Some Interesting Connections

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Re: Some Interesting Connections

Postby Annesse » Fri Oct 18, 2013 8:40 am

PointsNorth wrote:Found within a CFS/ME forum:

http://informahealthcare.com/doi/abs/10 ... 9709105320


Thanks PN~I have the same study in my book.

Recent cerebrospinal fluid studies have confirmed that protease are also involved in CFS and fibromyalgia. These diseases have been named after their primary symptoms, but a lack of protease will lead to the same findings in CFS and fibro that we have seen in MS; low B12, high homocysteine, missing essential amino acids, subacute combined degeneration of the spinal cord, elevated prolactin, autonomic nervous system dysfunction, elevated TNF, IL-6, and interferon-gamma, activated dendritic cells, dysregulated iron, white matter lesions, activated kynurenine pathway, low vitamin D, brain gray matter loss, low dopamine, etc.

Here are a few studies that demonstrate this.

ELEVATED TNF

In the following study researchers found that fibromyalgia (FM) patients had higher levels than normal of TNF.

Cytokine patterns in fibromyalgia and their correlation with clinical manifestations.
Bazzichi, L., A. Rossi, G. Massimetti, G. Giannaccini, T. Giuliano, F. De Feo, A. Ciapparelli, L. Dell’Osso, S. Bombardieri. 2007. Clin Exp Rheumatol. 25(2):225-30.

"Higher levels of …TNF-alpha were found in FM patients than in controls. Significant correlations between the biochemical parameters and clinical data were found.”




The following study identified elevated tumor necrosis factor in chronic fatigue syndrome.


Dysregulated expression of tumor necrosis factor in chronic fatigue syndrome: interrelations with cellular sources and patterns of soluble immune mediator expression.
Patarca, R., N.G. Kilmas, S. Lugtendorf, M. Antoni, M.A. Fletcher. 1994. Clin Infect Dis. 18(Suppl.1):S147-53.


“Among a group of 70 individuals who met the criteria established by the Centers for Disease Control and Prevention (Atlanta) for chronic fatigue syndrome (CFS), 12%-28% had serum levels exceeding 95% of control values for tumor necrosis factor (TNF) alpha…”




ACTIVATED KYNURENINE PATHWAY


The following study confirms kynurenine pathway (KYN-p) activity is involved in fibromyalgia.
Kynurenine pathway activity linked to fibromyalgia fatigue.


Boomershine, C.S., D. Titova, C. Zhu, A.M. Oeser, M.W. Calcutt, A. Bian, T. Gebretsadik, R. Johnson, C. Michael Stein. 2009.

“Increased KYN-p activity is associated with FM fatigue in humans and a murine model. IDO enzyme inhibition may be a novel method for treating FM fatigue.”




AUTONOMIC NERVOUS SYSTEM DYSFUNCTION


The following study concludes that autonomic dysfunction is “inherent” to fibromyalgia (FM).


Autonomic dysfunction in fibromyalgia assessed by the Composite Autonomic Symptoms Scale (COMPASS).
Solano, C., A. Martinez, L. Becerril, A. Vargas, J. Figueroa, C. Navarro, C. Ramos-Remus, M. Martinez-Lavin. 2009. J Clin Rheumatol 15(4):172-6.

“Patients with FM have multiple nonpain symptoms related to different expressions of autonomic dysfunction. There is a correlation between a questionnaire that measures FM severity (FIQ) and an autonomic dysfunction questionnaire (COMPASS). Such correlation suggests that autonomic dysfunction is inherent to FM.”




MISSING ESSENTIAL AMINO ACIDS


Studies confirm that fibromyalgia (FM) patients lack numerous essential amino acids (AAs). In the following study entitled “Altered amino acid homeostasis in subjects affected by fibromyalgia” researchers found that fibromyalgia patients had significantly lower levels of the essential amino acids valine, methionine, phenylalanine, and threonine. The patients also lacked the amino acid tyrosine. Tyrosine is an amino acid the body makes from the essential amino acid phenylalanine.


Altered amino acid homeostasis in subjects affected by fibromyalgia.
Bazzichi, L., L. Palego, G. Giannaccini, A. Rossi, F. De Feo, C. Giacomelli, L. Betti, L. Giusti, G. Mascia, S. Bombardieri, A. Lucacchini. 2009. Clin Bioche. 42(10-11):1064-70.

“Significant lower plasma…tyrosine (Tyr), valine, methionine, phenylalanine and threonine concentrations, and the sum of essential AAs were observed in FM patients vs. healthy controls…”




LOW DOPAMINE

In the following study published in The Journal of Pain, Dr. Patrick Wood, a former scientific advisor for the National Fibromyalgia Association, found that the brains of people with fibromyalgia syndrome (FMS) have reduced levels of dopamine.

Reduced presynaptic dopamine activity in fibromyalgia syndrome demonstrated with positron emission tomography: a pilot study.
Wood, P.B., J.C. Patterson 2nd, J.J. Sunderland, K.H. Tainter, M.F. Glabus, D.L. Lilien. 2007. J Pain 8(1):51-8. Epub 2006 Oct 4.

“It appears that FMS might be characterized by a disruption of dopaminergic neurotransmission…An association between FMS and reduced dopamine metabolism within the pain neuromatrix provides important insights into the pathophysiology of this mysterious disorder.”




BRAIN GRAY MATTER LOSS


Low dopamine will lead to brain gray matter loss.In the following study published in the Journal of Neuroscience researchers found that the longer the individuals had fibromyalgia, the greater the brain gray matter loss, with each year of fibromyalgia being equivalent to 9.5 times the loss in normal aging.

