Some Interesting Connections

If it's on your mind and it has to do with multiple sclerosis in any way, post it here.

Re: Some Interesting Connections

Postby Annesse » Mon Oct 07, 2013 11:55 am

Tumor necrosis factor is also associated with blood-brain barrier damage, reduced cerebral blood volume, vasoconstriction, and reduced cerebral oxygen metabolism. In the following study on TNF, MS, and blood-brain barrier damage the researchers found that cerebral spinal fluid levels of TNF-alpha were significantly higher in active MS compared to stable MS or other controls and that TNF has well recognized effects on cerebral endothelial cells.

J Neuroimmunol. 1992 May;38(1-2):27-33.
In vivo relationship of tumor necrosis factor-alpha to blood-brain barrier damage in patients with active multiple sclerosis.
Sharief MK, Thompson EJ.


"Tumor necrosis factor-alpha (TNF-alpha) has well recognized effects on cerebral endothelial cells and, therefore, may mediate disruption of blood-brain barrier in patients with multiple sclerosis (MS). To evaluate the in vivo relationship of TNF-alpha to blood-brain barrier impairment in MS, levels of this cytokine in cerebrospinal fluid (CSF) and serum samples from 38 patients with active MS and 48 controls were correlated with CSF to serum albumin ratios. TNF-alpha was detected in the serum of 74% and the CSF of 66% of patients with active MS. CSF levels of TNF-alpha were significantly higher in active MS compared to stable MS or other controls, and were significantly higher than corresponding serum levels. In patients with active MS, only those with detectable TNF-alpha showed signs of blood-brain barrier damage. Moreover, intrathecal levels of TNF-alpha in active MS correlated with albumin ratios and with the degree of barrier damage. Our findings are important in understanding some of the pathological changes in active multiple sclerosis.
http://www.ncbi.nlm.nih.gov/pubmed/1577950





In the following study the researchers found that TNF caused a significant acute reduction in cerebral blood volume and concluded their findings identify vasoconstriction, disrupted tissue homeostasis and damage to the blood-brain barrier as adverse effects of TNF-alpha within the brain.




Brain. 2002 Nov;125(Pt 11):2446-59.
TNF-alpha reduces cerebral blood volume and disrupts tissue homeostasis via an endothelin- and TNFR2-dependent pathway.
Sibson NR, Blamire AM, Perry VH, Gauldie J, Styles P, Anthony DC.

"TNF-alpha expression is elevated in a variety of neuropathologies, including multiple sclerosis, cerebral malaria and HIV encephalitis. However, the consequences of such high cerebral TNF-alpha expression remain unresolved. Here, using MRI, we demonstrate that a focal intrastriatal injection of TNF-alpha causes a significant, acute reduction (15-30%) in cerebral blood volume (CBV), which is dependent on TNF-alpha-type 2 receptor (TNFR2) activation, and can be ameliorated by pre-treatment with a non-specific endothelin (ET) receptor antagonist. An acute breakdown of the blood-cerebrospinal fluid barrier (B-CSF-B) and a delayed breakdown of the blood-brain barrier (BBB) were also observed using contrast-enhanced MRI. Furthermore, a significant reduction in tissue water diffusion was apparent 24 h after intrastriatal injection of TNF-alpha injection, which may indicate compromise of tissue energy metabolism. Prolonged expression of endogenous TNF-alpha, achieved through the use of an adenoviral vector expressing TNF-alpha cDNA (Ad5TNF-alpha(m)), caused a sustained depression in CBV in accordance with the single TNF-alpha bolus data. These findings identify vasoconstriction, disrupted tissue homeostasis and damage to the BBBs as adverse effects of TNF-alpha within the brain, and suggest that antagonists of the endothelin and TNF-alpha type 2 receptors may be therapeutic in TNF-alpha-associated neuropathologies."
http://www.ncbi.nlm.nih.gov/pubmed/12390971








In the following study the researchers concluded their results suggested that TNF may be a "critical" mediator of changes in cerebral circulation and metabolism. The researchers found that tumor necrosis factor led to an acute reduction in cerebral oxygen uptake and a reduction in cerebral blood flow.

Effect of recombinant human tumor necrosis factor-alpha on cerebral oxygen uptake, cerebrospinal fluid lactate, and cerebral blood flow in the rabbit: role of nitric oxide.
J Tureen


"Among the important pathophysiologic alterations in the brain in bacterial meningitis are abnormalities of cerebral circulation and metabolism; however, the precise mechanisms by which these disturbances occur are not completely delineated. It has been recently recognized that cytokines are produced by tissues in the central nervous system in meningitis and play a critical role in the host inflammatory response. Because these mediators are involved in circulatory and metabolic disturbances in other tissues in sepsis, we investigated the role of tumor necrosis factor-alpha in the central nervous system in a rabbit model. We found that injection of recombinant human TNF into the cisterna magna in the rabbit led to an acute reduction in cerebral oxygen uptake and a more prolonged reduction in cerebral blood flow. This was accompanied by an increase in intracranial pressure and an increase in cerebrospinal fluid lactate. Reduction in oxygen uptake and increases in intracranial pressure and CSF lactate were blocked by pretreatment with L-NAME, an inhibitor of nitric oxide synthase. Reduction in cerebral blood flow was not affected by L-NAME treatment and was due to increased cerebrovascular resistance and reduced oxygen demand. These results suggest that TNF may be a critical mediator of changes in cerebral circulation and metabolism..."
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC441444/


In the following study the researchers found that patients with MS had reduced cerebral blood flow and oxygen metabolism and concluded there was a correlation between the number and size of lesions and levels of cognitive impairment and these findings.



Ann Nucl Med. 1998 Apr;12(2):89-94.
Clinical significance of reduced cerebral metabolism in multiple sclerosis: a combined PET and MRI study.
Sun X, Tanaka M, Kondo S, Okamoto K, Hirai S.

"Magnetic resonance imaging (MRI) in patients with multiple sclerosis (MS) has provided major insights into the disease's natural history, and many studies have focussed on possible correlations between MRI findings and the clinical manifestations of MS. In contrast, there are few reports on possible relationships between functional imaging data and cognitive function. The present study assessed the relationship between clinical presentation and combined anatomical and functional imaging data in MS. Twenty patients with definite MS underwent MRI and positron emission tomography (PET) to evaluate cerebral blood flow (rCBF) and oxygen metabolism (rCMRO2). The relationships between these neuroimaging findings and clinical data, including the Expanded Disability Status Scale (EDSS), Mini-mental status scale, Hasegawa Dementia Scale and relapse time, were evaluated with Spearman's rank correlation coefficients. A general reduction in rCBF and rCMRO2 in the gray and white matter were found in the MS patients. EDSS was correlated with the number and size of the lesions on MRI and was negatively correlated with rCMRO2. A correlation between the decrease in rCMRO2 and the level of cognitive impairment was also found. The severity of cerebral hypometabolism was also related to the number of relapses. Morphological and functional findings obtained by MRI and PET are closely related to the clinical status in MS. Our results suggest that measurement of cerebral metabolism in MS has the potential to be an objective marker for monitoring disease activity and to provide prognostic information.


