baseline levels of CORT and ACTH. However, both candesartan and ramipril significantly reduced CRH-stimulated plasma levels of ACTH (-26 and -15%) and CORT (-36 and -18%) and lowered hypothalamic CRH mRNA (-25 and -29%). Mibefradil did not affect any of these parameters. Gene expression of AT(1A), AT(1B), and AT(2) receptors within the HPA axis was not altered by any drug. We show for the first time that antihypertensive treatment by inhibition of AT(1) receptors or angiotensin-converting enzyme attenuates HPA axis reactivity independently of blood pressure reduction. This action is solely evident after CRH stimulation but not under baseline conditions. Both a reduced pituitary sensitivity to CRH and a down-regulation of hypothalamic CRH expression have the potential to reduce HPA axis activity during chronic AT(1) blockade or angiotensin-converting enzyme inhibition.

http://www.futurity.org/health-medicine ... ve-damage/
The protein, pigment epithelium-derived factor (PEDF), has well-known anti-tumor generating properties. But its role in promoting growth of a type of brain cell and regenerating the protective myelin sheaths around nerve cells had not been known, the researchers say.
Straight from the Source
Read the original study
DOI: 10.1523/​JNEUROSCI.0628-12.2012
“Our investigation found that PEDF plays a key role in accelerating regeneration of the myelin sheath,” says study senior author David Pleasure, professor of neurology and pediatrics, and director of the Institute for Pediatric Regenerative Medicine, a collaborative initiative of the University of California, Davis, School of Medicine and Shriners Hospitals for Children Northern California.
“That makes PEDF a strong drug-therapy candidate, because it appears to encourage the regeneration of a type of brain cell called oligodendocyte and is able to repair the damage caused by demyelinative diseases, including MS.”

http://www.ncbi.nlm.nih.gov/pubmed/21330424
Significance of pigment epithelium-derived factor levels with angiotensin II type 1 receptor blockers in patients with successful coronary stent implantation.
Sugihara M, Miura S, Takamiya Y, Kiya Y, Arimura T, Iwata A, Kawamura A, Nishikawa H, Yamagishi S, Saku K.
Source
Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.
Abstract
Pigment epithelium-derived factor (PEDF) and pentosidine have received growing attention as sensitive biomarkers of the progression of atherosclerosis. The present study was performed to evaluate the utility of these biomarkers for assessing the effects of angiotensin II type 1 receptor blockers (ARBs). Sixty-three patients with coronary artery disease (CAD) following successful stent implantation were divided into an ARB group (n = 50), who initially received valsartan or olmesartan immediately following stent implantation, and a non-ARB group (n = 13) according to their blood pressure (BP) at baseline. Measurement of BP and blood sampling was performed prior to (at baseline) and 6-8 months following stent implantation (at follow-up). There were no significant differences in the baseline characteristics between the groups. Although there were no differences in the percentage of diameter re-stenosis between the groups, the BP level in the ARB group at follow-up showed a significant reduction and reached the target BP. The levels of plasma PEDF were significantly increased at follow-up in the ARB group, but not in the non-ARB group, while there were no differences in the levels of pentosidine between the groups. Changes in BP (ΔBP = BP at follow-up minus BP at baseline) were not associated with ΔPEDF. In conclusion, PEDF may be a useful biomarker for assessing the effects of ARBs independent of a reduction in BP.
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Re: hpa-axis and MS disease progression research

Postby CaliReader » Tue Mar 19, 2013 2:42 pm

So I just spoke with my endocrinologist about a thyroid issue and asked him about the HPA-axis and MS.

Did not get a good response. Apparently 'MS is not a hormonal disease'. The best he could offer me is that problems with the HPA axis and MS would come after treatment with high dose steroids and last not more than a year typically.

Nothing to see here.

I don't want to pay out of pocket for an academic endocrinologist, but I thought it was interesting.
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Re: hpa-axis and MS disease progression research

Postby Anonymoose » Tue Mar 19, 2013 3:01 pm

That's not encouraging at all. Hormones are part of everything at some level! They regulate our bodies. Sigh. I understand his/her reluctance to think hormones are all ms is about...but to ignore the hormonal issues seen in ms is disappointing and mind boggling. You would think he'd be excited to be able to do something to help. Maybe he/she hasn't mucked through much ms literature and doesn't know.

Hope he/she helped you with the thyroid thing anyway. :roll:
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Re: hpa-axis and MS disease progression research

Postby CaliReader » Tue Mar 19, 2013 5:10 pm

Thanks Anonymoose!

Re the thyroid thing, I was just checking in and requesting a lab. No big deal.

Still, I hope the new generation of endocrinologists are more willing to help neuro patients. The research quoted at the start of this thread seems pretty clear that MS leads to hormone disruption... or hormone disruption leads to MS. It's a chicken egg question. But even if the cause is immune attack in the brain, hormone disruption as a symptom can lead to some strong bad effects, which could then be treated.
If the doctors would cross their turf boundaries and allow it.

I was hoping for better from my endocrinologist.
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