Accelerated brain gray matter loss in fibromyalgia patients: premature aging of the brain?
Kuchinad, A. P. Schweinhardt, D.A. Seminowicz, P.B. Wood, B.A. Chizh, M.C. Bushnell. 2007. J Neurosci 11;27(15):4004-7.


“We found that fibromyalgia patients had significantly less total gray matter volume and showed a 3.3 times greater age-associated decrease in gray matter than healthy controls. The longer the individuals had had fibromyalgia, the greater the gray matter loss, with each year of fibromyalgia being equivalent to 9.5 times the loss in normal aging.”



VIAMIN D DEFICIENCY

Vitamin D deficiency is also common in fibromyalgia, as the following study states.

Vitamin D deficiency is associated with anxiety and depression in fibromyalgia.
Armstrong, D.J., G.K. Meenagh, I. Bickle, A.S. Lee, E.S. Curran, M.B. Finch. 2007. Clin Rheumatol. (4):551-4.

“Vitamin D deficiency is common in fibromyalgia and occurs more frequently in patients with anxiety and depression. The nature and direction of the causal relationship remains unclear, but there are definite implications for long-term bone health.”


ACTIVATED DENDRITIC CELLS

Plasmacytoid dendritic cells (pDCs) are also involved in the pathogenesis of chronic fatigue syndrome (CFS). One study found that CFS patients had approximately 4.7 times as many pDCs as the controls (De Meirleir, 2013).


ELEVATED PROLACTIN


Researchers in the following study found that prolactin was “significantly increased” in patients with fibromyalgia.

Biochemical changes in fibromyalgia.
Samborski, W., T. Stratz, T. Schochat, P. Mennet, W. Müller. 1996. Z Rheumatol. 55(3):168-73.

“In comparison to healthy controls, patients with fibromyalgia revealed…significantly increased level of prolactin.”
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Re: Some Interesting Connections

Postby Annesse » Sat Oct 19, 2013 7:37 am

ALZHEIMER'S DISEASE, SEIZURES, QUINOLINIC ACID, AND THE KYNURENINE PATHWAY


Patients with Alzheimer's disease are also prone to seizures. As we have seen, research has implicated the involvement of protease in Alzheimer's disease. A lack of protease would lead to activation of the kynurenine pathway. In the following study the researchers stated there is now evidence of the kynurenine pathway (KP) being associated with Alzheimer's disease and that quinolinic acid (QUIN) may be one of the critical factors in the pathogenesis of neuronal damage in Alzheimer's.



Redox Rep. 2002;7(4):199-206.
Implications of the kynurenine pathway and quinolinic acid in Alzheimer's disease.
Guillemin GJ, Brew BJ.


"The kynurenine pathway (KP) is a major route of L-tryptophan catabolism leading to production of a number of biologically active molecules. Among them, the neurotoxin quinolinic acid (QUIN), is considered to be involved in the pathogenesis of a number of inflammatory neurological diseases. Alzheimer's disease is the major dementing disorder of the elderly that affects over 20 million peoples world-wide...There is now evidence for the KP being associated with Alzheimer's disease. Disturbances of the KP have already been described in Alzheimer's disease...Senile plaques in Alzheimer's disease are associated with evidence of chronic local inflammation (especially activated microglia)..Together, these data imply that QUIN may be one of the critical factors in the pathogenesis of neuronal damage in Alzheimer's disease. This review describes the multiple correlations between the KP and the neuropathogenesis of Alzheimer's disease and highlights more particularly the aspects of QUIN neurotoxicity, emphasizing its roles in lipid peroxidation and the amplification of the local inflammation."
http://www.ncbi.nlm.nih.gov/pubmed/12396664




In the following study the researchers stated that seizures are common in Alzheimer's disease and that quinolinic acid (QA) increases seizures and concurrently contributes to neuronal loss via excitotoxicity.

Int J Tryptophan Res. 2010; 3: 169–173.
Published online 2010 October 15. doi: 10.4137/IJTR.S4603PMCID: PMC3195251
Alzheimer’s and Seizures: Interleukin-18, Indoleamine 2,3-Dioxygenase and Quinolinic Acid


"Emergent seizures are common in Alzheimer’s disease (AD)...interferon-gamma (IFNy)...increases indoleamine 2,3-dioxygenase (IDO) and subsequent quinolinic acid (QA) in microglia. QA increases seizures and concurrently contributes to neuronal loss via excitotoxicity..."
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195251/





In the following study the researchers stated the kynurenine pathway has been shown to be involved in Alzheimer's disease (AD) pathogenesis, and that oxidative stress, glutamate excitotoxicity and the neuroinflammation involved in AD pathogenesis have been revealed to be connected to the kynurenine pathway

J Cell Mol Med. 2010 Aug;14(8):2045-54. doi: 10.1111/j.1582-4934.2010.01123.x. Epub 2010 Jul 12.
Kynurenines, neurodegeneration and Alzheimer's disease.


"Alzheimer's disease (AD) is one of the major causes of dementia...The kynurenine (KYN) pathway is the major route for the metabolism of the essential amino acid tryptophan. Some of the metabolites of this pathway, such as 3-hydroxykynurenine and quinolinic acid, are known to have neurotoxic properties, whereas others, such as kynurenic acid, are putative neuroprotectants. Among other routes, the KYN pathway has been shown to be involved in AD pathogenesis, and connections to other known mechanisms have also been demonstrated. Oxidative stress, glutamate excitotoxicity and the neuroinflammation involved in AD pathogenesis have been revealed to be connected to the KYN pathway..."
http://www.ncbi.nlm.nih.gov/pubmed/20629991




Following is an additional study on the involvement of IDO, the kynurenine pathway and quinolinic acid in Alzheimer's disease.