In the following study the researchers discuss the role of TNF in ischemic stroke.

Evolution of Cerebral Tumor Necrosis Factor-α Production During Human Ischemic Stroke
Tiina Sairanen, MD; Olli Carpén, MD, PhD; Marja-Liisa Karjalainen-Lindsberg, MD, PhD; Anders Paetau, MD, PhD; Ursula Turpeinen, PhD; Markku Kaste, MD, PhD; Perttu J. Lindsberg, MD, PhD


Tumor-necrosis factor-α (TNF-α) is a cytokine with potent stimulatory actions in immune and vascular responses. It has been suggested to play a role in a legion of neurological disease, including infectious and immunological diseases such as multiple sclerosis, bacterial meningitis, cerebral malaria, and AIDS, as well as noninfectious acute brain insults like ischemic stroke..."
http://stroke.ahajournals.org/content/32/8/1750.full


In the next study the researchers concluded that circulating TNF-alpha generated during sepsis induced the increase in BBB permeability.

J Med Microbiol. 2001 Sep;50(9):812-21.
Tumour necrosis factor-alpha causes an increase in blood-brain barrier permeability during sepsis.
Tsao N, Hsu HP, Wu CM, Liu CC, Lei HY.

"Blood-brain barrier (BBB) permeability during sepsis with Escherichia coli or Streptococcus pneumoniae was examined in a mouse model and measured by a circulating beta-galactosidase tracer. The leakage of brain microvascular vessels during sepsis was confirmed by transmission electron microscopic examination of brain tissues stained with horseradish peroxidase. The increase of BBB permeability induced by E. coli and S. pneumoniae, which was maximal at 3 h and 12 h after injection, respectively, was transient because of rapid clearance of the bacteria from the blood. Tumour necrosis factor-alpha (TNF-alpha) was stained on microvascular vessels of the brain during sepsis and intravenous injection of recombinant TNF-alpha also increased the BBB permeability. The increase in BBB permeability induced by either E. coli or S. pneumoniae could be inhibited by anti-TNF-alpha antibody. It was concluded that circulating TNF-alpha generated during sepsis induced the increase in BBB permeability."


In the following study the researchers concluded that TNF was also involved in the blood-barrier permeability found in acetaminophen-induced acute liver failure.

Eur J Gastroenterol Hepatol. 2011 Jul;23(7):552-8. doi: 10.1097/MEG.0b013e3283470212.
Tumor necrosis factor-α affects blood-brain barrier permeability in acetaminophen-induced acute liver failure.
Wang W, Lv S, Zhou Y, Fu J, Li C, Liu P.


OBJECTIVES: Cerebral edema is a major cause of death during acute liver failure (ALF), but the exact mechanism of this condition is still not entirely clear. The aim of this study was to investigate the role of tumor necrosis factor α (TNFα) in changing the permeability of the blood-brain barrier (BBB) during acetaminophen (APAP)-induced ALF...


RESULTS: BBB permeability increased in APAP-induced ALF mice and correlated with elevated serum TNFα levels. Electron microscopy of mouse brain tissues revealed tight junction (TJ) disruptions and endothelial cell shrinkage, as well as increased vesicles and vacuoles. In addition, the expression of the TJ-associated protein, occludin, was significantly decreased in APAP-induced ALF mice. Changes in BBB permeability and occludin expression could be prevented by administering anti-TNFα-IgG 2 h after APAP challenge.

CONCLUSION: TNFα plays a critical role in the development of brain edema in APAP-induced ALF. Increased BBB permeability may be due to the loss of the TJ-associated protein occludin."
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Re: Some Interesting Connections

Postby Annesse » Tue Oct 08, 2013 7:48 am

INTERLEUKIN 6 (IL-6)

In addition to TNF, the activated dendritic cells (DC) also produce IL-6. Here is the study I posted earlier on this.


J Neuroimmunol. 1999 Sep 1;99(1):82-90.
Multiple sclerosis is associated with high levels of circulating dendritic cells secreting pro-inflammatory cytokines.
Huang YM, Xiao BG, Ozenci V, Kouwenhoven M, Teleshova N, Fredrikson S, Link H.

“Recent evidence emphasises a pivotal role for dendritic cells (DC) in the control of immunity by priming and tolerising T cells. DC capture and process antigens, express co-stimulatory molecules, migrate to lymphoid organs and secrete cytokines to initiate immune responses…Patients with MS had higher levels of IFN-gamma, TNF-alpha and IL-6 secreting DC than healthy subjects…”





In the following study the researchers concluded that IL-6 participation in the basic MS immune process is confirmed by its elevated concentration in serum and cerebrospinal spinal fluid and its relation to disease severity.


Interleukin-6 concentration in serum and cerebrospinal fluid in multiple sclerosis patients.
Stelmasiak Z, Kozioł-Montewka M, Dobosz B, Rejdak K, Bartosik-Psujek H, Mitosek-Szewczyk K, Belniak-Legieć E.
Med Sci Monit. 2000 Nov-Dec;6(6):1104-8.

“…Increase of Il-6 in serum of MS patients was found…in comparison to the control group...IL-6 participation in the basic MS immune processes is confirmed by its elevated concentration in serum and CSF, its relation to disease severity with the more expressed rise in cerebrospinal fluid.”




IL-6 is involved in the regulation of Th17 cells. Th17 cells are a subtype of CD4+ helper T cells that secrete proinflammatory cytokines such as IL-17. In the following study the researchers stated that Th17 is a key player in the pathogenesis of autoimmune diseases and that dysregulation or overproduction of IL-6 is involved in autoimmune diseases, such as MS, due to its critical role in Th17 regulation.


Eur J Immunol. 2010 Jul;40(7):1830-5. doi: 10.1002/eji.201040391.
IL-6: regulator of Treg/Th17 balance.
Kimura A, Kishimoto T.

“IL-6 is a pleiotropic cytokine involved in the physiology of virtually every organ system. Recent studies have demonstrated that IL-6 has a very important role in regulating the balance between IL-17-producing Th17 cells and regulatory T cells (Treg). The two T-cell subsets play prominent roles in immune functions: Th17 cell is a key player in the pathogenesis of autoimmune diseases and protection against bacterial infections, while Treg functions to restrain excessive effector T-cell responses. IL-6 induces the development of Th17 cells from naïve T cells together with TGF-beta; in contrast, IL-6 inhibits TGF-beta-induced Treg differentiation. Dysregulation or overproduction of IL-6 leads to autoimmune diseases such as multiple sclerosis (MS)…Given the critical role of IL-6 in altering the balance between Treg and Th17 cells, controlling IL-6 activities is potentially an effective approach in the treatment of various autoimmune and inflammatory diseases…”




In the following study the researchers stated that development of Th17 cells is a key event in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), the animal model of MS. The researchers found that IL-6 blockade inhibited the development of EAE and inhibited the induction of Th17 T cells.

Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9041-6. doi: 10.1073/pnas.0802218105. Epub 2008 Jun 24.
IL-6 blockade inhibits the induction of myelin antigen-specific Th17 cells and Th1 cells in experimental autoimmune encephalomyelitis.
Serada S, Fujimoto M, Mihara M, Koike N, Ohsugi Y, Nomura S, Yoshida H, Nishikawa T, Terabe F, Ohkawara T, Takahashi T, Ripley B, Kimura A, Kishimoto T, Naka T.

“The development of Th17 cells is a key event in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a murine model of human multiple sclerosis (MS). Previous studies have demonstrated that an IL-6-dependent pathway is involved in the differentiation of Th17 cells from naïve CD4-positive T cells in vitro. However, the role of IL-6 in vivo in the development of Th17 cells in EAE has remained unclear. In the present study, we found that IL-6 blockade by treatment with an anti-IL-6 receptor monoclonal antibody (anti-IL-6R mAb) inhibited the development of EAE and inhibited the induction of myelin oligodendrocyte glycoprotein (MOG) peptide-specific CD4-positive, CD8-positive, and Th17 T cells, in inguinal lymph nodes. Thus, the protective effect of IL-6 blockade in EAE is likely to be mediated via the inhibition of the development of MOG-peptide-specific Th17 cells and Th1 cells, which in turn leads to reduced infiltration of T cells into the CNS. These findings indicate that anti-IL-6R mAb treatment might represent a novel therapy for human MS.”





The Interferon beta medications used in the treatment of MS have been found to lower IL-6 and TNF. Three interferon beta medications are used in the treatment of MS: Avonex, Bestaseron, and Rebif. Rebif and Avonex are chemically identical. In the following study the researchers concluded that Rebif and Avonex both significantly and equally suppressed TNF and IL-6.

J Neurol Sci. 2011 Aug 15;307 (1-2):41-5 21658727
Quantitative differences in the immunomodulatory effects of Rebif and Avonex in IFN-β 1a treated multiple sclerosis patients.
George P Christophi, Jennifer A Christophi, Ross C Gruber, Cornelia Mihai, Luis J Mejico, Paul T Massa, Burk Jubelt

“Interferon-β (IFN-β) is a current effective treatment for multiple sclerosis (MS) and exerts its therapeutic effects by down-modulating the systemic immune response and cytokine signaling. In clinical practice there are several formulations of interferon including a low dose of IFN-β 1a formulation of 30 μg IM once weekly (Avonex) and a high dose formulation of 44 μg SC three times weekly (Rebif)… Rebif and Avonex both significantly and equally suppressed plasma TNF-α and IL-6 levels…”



CHRONIC SINUSITIS

IL-6 and TNF have both been implicated in chronic sinusitis, which is often reported in patients with MS. In the following study the researchers found that in chronic rhinosinusitis subjects, mucosal levels of IL-6 and TNF-alpha were significantly elevated when compared with control subjects


Am J Rhinol. 2000 Nov-Dec;14(6):367-73.
Interleukin-1 beta, interleukin-5, interleukin-6, interleukin-8, and tumor necrosis factor-alpha in chronic sinusitis: response to systemic corticosteroids.
Lennard CM, Mann EA, Sun LL, Chang AS, Bolger WE.

"Recently, the role of various cytokines in the pathogenesis of chronic rhinosinusitis has come under investigation...In chronic rhinosinusitis subjects, mucosal levels of IL-1 beta, IL-6, IL-8, and TNF-alpha were significantly elevated when compared with control subjects, and levels of IL-5 demonstrated a strong trend toward elevation. In posttreatment chronic rhinosinusitis subjects, levels of IL-6 were significantly decreased when compared with pretreatment levels, and TNF-alpha levels demonstrated a significant trend toward reduction. These findings support the hypothesis that the inflammatory response in chronic rhinosinusitis is associated with elevated levels of pro-inflammatory cytokines, and suggest that oral corticosteroids may exert a beneficial effect by significantly reducing the levels of IL-6 and TNF-alpha."
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Re: Some Interesting Connections

Postby grandsons4 » Tue Oct 08, 2013 8:20 am

Do it naturally.
Zinc suppresses Th17 development via inhibition of STAT3 activation.
We have shown that Zn suppressed CIA development, decreased serum levels of IL-17A, but not those of IFN-γ, and reduced the numbers of Th17 cells, but not those of Th1 cells, in regional lymph nodes. Importantly, IL-6 induced STAT3 phosphorylation in CD4+ T cells was inhibited by Zn treatment in vivo. Moreover, Zn suppressed Th17 cell development and IL-6-induced STAT3 phosphorylation in vitro. Collectively, these results strongly suggested that Zn suppresses Th17- cell development after the induction of CIA. Mechanistic analysis showed that Zn structurally altered STAT3 to inhibit its activation after IL-6 stimulation. Thus, we conclude that Zn directly suppresses STAT3 activation, which in turn inhibits Th17-cell development.
http://m.intimm.oxfordjournals.org/cont ... 5/375.full
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Re: Some Interesting Connections

Postby Annesse » Tue Oct 08, 2013 8:42 am

grandsons4 wrote:Do it naturally.
Zinc suppresses Th17 development via inhibition of STAT3 activation.
We have shown that Zn suppressed CIA development, decreased serum levels of IL-17A, but not those of IFN-γ, and reduced the numbers of Th17 cells, but not those of Th1 cells, in regional lymph nodes. Importantly, IL-6 induced STAT3 phosphorylation in CD4+ T cells was inhibited by Zn treatment in vivo. Moreover, Zn suppressed Th17 cell development and IL-6-induced STAT3 phosphorylation in vitro. Collectively, these results strongly suggested that Zn suppresses Th17- cell development after the induction of CIA. Mechanistic analysis showed that Zn structurally altered STAT3 to inhibit its activation after IL-6 stimulation. Thus, we conclude that Zn directly suppresses STAT3 activation, which in turn inhibits Th17-cell development.
http://m.intimm.oxfordjournals.org/cont ... 5/375.full



Notice the study states that IL-6 induced STAT3 phosphorylation in CD4+T cells.

Research has found that MS patients lack histidine, which is the binding protein for zinc. Histidine is an essential amino acid found in high protein foods, which "protease" digest.

Here is some information from my book on zinc that I previously posted.


"Although zinc is an essential requirement for a healthy body, zinc, like iron, is a heavy metal ion and must be carefully controlled. Heavy metal ions are toxic to cells. Our bodies take great care to make sure metals go only where they need to and in exactly the right amount.

Scientists have discovered that metals, such as zinc, have special “chaperone” proteins that safely escort the metal through the interior of the cell and deliver it to the specific site where it is needed. Zinc also has “binding proteins” to prevent it from accumulating within the cell and poisoning the cell. The essential amino acid histidine, which is lacking in patients with MS, is an essential component of zinc binding proteins, such as ZntR and Zur.


According to Thomas O’Halloran, professor of chemistry at Northwestern University, “The zinc regulatory system is so sensitive and finely tuned-at the femtomolar level-that the metal ions have no chance to float freely in the cell’s cytoplasm before they are bound up in ZntR or Zur. Free floating zinc just doesn’t exist” (Northwestern University, 2001).


In the following study the researchers stated that although zinc is an essential trace element, excess zinc can cause neuronal death. In addition, the researchers concluded that histidine was protective against zinc-induced neurotoxicity.