Neuropathol Appl Neurobiol. 2005 Aug;31(4):395-404.
Indoleamine 2,3 dioxygenase and quinolinic acid immunoreactivity in Alzheimer's disease hippocampus.
Guillemin GJ, Brew BJ, Noonan CE, Takikawa O, Cullen KM.


"...The present immunohistochemical study provides evidence that the kynurenine pathway is up-regulated in Alzheimer's disease (AD) brain, leading to increases in the excitotoxin quinolinic acid (QUIN). We show that the regulatory enzyme of the pathway leading to QUIN synthesis, indoleamine 2,3 dioxygenase (IDO) is abundant in AD compared with controls. In AD hippocampus, both IDO- and QUIN-immunoreactivity (-IR) was detected in cortical microglia, astrocytes and neurones, with microglial and astrocytic expression of IDO and QUIN highest in the perimeter of senile plaques. QUIN-IR was present in granular deposits within the neuronal soma of AD cortex and was also seen uniformly labelling neurofibrillary tangles. Our data imply that QUIN may be involved in the complex and multifactorial cascade leading to neuro-degeneration in AD..."
http://www.ncbi.nlm.nih.gov/pubmed/16008823
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Re: Some Interesting Connections

Postby Annesse » Sun Oct 20, 2013 8:39 am

LOW GABA AND SPASTICITY

Low GABA levels can lead to a common symptom in MS--spasticity, or muscle stiffness and spasms. GABA is needed for the muscles to relax.


Baclofen and Gabapentin (Neurontin) are two of the medications used to treat spasticity in patients with MS. Baclofen is a derivative of GABA and Gabapentin increases GABA concentration in the brain, as the following study confirms.


The impact of gabapentin administration on brain GABA and glutamate concentrations: a 7T ¹H-MRS study.
Cai K, Nanga RP, Lamprou L, Schinstine C, Elliott M, Hariharan H, Reddy R, Epperson CN.
Neuropsychopharmacology. 2012 Dec;37(13):2764-71. doi: 10.1038/npp.2012.142. Epub 2012 Aug 8.

“…Gabapentin, marketed for the treatment of seizures and neuropathic pain, has been shown to increase in vivo GABA concentration in the brain…”



LOW GABA AND SOUND SENSITIVITY

Low GABA levels can also lead to increased “sound sensitivity”, which is often experienced by MS patients. In the following study published in The Journal of Neuroscience the researchers discovered that blocking GABA increased sensitivity to sound.


Blocking GABAergic inhibition increases sensitivity to sound motion cues in the inferior colliculus.
McAlpine, D. and A.R. Palmer. 2002. The Journal of Neuroscience 22(4):1443–1453.

“These results indicate that GABAergic inhibition strongly influences the context-dependent processing of low-frequency binaural signals in the IC.”
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Re: Some Interesting Connections

Postby PointsNorth » Sun Oct 20, 2013 9:36 am

Hi Annesse,

I have tried baclofen for spasticity but it has no effect and it makes other symptoms I have e.g. balance, fatigue much worse! I take slow release magnesium which helps take the 'edge' off but not anything more. Do you have any suggestions?

Thx, PN
Albany 2010. Brooklyn 2011
Calcitriol+D3 2013-
Hurry up and wait.
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Re: Some Interesting Connections

Postby Annesse » Sun Oct 20, 2013 11:24 am

Hi PN~There are some good herbs that can address the induction of IDO by interferon-gamma and thus help regulate the kynurenine pathway (KP). This would help restore GABA and also help with all of the other problems being created by upregulation of the KP.

Tumeric and rosemary would be good. Tumeric does need to be consumed with some type of fat.I think I posted a study on the thread for tumeric tea. Rosemary can also be consumed as a tea.



Here is a study on rosmarinic acid (a compound of rosemary) and its effects on IDO.


Biochem Pharmacol. 2007 May 1;73(9):1412-21. Epub 2006 Dec 20.
Rosmarinic acid inhibits indoleamine 2,3-dioxygenase expression in murine dendritic cells.
Lee HJ, Jeong YI, Lee TH, Jung ID, Lee JS, Lee CM, Kim JI, Joo H, Lee JD, Park YM.


"Indoleamine 2,3-dioxygenase (IDO), a key enzyme that catalyses the initial and rate-limiting step in the degradation of the tryptophan, is simultaneously expressed in murine dendritic cells and macrophages stimulated with interferon-gamma (IFN-gamma). In the present study, we investigated whether rosmarinic acid (RA), which is suggested to exhibit anti-oxidant and anti-cyclooxygenase properties, could suppress the functional expression of IDO in murine bone marrow-derived dendritic cells (BMDCs) stimulated with IFN-gamma. Treatment with RA reduced intracellular expression of IDO both in IFN-gamma-activated BMDCs in vitro and in CD11c(+)CD8alpha(+) DCs in vivo tumor-bearing mice model. Consequently, we obtained evidence that RA suppresses the functional activity of IDO and blocks the IDO-dependent T cell suppression. In IFN-gamma-mediated induction of IDO transcription, activation of the signal transducer and activator of transcription 1 (STAT1) is important to be express IDO in IFN-gamma-stimulated BMDCs. In this study, we demonstrated that the RA could also suppress IFN-gamma-induced STAT1 activation. These novel findings provide a new insight into that RA as a pharmacological and transcriptional inhibitor of IDO is worthy of clinical application as well as further investigation for IDO regulation."