D-Histidine and L-histidine attenuate zinc-induced neuronal death in GT1-7 cells.
Kawahara M, Sadakane Y, Koyama H, Konoha K, Ohkawara S. 2013. Metallomics. 5, 453-460

“Although zinc (Zn) is an essential trace element, excess Zn causes neuronal death following transient global ischemia and plays a central role in the pathogenesis of vascular-type dementia…both L-histidine and D-histidine exhibit the same neuroprotective activity…that histidine protects against Zn-induced neurotoxicity…”



We know that patients with MS already lack one of the essential components necessary to prevent zinc toxicity, but science doesn’t fully understand the complexities involved in how the body protects itself from zinc, while at the same time benefitting from it, so taking isolated zinc in supplement form could prove harmful."
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Re: Some Interesting Connections

Postby Annesse » Wed Oct 09, 2013 9:17 am

In the following study the researchers discuss the roles that IL-6 and Th17 cells play in "viral persistence". The researchers stated, "We report that Th17 cells preferentially develop in vitro and in vivo in an IL-6 dependent manner..."


J Exp Med. 2009 Feb 16;206(2):313-28. doi: 10.1084/jem.20082030. Epub 2009 Feb 9.
Th17 cells enhance viral persistence and inhibit T cell cytotoxicity in a model of chronic virus infection.
Hou W, Kang HS, Kim BS.
SourceDepartment of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.


"Persistent viral infection and its associated chronic diseases are a global health concern. Interleukin (IL) 17-producing Th17 cells have been implicated in the pathogenesis of various autoimmune diseases, and in protection from bacterial or fungal infection. However, the role of Th17 cells in persistent viral infection remains unknown. We report that Th17 cells preferentially develop in vitro and in vivo in an IL-6-dependent manner after Theiler's murine encephalomyelitis virus infection. Th17 cells promote persistent viral infection and induce the pathogenesis of chronic demyelinating disease. IL-17 up-regulates antiapoptotic molecules and, consequently, increases persistent infection by enhancing the survival of virus-infected cells and blocking target cell destruction by cytotoxic T cells. Neutralization of IL-17 augments virus clearance by eliminating virus-infected cells and boosting lytic function by cytotoxic T cells, leading to the prevention of disease development. Thus, these results indicate a novel pathogenic role of Th17 cells via IL-17 in persistent viral infection and its associated chronic inflammatory diseases."





In the following study the researchers found that CD8+T cells that were activated in the presence of IL-6 displayed greatly suppressed cytotoxic function.


Eur J Immunol. 2009 Jul;39(7):1716-25. doi: 10.1002/eji.200939412.
A Th17-like developmental process leads to CD8(+) Tc17 cells with reduced cytotoxic activity.
Huber M, Heink S, Grothe H, Guralnik A, Reinhard K, Elflein K, Hünig T, Mittrücker HW, Brüstle A, Kamradt T, Lohoff M.

Activation of naive CD8(+) T cells with antigen in the absence of skewing cytokines triggers their differentiation into effector CTL, which induces death of target cells. We show that CD8(+) T cells activated in the presence of the cytokines IL-6 or IL-21 plus TGF-beta similar to CD4(+) T cells, develop into IL-17-producing (Tc17) cells. These cells display greatly suppressed cytotoxic function along with low levels of the CTL markers: T-box transcription factor Eomesodermin, granzyme B and IFN-gamma. Instead, these cells express hallmark molecules of Th17 program including retinoic acid receptor-related orphan receptor (ROR)gammat, RORalpha, IL-21 and IL-23R. The expression of the type 17 master regulator RORgammat is causally linked to Tc17 generation, because its overexpression stimulates production of IL-17 in the presence of IL-6 or IL-21. Both, upregulation of the type 17 program as well as suppression of CTL differentiation are STAT3 dependent. Furthermore, Tc17 cells producing IL-17 but not granzyme B are also detectable in EAE, a mouse model for multiple sclerosis. Our data point to the existence of mutually exclusive CTL and Tc17 developmental pathways in vitro and in vivo."









INTERFERON GAMMA (IFN-g)

Dendritic cells also release interferon gamma (IFN-g).

Research has found that interferon gamma IFN-g inhibits remyelination in demyelinated lesions. In the following study the researchers discovered that central nervous system (CNS) delivery of IFN-g severely suppressed remyelination and impaired clinical recovery.

Brain (2006), 129, 1306–1318
Interferon-g inhibits central nervous system remyelination through a process modulated by endoplasmic reticulum stress.
Wensheng Lin,1 April Kemper,2 Jeffrey L. Dupree,3 Heather P. Harding,4 David Ron4 and Brian Popko1


“Interferon-g (IFN-g) is believed to play a deleterious role in the immune-mediated demyelinating disorder multiple sclerosis. Here we have exploited transgenic mice that ectopically express IFN-g in a temporally controlled manner in the CNS to specifically study its effects on remyelination in the cuprizone-induced demyelination model and in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. CNS delivery of IFN-g severely suppressed remyelination in both models and impaired the clinical recovery of the mice experiencing EAE. These observations correlated with a dramatic reduction of oligodendroglial repopulation in the demyelinated lesions…Thus, these data suggest that IFN-g is capable of inhibiting remyelination in demyelinated lesions…”




In the next study the researchers found that even during clinical remission patients with MS had a significant increase of the proinflammatory cytokines TNF and IFN-g. The study authors concluded their results suggested that even when the disease is clinically silent, inflammatory activity can be observed in MS patients.


Arq Neuropsiquiatr. 2005 Dec;63(4):914-9. Epub 2005 Dec 15.
Cytokines and intrathecal IgG synthesis in multiple sclerosis patients during clinical remission.
Brandão CO, Ruocco HH, Farias Ados S, Oliveira C, Hallal-Longo DE, Mirandola SR, Oliveira EC, Cendes F, Damasceno BP, Santos LM.

“Cytokines and intrathecal IgG synthesis were determined in the cerebrospinal fluid (CSF) and sera to evaluate inflammatory activity in multiple sclerosis (MS) patients during clinical remission. Although the disease was stable, there had been a significant increase of proinflammatory cytokines such as TNFalpha and IFNgamma in the CSF and serum…These results suggest that even when the disease is clinically silent, one can observe inflammatory activity in these MS patients.”
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Re: Some Interesting Connections

Postby Annesse » Thu Oct 10, 2013 9:28 am

Histamine, which has been discussed on the board, has been found to reduce interferon-gamma.
Prokarin, a drug used in the treatment of MS, is a combination of histamine and caffeine. Here is a link to some information on histamine and interferon-gamma and a quote from the link.

http://www.sciencedaily.com/releases/20 ... 133317.htm

"Results showed that histamine reduces the proliferation of myelin autoreactive T lymphocytes and the production of interferon-gamma, a crucial cytokine involved in brain inflammation and demyelination. Additionally, histamine reduced the ability of myelin autoreactive T cells to adhere to inflamed brain vessels, a crucial step in the development of MS."


In the following study the researchers found that histamine also diminished TNF-mediated induction of endothelial adhesion molecules.

J Biol Chem. 2003 Jun 13;278(24):21751-60. Epub 2003 Mar 19.
Histamine antagonizes tumor necrosis factor (TNF) signaling by stimulating TNF receptor shedding from the cell surface and Golgi storage pool.
Wang J, Al-Lamki RS, Zhang H, Kirkiles-Smith N, Gaeta ML, Thiru S, Pober JS, Bradley JR.

Tumor necrosis factor (TNF) activates pro-inflammatory functions of vascular endothelial cells (EC) through binding to receptor type 1 (TNFR1) molecules expressed on the cell surface. The majority of TNFR1 molecules are localized to the Golgi apparatus. Soluble forms of TNFR1 (as well as of TNFR2) can be shed from the EC surface and inhibit TNF actions. The relationships among cell surface, Golgi-associated, and shed forms of TNFR1 are unclear. Here we report that histamine causes transient loss of surface TNFR1, TNFR1 shedding, and mobilization of TNFR1 molecules from the Golgi in cultured human EC. The Golgi pool of TNFR1 serves both to replenish cell surface receptors and as a source of shed receptor. Histamine-induced shedding is blocked by TNF-alpha protease inhibitor, an inhibitor of TNF-alpha-converting enzyme, and through the H1 receptor via a MEK-1/p42 and p44 mitogen-activated protein kinase pathway. Cultured EC with histamine-induced surface receptor loss become transiently refractory to TNF. Histamine injection into human skin engrafted on immunodeficient mice similarly caused shedding of TNFR1 and diminished TNF-mediated induction of endothelial adhesion molecules. These results both clarify relationships among TNFR1 populations and reveal a novel anti-inflammatory activity of histamine."





Histamine has also been found to inhibit the release of TNF by mast cells (MC).


Am J Respir Cell Mol Biol. 1996 Jun;14(6):620-6.
Histamine inhibits tumor necrosis factor alpha release by mast cells through H2 and H3 receptors.
Bissonnette EY.
SourceDepartment of Medicine, University of Alberta, Edmonton, Canada.


"Histamine was one of the first inflammatory mediators thought to be important in the pathophysiology of asthma, but it is not now thought to be a mediator with primary importance in airway constriction. However, histamine has several effects that may be relevant. One of these effects, its immunoregulatory role, has been largely ignored in asthma. Thus, because mast cells (MC) are an important source of histamine and cytokines, the modulation by histamine of the release of one cytokine, tumor necrosis factor alpha (TNF alpha), was investigated. Rat peritoneal MC (PMC) were pretreated with different concentrations of histamine (10(-14) to 10(-4) M) for 2 h before being tested for their TNF alpha-dependent cytotoxicity. A concentration-dependent inhibition of cytotoxicity was observed from 21% at 10(-12) M to 38% at 10(-4) M, reaching a plateau at 10(-8) M. At least 1 h pretreatment with histamine or its presence throughout the cytotoxic assay was required for the inhibitory effect of histamine. This inhibition was abrogated by indomethacin or anti-PGE2, suggesting that PGE2 may be an important mediator in the inhibition of TNF alpha by histamine. To investigate the type of histamine receptor implicated in this effect, PMC were treated for 20 min with H1 (clemastine and diphenhydramine), H2 (ranitidine and cimetidine), or H3 (thioperamide) receptor antagonists before the addition of histamine. H2 or H3 antagonists abrogated the inhibitory effect of histamine on PMC TNF alpha-dependent cytotoxicity. Furthermore, blockage of H2 receptors with ranitidine increased the release of TNF alpha from PMC stimulated with antigen, suggesting that histamine released by MC within 10 min of antigen stimulation downregulates the subsequent release of TNF alpha from the same MC population. These results suggest that histamine may act as an autocrine regulator of cytokine release by MC and thus modulate inflammatory responses in allergic asthma."
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Re: Some Interesting Connections

Postby Annesse » Fri Oct 11, 2013 8:28 am

MS and Parkinson's disease (PD) share a common underlying disease pathway. For instance, patients with PD also have elevated levels of TNF, IL-6, and interferon-gamma. I thought the following study on the association of interferon-gamma with PD and the loss of dopaminergic neurons was especially interesting.

J Neurosci. 2007 Mar 21;27(12):3328-37.
Involvement of interferon-gamma in microglial-mediated loss of dopaminergic neurons.
Mount MP, Lira A, Grimes D, Smith PD, Faucher S, Slack R, Anisman H, Hayley S, Park DS.


"Growing evidence implicates microglia in the loss of dopaminergic neurons in Parkinson's disease (PD). However, factors mediating microglial activation in PD are poorly understood. Proinflammatory cytokines, such as interferon-gamma (IFN-gamma), orchestrate the actions of microglia. We report here that PD patients express significantly elevated levels of IFN-gamma in their blood plasma...Together, these data suggest that IFN-gamma participates in death of dopaminergic neurons by regulating microglial activity.
http://www.ncbi.nlm.nih.gov/pubmed/17376993





TNF has also been implicated in PD and the death of dopaminergic neurons, as the following study confirms.

Exp Neurol. 2001 Jun;169(2):219-30.
Tumor necrosis factor alpha is toxic to embryonic mesencephalic dopamine neurons.
McGuire SO, Ling ZD, Lipton JW, Sortwell CE, Collier TJ, Carvey PM.

"Levels of the proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) are increased in postmortem brain and cerebral spinal fluid from patients with Parkinson's disease (PD). This observation provides a basis for associating TNFalpha with neurodegeneration...These data strongly suggest that TNFalpha mediates cell death in a sensitive population of DA neurons and support the potential involvement of proinflammatory cytokines in the degeneration of DA neurons in PD."

http://www.ncbi.nlm.nih.gov/pubmed/11358437





INTERFERON-GAMMA AND INCREASED KYNURENINE PATHWAY ACTIVITY

The "kynurenine pathway" is a tryptophan degrading pathway. The body has alternate pathways to metabolize the essential amino acid tryptophan. In one pathway, tryptophan is metabolized through the serotonin pathway. In another, called the kynurenine pathway, tryptophan is used to make niacin (B3). The majority of dietary tryptophan (95%) is oxidized through the kynurenine pathway, and just a small portion is used for the synthesis of serotonin.


Indoleamine 2,3 dioxygenase (IDO) is one of the enzymes that degrades tryptophan in the kynurenine pathway. Tryptophan degradation by IDO is normally very moderate, but if the cytokines interferon-gamma and tumor necrosis factor are elevated, IDO can be upregulated. The upregulation of IDO by interferon-gamma and tumor necrosis factor depletes tryptophan and creates an excess of toxic metabolites such as kynurenic acid, kynurenine, and quinolinic acid.


In the following study the researchers concluded that interferon-gamma, “in particular”, induced the enzyme IDO.

FASEB J. 1991 Aug;5(11):2516-22.
Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism.
Taylor MW, Feng GS
.
“…In particular, interferon-gamma (IFN-gamma) induces an enzyme of tryptophan catabolism, indoleamine 2,3-dioxygenase (IDO), which is responsible for conversion of tryptophan and other indole derivatives to kynurenine…”




The following study confirms that kynurenine pathway activity is involved in MS. The researchers found elevated levels of the toxic tryptophan metabolite “kynurenic acid” in patients with MS and concluded their data demonstrated the involvement of the kynurenine system in the pathogenesis of MS.