Here is one on curcumin (a component of tumeric).

J Biol Chem. 2009 Feb 6;284(6):3700-8. doi: 10.1074/jbc.M807328200. Epub 2008 Dec 15.
Curcumin suppresses the induction of indoleamine 2,3-dioxygenase by blocking the Janus-activated kinase-protein kinase Cdelta-STAT1 signaling pathway in interferon-gamma-stimulated murine dendritic cells.
Jeong YI, Kim SW, Jung ID, Lee JS, Chang JH, Lee CM, Chun SH, Yoon MS, Kim GT, Ryu SW, Kim JS, Shin YK, Lee WS, Shin HK, Lee JD, Park YM.

"Indoleamine 2,3-dioxygenase (IDO) catalyzes the initial and rate-limiting step in the degradation of tryptophan and is strongly induced in interferon-gamma (IFNgamma)-stimulated dendritic cells (DCs). IDO has recently been established as a key enzyme in T-cell suppression-mediated immune tolerance to tumors. STAT1 phosphorylation appears to play an important role in the control of IDO expression by IFNgamma, but the precise regulatory mechanism remains obscure. Here we present a novel mechanism of IFNgamma-induced IDO expression in bone marrow-derived dendritic cells. In addition, we demonstrate that curcumin, an active component of turmeric, significantly inhibited the induction of IDO expression and activity by IFNgamma. We found that curcumin suppressed STAT1 activation by directly inhibiting Janus-activated kinase 1/2 and protein kinase Cdelta phosphorylation in bone marrow-derived DCs, suppressing the subsequent translocation and binding of STAT1 to the GAS element of the IRF-1 promoter. Coincident with these inhibitory effects on IFNgamma-induced IDO expression, curcumin reversed IDO-mediated suppression of T-cell responses. Our results, thus, suggest that down-regulation of IDO in DCs is an important immunomodulatory property of curcumin that may be exploited therapeutically in the control of cancers."


Personally, I would only use whole organic herbs and foods to restore health.
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Re: Some Interesting Connections

Postby PointsNorth » Sun Oct 20, 2013 12:14 pm

Thanks Annesse,

I will try and report back. I will try placing curcumin/turmeric into gel caps. And/or eat more Indian food.

PN
Albany 2010. Brooklyn 2011
Calcitriol+D3 2013-
Hurry up and wait.
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Re: Some Interesting Connections

Postby Anonymoose » Sun Oct 20, 2013 12:50 pm

Annesse wrote:Hi PN~There are some good herbs that can address the induction of IDO by interferon-gamma and thus help regulate the kynurenine pathway (KP). This would help restore GABA and also help with all of the other problems being created by upregulation of the KP.

Tumeric and rosemary would be good. Tumeric does need to be consumed with some type of fat.I think I posted a study on the thread for tumeric tea. Rosemary can also be consumed as a tea.



Here is a study on rosmarinic acid (a compound of rosemary) and its effects on IDO.


Biochem Pharmacol. 2007 May 1;73(9):1412-21. Epub 2006 Dec 20.
Rosmarinic acid inhibits indoleamine 2,3-dioxygenase expression in murine dendritic cells.
Lee HJ, Jeong YI, Lee TH, Jung ID, Lee JS, Lee CM, Kim JI, Joo H, Lee JD, Park YM.


"Indoleamine 2,3-dioxygenase (IDO), a key enzyme that catalyses the initial and rate-limiting step in the degradation of the tryptophan, is simultaneously expressed in murine dendritic cells and macrophages stimulated with interferon-gamma (IFN-gamma). In the present study, we investigated whether rosmarinic acid (RA), which is suggested to exhibit anti-oxidant and anti-cyclooxygenase properties, could suppress the functional expression of IDO in murine bone marrow-derived dendritic cells (BMDCs) stimulated with IFN-gamma. Treatment with RA reduced intracellular expression of IDO both in IFN-gamma-activated BMDCs in vitro and in CD11c(+)CD8alpha(+) DCs in vivo tumor-bearing mice model. Consequently, we obtained evidence that RA suppresses the functional activity of IDO and blocks the IDO-dependent T cell suppression. In IFN-gamma-mediated induction of IDO transcription, activation of the signal transducer and activator of transcription 1 (STAT1) is important to be express IDO in IFN-gamma-stimulated BMDCs. In this study, we demonstrated that the RA could also suppress IFN-gamma-induced STAT1 activation. These novel findings provide a new insight into that RA as a pharmacological and transcriptional inhibitor of IDO is worthy of clinical application as well as further investigation for IDO regulation."


Here is one on curcumin (a component of tumeric).

J Biol Chem. 2009 Feb 6;284(6):3700-8. doi: 10.1074/jbc.M807328200. Epub 2008 Dec 15.
Curcumin suppresses the induction of indoleamine 2,3-dioxygenase by blocking the Janus-activated kinase-protein kinase Cdelta-STAT1 signaling pathway in interferon-gamma-stimulated murine dendritic cells.
Jeong YI, Kim SW, Jung ID, Lee JS, Chang JH, Lee CM, Chun SH, Yoon MS, Kim GT, Ryu SW, Kim JS, Shin YK, Lee WS, Shin HK, Lee JD, Park YM.