Acta Neurol Scand. 2005 Aug;112(2):93-6.
Kynurenine metabolism in multiple sclerosis.
Hartai Z, Klivenyi P, Janaky T, Penke B, Dux L, Vecsei L.

“…The concentration of kynurenic acid is elevated in the plasma of MS patients, and there is a tendency to an elevation in the RBC…Our data demonstrate the involvement of the kynurenine system in the pathogenesis of MS…”



Researchers in the following study stated that evidence has progressively emerged suggesting that the kynurenine pathway (KP) is involved in the pathogenesis of autoimmune diseases, especially MS. We would also expect to find the kynurenine pathway involved in Parkinson's disease, due to the elevated levels of interferon-gamma and TNF. As the following study states, "The KP is known to be involved in several neuroinflammatory disorders including...Parkinson's disease."

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

“…The KP is known to be involved in several neuroinflammatory disorders including Alzheimer's disease, amyotrophic lateral sclerosis, AIDS dementia complex, Parkinson's disease, schizophrenia, Huntington's disease and brain tumours…Over the last 2–3 years, some evidence has progressively emerged suggesting that the KP is likely to be involved in the pathogenesis of autoimmune diseases especially MS. Some KP modulators are already in clinical trials for other inflammatory diseases and would potentially provide a new and important therapeutic strategy for MS patients…”




In the following study researchers discovered that the kynurenine pathway neurotoxin “quinolinic acid” was selectively elevated in experimental allergic encephalomyelitis, the animal model of MS.

J Neurochem. 1995 Mar;64(3):1192-6.
Neurotoxin quinolinic acid is selectively elevated in spinal cords of rats with experimental allergic encephalomyelitis.
Flanagan EM, Erickson JB, Viveros OH, Chang SY, Reinhard JF Jr
.
“Experimental allergic encephalomyelitis (EAE) is an autoimmune, animal model of multiple sclerosis (MS) in which demyelination and paralysis are evident. Quinolinic acid (QUIN) is a neurotoxin…formed from tryptophan…Lewis rats inoculated with myelin basic protein developed signs of EAE by day 12, were killed, and their tissues assayed for QUIN by gas chromatography with mass spectrometry. QUIN levels were significantly elevated in the more caudal regions of the spinal cords of animals with EAE…”




The toxic metabolites produced through increased kynurenine pathway activity--kynurenic acid, kynurenine, and quinolinic acid--have been demonstrated to be involved in oligodendrocyte loss, depression, bipolar disorder, seizures, low GABA, elevated glutamate, sensorineural hearing loss, suicide, interstitial cystitis, and irritable bowel syndrome.


In the following study the researchers concluded their data indicated up to 54% reductions in the number of oligodendrocytes after exposure to quinolinic acid.

Brain Res. 2001 Mar 30;896(1-2):157-60.
Oligodendrocyte killing by quinolinic acid in vitro.
Cammer W.

“Quinolinic acid…can kill neurons in vivo and in vitro. To test whether quinolinic acid is toxic to oligodendrocytes, glial cells cultured from the brains of 2-day-old rats were incubated with quinolinic acid at concentrations known to kill neurons. The cells were then fixed and immunostained with MAbO4 to mark immature and mature oligodendrocytes and anti-myelin basic protein (MBP) to mark mature oligodendrocytes. The data indicated up to 54% reductions in the numbers of O4-positive cells in cultures after incubation with quinolinic acid. Apoptosis of O4-positive cells began during the first 6 h, and some of the apoptotic cells became fragmented. Further apoptosis, and clumping of dead MBP-positive oligodendrocytes, occurred during longer incubation with quinolinic acid…”
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Re: Some Interesting Connections

Postby Annesse » Sat Oct 12, 2013 8:30 am

MS, DEPRESSION, AND THE KYNURENINE PATHWAY

Depression is commonly associated with MS. In the following study the researchers stated that mood disturbance and depression occur in more than half of MS patients.

Rev Neurol (Paris). 2009 Mar;165 Suppl 4:S156-62. doi: 10.1016/S0035-3787(09)72128-9.
Depression in multiple sclerosis.The neuropsychiatry of multiple sclerosis.
Lebrun C, Cohen M.

“Mood disturbance and depression occur in more than half of multiple sclerosis patients. It can be diagnosed in established cases, although it can be present early in the disease course. Depression is not clearly related to specific MS brain lesions, but is frequently associated with other symptoms such as fatigue or cognitive impairment. Depression in MS is more frequent than in an age-matched population or in other chronic diseases…”





In the following study, the researchers discussed the major role that the neurotoxic tryptophan metabolites kynurenine and quinolinic acid play in depression. In addition, the study authors stated that research has revealed alterations in brain serotonin levels do not play a major role in depression, especially when compared to activation of the kynurenine pathway.

The researchers also stated that the depression in inflammation-associated depression is a “late” phenomenon that develops over a background of sickness. In other words, you aren’t physically sick because you are depressed; it is the other way around.

Inflammation-associated depression: from serotonin to kynurenine.
Dantzer, R., J.C. O’Connor, M.A. Lawson, K.W. Kelley. 2011. Psychoneuroendocrinology 36(3):426-36. Epub 2010 Oct 30.

“In the field of depression, inflammation-associated depression stands up as an exception since its causal factors are obvious and it is easy to mimic in an animal model…These clinical studies have revealed that depression is a late phenomenon that develops over a background of early appearing sickness. Incorporation of this feature in animal models of inflammation-associated depression has allowed the demonstration that alterations of brain serotoninergic neurotransmission do not play a major role in the pathogenesis. This is in contrast to the activation of the tryptophan degrading enzyme indoleamine 2,3-dioxygenase that generates potentially neurotoxic kynurenine metabolites such as 3-hydroxy kynurenine and quinolinic acid.”



Interferon beta medications have been shown to induce the kynurenine pathway, as the following studies confirm. This would explain the association between depression and interferon beta medications such as Rebif and Avonex. According to the National MS Society, “The FDA advises that Rebif, like all interferon beta products, be used with caution in patients with depression…The FDA also recommends that Avonex be used with caution in patients with depression and mood disorders.”



J Interferon Cytokine Res. 2001 Dec;21(12):1097-101.
IFN-beta1b induces kynurenine pathway metabolism in human macrophages: potential implications for multiple sclerosis treatment.
Guillemin GJ, Kerr SJ, Pemberton LA, Smith DG, Smythe GA, Armati PJ, Brew BJ.