"Indoleamine 2,3-dioxygenase (IDO) catalyzes the initial and rate-limiting step in the degradation of tryptophan and is strongly induced in interferon-gamma (IFNgamma)-stimulated dendritic cells (DCs). IDO has recently been established as a key enzyme in T-cell suppression-mediated immune tolerance to tumors. STAT1 phosphorylation appears to play an important role in the control of IDO expression by IFNgamma, but the precise regulatory mechanism remains obscure. Here we present a novel mechanism of IFNgamma-induced IDO expression in bone marrow-derived dendritic cells. In addition, we demonstrate that curcumin, an active component of turmeric, significantly inhibited the induction of IDO expression and activity by IFNgamma. We found that curcumin suppressed STAT1 activation by directly inhibiting Janus-activated kinase 1/2 and protein kinase Cdelta phosphorylation in bone marrow-derived DCs, suppressing the subsequent translocation and binding of STAT1 to the GAS element of the IRF-1 promoter. Coincident with these inhibitory effects on IFNgamma-induced IDO expression, curcumin reversed IDO-mediated suppression of T-cell responses. Our results, thus, suggest that down-regulation of IDO in DCs is an important immunomodulatory property of curcumin that may be exploited therapeutically in the control of cancers."


Personally, I would only use whole organic herbs and foods to restore health.


Are you sure IDO inhibition is something that would be good for pwms? I think I've experienced a relapse due to IDO inhibition. The science folks seem to think its protective.
http://www.ncbi.nlm.nih.gov/m/pubmed/15206723/
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Re: Some Interesting Connections

Postby Annesse » Sun Oct 20, 2013 2:36 pm

Hi Anonymoose~I think the problem is the expression of IDO is being accelerated and sustained. This upregulates the kynurenine pathway and leads to toxic metabolites such as quinolinic acid. In the first paragraph of the following study the researchers explain the biological significance of the upregulation of the kynurenine pathway by IDO when the immune response is activated. This shouldn't be a continuous activation though. Continuous activation of IDO by interferon gamma will lead to the accelerated degradation of tryptophan and the production of toxic metabolites, which, as the following study explains, are involved in many disease states.

Just like tumor necrosis factor, IDO is a normal necessary part of the immune system. You don't want to completely block it, but if its expression is being accelerated and sustained, it does need to be downregulated. The possible ramifications of not controlling IDO are an increased risk of cancer, seizures, IBS, oligodendrocyte loss, depression, anxiety, bipolar disorder, low GABA, elevated glutamate, hearing loss, increased risk of suicide, etc.

Int J Tryptophan Res. 2009; 2: 1–19.
Published online 2009 January 8.

Kynurenine Pathway Metabolites in Humans: Disease and Healthy States
Yiquan Chen1 and Gilles J. Guillemin1,2

"Tryptophan is an essential amino acid that can be metabolised through different pathways, a major route being the kynurenine pathway. The first enzyme of the pathway, indoleamine-2,3-dioxygenase, is strongly stimulated by inflammatory molecules, particularly interferon gamma. Thus, the kynurenine pathway is often systematically up-regulated when the immune response is activated. The biological significance is that 1) the depletion of tryptophan and generation of kynurenines play a key modulatory role in the immune response; and 2) some of the kynurenines, such as quinolinic acid, 3-hydroxykynurenine and kynurenic acid, are neuroactive.


The kynurenine pathway has been demonstrated to be involved in many diseases and disorders, including Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, AIDS dementia complex, malaria, cancer, depression and schizophrenia, where imbalances in tryptophan and kynurenines have been found...Under various pathological conditions, an accelerated degradation of tryptophan with an accompanying increase in kynurenines is often observed in the serum, CSF and/or brain tissue...Moreover, the breakdown of tryptophan via the kynurenine pathway is often routed preferentially towards the production of quinolinic acid. The pathologies associated with the up-regulation of the kynurenine pathway include infectious diseases (e.g. HIV), neurological disorders (e.g. AD, HD and ALS), affective disorders (e.g. schizophrenia, depression and anxiety), autoimmune diseases (e.g. MS and rheumatoid arthritis), peripheral conditions (e.g. cardiovascular disease) and malignancy (e.g. haematological neoplasia and colorectal cancer). However, significant elevations in tryptophan levels in lung and breast cancer have also been reported."


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195227/
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Re: Some Interesting Connections

Postby Annesse » Tue Oct 22, 2013 7:34 am

I thought this was a good study as well to explain that the kynurenine pathway can go from neuroprotective to neurotoxic if the compounds of this pathway become unbalanced. As the following study states, the break-up of these compounds' balance can be observed in many disorders, including MS.



J Neural Transm Suppl. 2006;(70):285-304.
Kynurenines, Parkinson's disease and other neurodegenerative disorders: preclinical and clinical studies.
Németh H, Toldi J, Vécsei L.

"The kynurenine pathway is the main pathway of tryptophan metabolism. L-kynurenine is a central compound of this pathway since it can change to the neuroprotective agent kynurenic acid or to the neurotoxic agent quinolinic acid. The break-up of these endogenous compounds' balance can be observable in many disorders. It can occur in neurodegenerative disorders, such as Parkinson's disease, Huntington's and Alzheimer's disease, in stroke, in epilepsy, in multiple sclerosis, in amyotrophic lateral sclerosis, and in mental failures, such as schizophrenia and depression.
http://www.ncbi.nlm.nih.gov/pubmed/17017544



PREMENSTRUAL EXACERBATIONS AND LOW GABA

Low levels of GABA just prior to the onset of the menstrual cycle could also lead to increased symptom severity in women with MS. In the following study the researchers concluded the premenstrual period triggers exacerbations in a subgroup of females with MS.

Eur Neurol. 2002;48(4):204-6.
The premenstrual period and exacerbations in multiple sclerosis.
Zorgdrager A, De Keyser J.

“The aim of this study was to assess whether an association exists between the premenstrual period and exacerbations of multiple sclerosis (MS). The subjects were 56 premenopausal patients with relapsing MS and a regular menstrual cycle. Data over the previous 2 years were gathered from a structured MS database and a comprehensive questionnaire. 42% had exacerbations starting in the premenstrual phase. Within this group the proportion of premenstrual exacerbations was significantly higher than in the remaining period of the menstrual cycle, and in 45% all exacerbations had started during the premenstrual phase…Our results suggest that the premenstrual period triggers exacerbations in a subgroup of females with MS.”




Premenstrual syndrome (PMS) occurs when there is a drop in progesterone levels just prior to the start of the menstrual period. Common symptoms of PMS are anxiety, depression, and irritability. In the following study the researchers found that patients with premenstrual dysphoric disorder, or severe PMS, had low levels of GABA.


Low plasma gamma-aminobutyric acid levels during the late luteal phase of women with premenstrual dysphoric disorder.
Halbreich, U., F. Petty, K. Yonkers, G.L. Kramer, A.J. Rush, K.W. Bibi. 1996. Am J Psychiatry. 153(5):718-20.

“In women with premenstrual dysphoric disorder…plasma GABA levels decreased from the nonsymptomatic, mid-follicular phase to the symptomatic, late luteal phase.”





In the next study from Yale University School of Medicine the researchers confirmed the connection between low GABA and premenstrual dysphoric disorder (PMDD).



Cortical gamma-aminobutyric acid levels across the menstrual cycle in healthy women and those with premenstrual dysphoric disorder: a proton magnetic resonance spectroscopy study.
Epperson, C.N., K. Haga, G.F. Mason, E. Sellers, R. Gueorguieva, W. Zhang, E. Weiss, D.L. Rotham. 2002. Arch Gen Psychiatry. 59(9):851-8.

These data strongly suggest that the GABAergic system is substantially modulated by menstrual cycle phase in healthy women and those with PMDD. Furthermore, they raise the possibility of disturbances in cortical GABA neuronal function and modulation by neuroactive steroids as potentially important contributors to the pathogenesis of PMDD.”





The declining levels of progesterone just prior to the onset of the menstrual cycle are responsible for the low levels of GABA and resulting symptoms found in PMS and MS. The progesterone metabolite, allopregnanolone, is a potent modulator of GABA receptors. In the following study the researchers found that withdrawal from progesterone supplementation increased anxiety and seizure susceptibility, due to declining levels of this potent GABA-modulatory metabolite.



Progesterone withdrawal reduces paired-pulse inhibition in rat hippocampus: dependence on GABA(A) receptor alpha4 subunit upregulation.
Hsu, F.C. and S.S. Smith. 2003. J Neurophysiol. 89(1):186-98.

“Withdrawal from the endogenous steroid progesterone (P) after chronic administration increases anxiety and seizure susceptibility via declining levels of its potent GABA-modulatory metabolite…”
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Re: Some Interesting Connections

Postby Annesse » Wed Oct 23, 2013 7:56 am

ELEVATED GLUTAMATE AND QUINOLINIC ACID

While GABA is the major inhibitory neurotransmitter in the brain, glutamate is the major excitatory neurotransmitter. Not only does quinolinic acid (QUIN) reduce GABA, it increases glutamate, as the following study confirms.

Int J Tryptophan Res. 2010; 3: 157–167.
Understanding the roles of the kynurenine pathway in multiple sclerosis progression.
Chai K. Lim,1 Bruce J. Brew,2,3 Gayathri Sundaram,1 and Gilles J. Guillemin1

“…QUIN is capable of increasing the release of glutamate by neurons and decreasing glutamate uptake by astrocytes and can also inhibit astroglial glutamine synthetase consequently leading to the accumulation of glutamate in the microenvironment and excitotoxicity; QUIN can kill astrocytes resulting in neurotoxicity because of the loss of astrocytic detoxifying function; QUIN is associated with lipid peroxidation. Some studies have also shown that QUIN can potentiate oxidative stress through generating and working synergistically with ROS in the mitochondria.This leads to lipid peroxidation and energy depletion that ultimately results in cell death…”



In the following study from Albert Einstein College of Medicine the researchers stated that glutamate excitotoxicity is known not only to damage neurons, but also the myelin-producing cell of the central nervous system, the oligodendrocyte. The researchers concluded that glutamate excitotoxicity appears to be an important mechanism in autoimmune demyelination.

J Neural Transm Suppl. 2000;(60):375-85.
Glutamate excitotoxicity--a mechanism for axonal damage and oligodendrocyte death in multiple sclerosis?
Werner P, Pitt D, Raine CS.

“Glutamate excitotoxicity…is known not only to damage neurons but also the myelin-producing cell of the central nervous system (CNS), the oligodendrocyte. In multiple sclerosis (MS), myelin, oligodendrocytes and axons are lost or damaged as a result of an inflammatory attack on the CNS...glutamate excitotoxicity appears to be an important mechanism in autoimmune demyelination…”





As the following study confirms, MS patients have "significantly" higher levels of glutamate in their cerebrospinal fluid during relapse.