“Interferon-beta(1b) (IFN-beta(1b)) has limited efficacy in the treatment of relapsing-remitting multiple sclerosis (RRMS). The kynurenine pathway (KP) is chiefly activated by IFN-gamma and IFN-alpha, leading to the production of a variety of neurotoxins. We sought to determine whether IFN-beta(1b) induces the KP in human monocyte-derived macrophages, as one explanation for its limited efficacy. Serial dilutions of IFN-beta(1b) (at concentrations comparable to those found in the sera of IFN-beta(1b)-treated patients) were added to human macrophage cultures. Supernatants were collected at various time points and assayed for the KP end product, quinolinic acid (QUIN). The effect of IFN-beta(1b) on the KP enzymes indoleamine 2,3-dioxygenase (IDO)…IFN-beta(1b)…led to increased mRNA expression of both IDO and QUIN production...This study demonstrates that IFN-beta(1b), in pharmacologically relevant concentrations, induces KP metabolism in human macrophages and may be a limiting factor in its efficacy in the treatment of MS. Inhibitors of the KP may be able to augment the efficacy of IFN-beta in MS.”




Eur J Neurol. 2005 Aug;12(8):625-31.
Interferon-beta affects the tryptophan metabolism in multiple sclerosis patients.
Amirkhani A, Rajda C, Arvidsson B, Bencsik K, Boda K, Seres E, Markides KE, Vécsei L, Bergquist J.

Tryptophan and its metabolites are of great interest in understanding the pathogenesis of multiple sclerosis (MS). The total levels of tryptophan and its metabolites, kynurenine and kynurenic acid were determined in plasma…This is the first report of the plasma levels of these analytes in healthy controls and relapsing-remitting MS patients receiving long-term and acute interferon-beta (IFN-beta) treatment. Twenty-four hours post-administration increased kynurenine levels (first IFN MS versus healthy, P = 0.042) and kynurenine/tryptophan ratio (K/T; first IFN MS versus healthy, P =0.027; first IFN MS versus long-term IFN MS, P = 0.036) were found. The long-term IFN MS group had higher K/T ratios at 4 and 12 h post-administration (P = 0.015 and 0.009, respectively). The increase of K/T ratio in the first IFN MS group indicate an induction of the enzyme indolamine-2,3-dioxygenase (IDO), as reported earlier in experimental allergic encephalomyelitis. As IDO is participating in both inflammatory and neurodegenerative processes, further knowledge of its involvement in the pathogenesis of MS is of great importance.”
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Re: Some Interesting Connections

Postby Annesse » Sun Oct 13, 2013 7:50 am

MS, BIPOLAR DISORDER, AND THE KYNURENINE PATHWAY

Bipolar disorder, sometimes known as manic-depressive disorder, is also common in patients with MS. In the following study from Yale University School of Medicine the researchers stated that manic-depressive disorder (MDD) and anxiety disorders are "highly prevalent" among persons who have MS.

Psychiatr Clin North Am. 2007 Dec;30(4):803-17.
Psychiatric issues in multiple sclerosis.
Chwastiak LA, Ehde DM.
SourceDepartment of Psychiatry, Yale University School of Medicine,

"MDD and anxiety disorders are highly prevalent among persons who have MS and have been associated with decreased adherence to MS treatment and poorer functional status and quality of life..."
http://www.ncbi.nlm.nih.gov/pubmed/17938046



In the following study from the Karolinska Institute in Stockholm, Sweden, the institute that awards the Nobel prizes in medicine, the researchers stated that accumulating data suggest a causative link between immune stimulation, disturbed metabolism of tryptophan, and the pathogenesis of bipolar disorder and schizophrenia. In addition, the researchers concluded their own study findings also supported the concept of kynurenine pathway alterations in bipolar disorder and schizophrenia.


J Psychiatr Res. 2013 Nov;47(11):1815-23. doi: 10.1016/j.jpsychires.2013.08.008. Epub 2013 Aug 23.
Activation of kynurenine pathway in ex vivo fibroblasts from patients with bipolar disorder or schizophrenia: Cytokine challenge increases production of 3-hydroxykynurenine.
Johansson AS, Owe-Larsson B, Asp L, Kocki T, Adler M, Hetta J, Gardner R, Lundkvist GB, Urbanska EM, Karlsson H.
SourceDepartment of Neuroscience, Karolinska Institutet, Sweden.


"Accumulating data suggest a causative link between immune stimulation, disturbed metabolism of tryptophan, and pathogenesis of bipolar disorder and schizophrenia. The goal of this study was to examine the production of kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK) and the expression of kynurenine pathway enzymes involved in their synthesis and metabolism in cultured skin fibroblasts obtained from patients with bipolar disorder, schizophrenia or from healthy control individuals. The assessment was performed under basal conditions or following treatment with interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 or their combinations, in cells exposed to exogenous kynurenine. In both groups of patients, the baseline production of KYNA and 3-HK was increased, as compared to control subjects. Case-treatment analyses revealed significant interactions between bipolar case status and IL-1β, IL-6, IFN-γ + TNF-α, or IFN-γ + IL-1β, as well as between schizophrenia case status and IL-1β, IFN-γ + TNF-α, or IFN-γ + IL-1β, in terms of higher 3-HK...In conclusion, our present findings indicate the utility of skin-derived fibroblasts for kynurenines research and support the concept of kynurenine pathway alterations in bipolar disorder and schizophrenia. The increase in ratio between neurotoxic 3-HK and neuroinhibitory/neuroprotective KYNA following exposure to cytokines may account for altered neurogenesis and structural abnormalities characteristic for both diseases."
http://www.ncbi.nlm.nih.gov/pubmed/24012176




In the following study the researchers stated that an unbalanced kynurenine metabolism has been demonstrated in the major psychiatric disorders such as unipolar depression (a major depressive episode that occurs without the manic phase that occurs in the classic form of bipolar disorder), bipolar manic-depressive disorder and schizophrenia, and in drug-induced neuropsychiatric side effects such as interferon-α treated patients.

FEBS J. 2012 Apr;279(8):1375-85. doi: 10.1111/j.1742-4658.2012.08551.x. Epub 2012 Mar 27.
Kynurenines: from the perspective of major psychiatric disorders.
Myint AM.

"Psychiatric disorders are documented to be associated with a mild pro-inflammatory state. Pro-inflammatory mediators could activate the tryptophan breakdown and kynurenine pathway with a shift toward the neurotoxic arm where excitotoxic N-methyl-D-aspartate receptor agonist quinolinic acid is formed. An unbalanced metabolism in terms of neuroprotective and neurotoxic effects, such as reduced kynurenic acid to kynurenine ratio, has been demonstrated in the major psychiatric disorders such as unipolar depression, bipolar manic-depressive disorder and schizophrenia, and in drug-induced neuropsychiatric side effects such as interferon-α treated patients. The changes in serum or plasma are shown to be associated with central changes such as in the cerebrospinal fluid and certain brain areas...In this review the role of this unbalanced kynurenine metabolism through interactions with other neurochemicals is discussed as a major contributing pathophysiological mechanism in psychiatric disorders..."
http://www.ncbi.nlm.nih.gov/pubmed/22404766
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Re: Some Interesting Connections

Postby Annesse » Mon Oct 14, 2013 8:27 am

IRRITABLE BOWEL SYNDROME (IBS), MS, AND THE KYNURENINE PATHWAY


Researchers in the following study, published in Neuroepidemiology, concluded that MS patients have an increased prevalence of irritable bowel syndrome (IBS).