Arch Neurol. 2003 Aug;60(8):1082-8.
Excitatory amino acids and multiple sclerosis: evidence from cerebrospinal fluid.
Sarchielli P, Greco L, Floridi A, Floridi A, Gallai V.

“Recent evidence suggests an altered glutamate homeostasis in the brain of patients with multiple sclerosis (MS), as seen in experimental models of MS…Cerebrospinal fluid glutamate levels were significantly higher in patients assessed during relapse compared with those of the patients with relapsing-remitting MS examined during the stable clinical phase and the controls…”



In the following study published in Brain the researchers discovered elevated glutamate in acute lesions and concluded that altered glutamate metabolism was present in the brains of multiple sclerosis patients.

Brain. 2005 May;128(Pt 5):1016-25.
Evidence of elevated glutamate in multiple sclerosis using magnetic resonance spectroscopy at 3 T.
Srinivasan R, Sailasuta N, Hurd R, Nelson S, Pelletier D.

“Histopathological reports of multiple sclerosis and its animal models have shown evidence of a link between axonal injury in active lesions and impaired glutamate metabolism...Glutamate concentrations were found to be elevated in acute lesions…These in vivo results support the hypothesis that altered glutamate metabolism is present in brains of multiple sclerosis patients.”
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Re: Some Interesting Connections

Postby Annesse » Thu Oct 24, 2013 8:30 am

QUINOLINIC ACID, GLUTAMATE, AND SUICIDAL BEHAVIOUR


In the following study published in Neuropsychopharmacology the researchers concluded that quinolinic acid is linked to suicidal behaviour.The research showed that people who are suicidal had twice as much quinolinic acid in their bodies as healthy individuals.Those with the strongest desire to commit suicide had the highest levels of the acid. The researchers concluded that the correlation between QUIN and the Suicide Intent Scale indicated that changes in glutamatergic neurotransmission could be specifically linked to suicidality.The increase in glutamate, caused by quinolinic acid, would contribute to important risk factors in suicide such as increased arousal, agitation, and impulsivity.



Neuropsychopharmacology (2013) 38, 743–752; doi:10.1038/npp.2012.248; published online 9 January 2013
Connecting inflammation with glutamate agonism in suicidality.
Sophie Erhardt1, Chai K Lim2, Klas R Linderholm1, Shorena Janelidze3, Daniel Lindqvist3, Martin Samuelsson4, Kristina Lundberg4, Teodor T Postolache5, Lil Träskman-Bendz3, Gilles J Guillemin and Lena Brundin


“…Recent evidence points towards a low-grade inflammation in brains of suicide victims. Inflammation leads to production of quinolinic acid (QUIN) and kynurenic acid (KYNA)…We found that QUIN...was significantly elevated in the CSF of suicide attempters…Moreover, QUIN levels correlated with the total scores on Suicide Intent Scale. There was a significant decrease of QUIN in patients who came for follow-up lumbar punctures within 6 months after the suicide attempt. In summary, we here present clinical evidence of increased QUIN in the CSF of suicide attempters…The correlation between QUIN and the Suicide Intent Scale indicates that changes in glutamatergic neurotransmission could be specifically linked to suicidality.” .

http://www.nature.com/npp/journal/v38/n ... 2248a.html





Research has found that patients with MS have an increased risk of suicide. In the following study the researchers stated that most studies have documented a higher suicide rate in patients with MS.


Suicide risk in multiple sclerosis: A systematic review of current literature

“…Most studies have documented a higher suicide rate in patients with MS compared to the general population…Clinicians should be aware of the fact that suicidality may occur with higher frequency in MS patients, the available data suggest that the risk of self-harm is higher than expected in MS patients."

http://www.sciencedirect.com/science/ar ... 9912002498
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Re: Some Interesting Connections

Postby Annesse » Fri Oct 25, 2013 8:56 am

PRURITIS AND GLUTAMATE

Elevated glutamate would also explain another symptom found in patients with MS--pruritis (also known as itching). According to the National Multiple Sclerosis Society: “Pruritis (itching) may occur as a symptom of MS. It is one of the family of abnormal sensations—such as “pins and needles” and burning, stabbing, or tearing pains—which may be experienced by people with MS. These sensations are known as dysesthesias, and they are neurologic in origin.

Dysesthetic itching may occur suddenly and intensely, but for brief periods. It may be present over any part of the body or face. It is different from the generalized itching that can accompany an allergic reaction, as there is no external skin rash or irritation at the site of itching. Corticosteroid ointments applied to the skin are not helpful in relieving this type of itch.”



In the following study published in Molecular Pain the researchers concluded their findings provided direct evidence that glutamate is the principal excitatory transmitter between C fibers (fibers that transmit sensory information) and gastrin releasing peptide, a key neurotransmitter for itch.

Molecular Pain 2011, 7:47
Glutamate acts as a neurotransmitter for gastrin releasing peptide-sensitive and insensitive itch-related synaptic transmission in mammalian spinal cord.
Kohei Koga1†, Tao Chen1†, Xiang-Yao Li1,2†, Giannina Descalzi1, Jennifer Ling3, Jianguo Gu3 and Min Zhuo1,2


“Itch sensation is one of the major sensory experiences of human and animals. Recent studies have proposed that gastrin releasing peptide (GRP) is a key neurotransmitter for itch in spinal cord…Our findings provide the direct evidence that glutamate is the principal excitatory transmitter between C fibers and GRP positive dorsal horn neurons. Our results will help to understand the neuronal mechanism of itch and aid future treatment for patients with pruritic disease.”
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Re: Some Interesting Connections

Postby Annesse » Sat Oct 26, 2013 7:47 am

GLUTAMATE AND MIGRAINE HEADACHES


Patients with MS often suffer with frequent and debilitating migraine headaches. In the following study from New York University School of Medicine the researchers concluded that migraine is comorbid with MS and that migraine headaches were three-times more common in MS patients than in the general population.


Migraine is comorbid with multiple sclerosis and associated with a more symptomatic MS course.
Kister, I, Caminero AB, et al. 2010. J Headache Pain. 11(5):417-25. doi: 10.1007/s10194-010-0237-9. Epub 2010 Jul 13.

“…Migraine is three-times more common in MS…”




In the following study the researchers stated that findings from human and animal studies suggest that glutamate plays a "key role" in migraine mechanisms.


CNS Neurol Disord Drug Targets. 2007 Aug;6(4):251-7.
The role of glutamate and its receptors in migraine.
Vikelis M, Mitsikostas DD.

"Glutamate (Glu) is the principal excitatory neurotransmitter in the central nervous system. Its receptors are classified into ionotropic receptors, which are ion channels and include NMDA, AMPA and kainate receptors, named after the agonists that selectively bind to them, and metabotropic receptors, which are G-protein coupled receptors. The trigeminal system is considered to play a key role in migraine pathophysiology, trafficking pain signals from the head and face to the trigeminal nucleus caudalis. The role of glutamate in the pathophysiology of migraine is implicated by data from animal and human studies. Animal studies include experiments of cortical spreading depression, studies of c-fos protein expression in trigeminal nucleus caudalis, studies of plasma protein extravasation and electrophysiological studies. Human studies investigating the role of Glu in migraine pathogenesis measured the levels of Glu in plasma, platelets and cerebrospinal fluid, studied its effect on migraine symptoms and examined the effect of Glu in modulating sensitization. Findings from both the animal and the human studies suggest a link between glutamate and migraine and further suggest that glutamate plays a key role in migraine mechanisms...."



HOMOCYSTEINE AND MIGRAINES

Homocysteine has also been linked to migraines. In the following study the researchers found that homocysteine levels were significantly higher in patients with migraine (MA). In addition, the study authors stated they believe homocysteine may be a link between migraine and stroke.

Homocysteine plasma levels in patients with migraine with aura.
Moschiano. F, D’Amico D, Usai S, Grazzi L, Di Stefano M, Ciusani E, Erba N, Bussone G. 2008. Neurol Sci. 29(Suppl. 1):S173-5.

“We investigated homocysteine plasma levels in 136 MA sufferers and in 117 sex-and age-matched controls. Mean homocysteine plasma levels - as well as the proportion of subjects with hyperhomocysteinemia - were significantly higher in patients with MA than in healthy controls. Hyperhomocysteinemia may be a link between MA and ischaemic stroke.”
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Re: Some Interesting Connections

Postby Annesse » Mon Oct 28, 2013 8:33 am

Elevated glutamate is also linked to migraines in patients with fibromyalgia, as the following study confirms.

Cerebrospinal fluid glutamate levels in chronic migraine.
Peres, M.F., E. Zukerman, C.A. Senne Soares, E.O. Alonso, B.F. Santos, M.H. Faulhaber. 2004. Cephalalgia 24(9):735-9.

“Both preclinical and clinical data link glutamate to the migraine pathophysiology. Altered plasma, platelets and cerebrospinal (CSF) glutamate levels have been reported in migraine patients. Chronic migraine is comorbid with several conditions. It has been recently shown chronic migraine comorbidity with fibromyalgia…CSF glutamate demonstrated significantly higher levels in patients with fibromyalgia compared to those without fibromyalgia…Tender points, the hallmark of fibromyalgia…is probably mediated by central sensitization, with increase in CSF glutamate levels.”


GLUTAMATE AND CENTRAL SENSITIZATION


Glutamate mediates central sensitization (Gudin, 2004). Central sensitization is a condition of the nervous system that is associated with the development and maintenance of chronic pain. Research shows that central sensitization is associated with chronic low back pain and chronic neck pain, both of which are associated with MS (O'Connor, 2008).

In the previous study the researchers discussed the association between central sensitization and the “tender points” found in fibromyalgia, due to the increase in glutamate levels. Central sensitization can lead to heightened sensitivities across all senses, not just the sense of touch. MS patients often report other sensitivities, such as those to light and odors.
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Re: Some Interesting Connections

Postby Annesse » Thu Oct 31, 2013 7:14 pm

Additional evidence that patients with MS are unable to properly digest proteins can be found in the following study. The researchers discovered that 40.9% of the MS patients tested had undigested meat fibers in their stools. A lack of protease would explain the undigested meat fibers found in patients with MS, as they would necessary for the digestion of the proteins in meat, as well as the proteins found in other foods.


Multiple sclerosis and malabsorption.
Gupta, J.K., A.P. Ingegno, A.W. Cook, L.P. Pertschuk. 1977. Am J Gas¬troenterol. 68(6):560-5.


"Malabsorption tests were studied in 52 patients with multiple sclerosis. The stools were examined microscopically for fat and undigested meat fibers and were found to be abnormal in 41.6 and 40.9% respectively. Abnormally low five hour excretion of d-xylose was demonstrated in 26.6% cases. Malabsorption of Vitamin B12 was found in 11.9% cases..."

http://www.ncbi.nlm.nih.gov/pubmed/612212
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