Neuroepidemiology. 2013;40(2):85-92. doi: 10.1159/000343188. Epub 2012 Oct 24.
The utility of administrative data for surveillance of comorbidity in multiple sclerosis: a validation study.
Marrie RA, Yu BN, Leung S, Elliott L, Caetano P, Warren S, Wolfson C, Patten SB, Svenson LW, Tremlett H, Fisk J, Blanchard JF; CIHR Team in the Epidemiology and Impact of Comomrbidity on Multiple Sclerosis

“Although comorbidity is important in multiple sclerosis (MS), few validated methods for its assessment exist. We validated and applied administrative case definitions for several comorbidities in MS…The prevalence of epilepsy, IBD, IBS and migraine is increased in MS versus the general population.”



The following studies confirm that both males and females with irritable bowel syndrome (IBS) have abnormal tryptophan metabolism. In addition, the researchers discovered that the higher the level of kynurenine, the more likely the patients were to suffer with anxiety and depression.


Tryptophan catabolism in females with irritable bowel syndrome: relationship to interferon-gamma, severity of symptoms and psychiatric co-morbidity.
Fitzgerald, P., E.M. Cassidy, G. Clarke, P. Scully, S. Barry, E.M.M. Quig¬ley, F. Shanahan, J. Cryan, T.G. Dinan. 2008. Neurogastroenterol Motil. 20(12):1291-7.


“Irritable bowel syndrome (IBS) has been linked with abnormal serotonin functioning and immune activation. Tryptophan forms the substrate for serotonin biosynthesis, but it can alternatively be catabo¬lized to kynurenine (Kyn) by the enzyme indoleamine 2,3-dioxygenase (IDO), the main inducer of which is interferon-gamma…Irritable bowel syndrome subjects had increased Kyn concentrations compared with controls…and there was a trend for Kyn:Trp to be increased in the IBS group...There was a positive correlation between IBS severity and Kyn:Trp...Those with severe IBS symptoms had increased Kyn:Trp compared to those with less severe symptoms and controls, and were over twice as likely to have depression or anxiety compared to those with less severe IBS…Females with IBS have abnormal Trp catabolism. The Kyn:Trp is related to symptom severity, and those with severe IBS symptoms have increased shunting of Trp along the Kyn pathway which contributes to the abnormal serotonergic functioning in this syndrome.”



Tryptophan degradation in irritable bowel syndrome: evidence of indoleamine 2,3-dioxygenase activation in a male cohort.
Clarke, G., P. Fitzgerald, J.F. Cryan, E.M. Cassidy, E.M. Quigley, T.G. Dinan. 2009. BMC Gastroenterol. 9:6.

“…Both kynurenine levels and the kynurenine:tryptophan ratio were significantly increased in the IBS cohort compared with healthy controls…These findings suggest that the activity of IDO, the im-munoresponsive enzyme which is responsible for the degradation of tryptophan along this pathway, is enhanced in IBS patients relative to controls.”
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Re: Some Interesting Connections

Postby Annesse » Tue Oct 15, 2013 8:58 am

Kynurenine is also involved in the pathogenesis of interstitial cystitis. Interstitial cystitis, also known as painful bladder syndrome, is a chronic, oftentimes painful, inflammatory condition of the bladder that can affect patients with MS. Researchers in the following study identified kynurenine as a “blood marker” for interstitial cystitis (IC) in both humans and cats with feline IC. Feline IC is an often studied animal model for human IC.


The researchers collected samples from humans with IC, healthy humans, and humans with other urological illnesses. They also collected samples from cats with feline IC, healthy cats, and cats with other diseases. They discovered similar increased levels of kynurenine (at least 20 percent more) in both the human IC blood samples and feline IC blood samples, but not in the other samples.

A candidate serum biomarker for bladder pain syndrome/interstitial cystitis.
Rubio-Diaz, D.E., M.E. Pozza, J. Dimitrakov, J.P. Gilleran, M.M. Giusti, J.L. Stella, L.E. Rodriguez-Saona, C.A. Buffington. 2009. Analyst 134(6):1133-7. Epub 2009 Apr 16.

“…Analysis of cat samples using liquid chromatography-mass spectroscopy revealed differences in the concentration of tryptophan and its metabolites between healthy and affected cats. These results demonstrate the potential utility of infrared microspectroscopy to diagnose IC in both humans and cats.”
http://researchnews.osu.edu/archive/icbiomarker.htm





It is not surprising that tryptophan metabolites are linked to interstitial cystitis. In the following study the researchers stated that these metabolites produced bladder cancer when implanted in the bladder.


Possible roles of excess tryptophan metabolites in cancer.
Chung, K.T., G.S. Gadupudi. 2011. Environ Mol Mutagen. 52(2):81-104. doi: 10.1002/em.20588.

“…These metabolites could interact with nitrite to become mutagenic nitrosamines. They could be a promoter in the initiator-promoter model of carcinogenesis. They produced bladder cancer when implanted in the bladder…”
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Re: Some Interesting Connections

Postby Annesse » Wed Oct 16, 2013 7:32 am

SENSORINEURAL HEARING LOSS, MS, AND QUINOLINIC ACID


In the following study on MS and “sensorineural” hearing loss the study authors concluded that episodes of hearing loss are not uncommon in MS. Sensorineural hearing loss occurs when there is damage to the inner ear (cochlea), or to the nerve pathways from the inner ear to the brain.

Acta Neurol Scand. 2011 Oct;124(4):245-9. doi: 10.1111/j.1600-0404.2010.01463.x. Epub 2011 Jan 4.
Sudden sensorineural hearing loss in multiple sclerosis: clinical course and possible pathogenesis.
Hellmann MA, Steiner I, Mosberg-Galili R.

"We were able to identify 11 of 253 patients (4.35%) with sudden hearing loss. In seven patients, the hearing decline was the presenting symptom of MS and in all 11 patients, it appeared early in the course of the disease. There was no residual hearing deficit in 9/11 patients...Episodes of hearing loss are not uncommon in MS..."
http://www.ncbi.nlm.nih.gov/pubmed/21198448


Although rare, sudden sensorineural hearing loss may be the first symptom manifestation of MS, as the following study confirms.


Otolaryngol Pol. 2004;58(6):1143-9.
[Sudden sensorineural hearing loss as the first symptom of multiple sclerosis. Review of literature and case report].
Szymańska M, Gerwel A, Cieszyńska J.


"Sudden sensorineural hearing loss is rarely the first manifestation of multiple sclerosis (MS). In the presented case of a 31-year-old woman, sudden hearing loss in the left ear was the first monosymptomatic manifestation of the disease. Based on clinical evaluation and MRI, we diagnosed the relapsing-remitting variant of MS. The several-month long observation of the patient included noting the fluctuations in the patient's hearing capability in correlation with the continuously abnormal auditory brainstem responses."
http://www.ncbi.nlm.nih.gov/pubmed/15732838





In the following study the researchers concluded that the kynurenine pathway neurotoxin quinolinic acid (QUIN) can cause sensorineural hearing loss.


Laryngoscope. 1994 Feb;104(2):176-81.
Sensorineural hearing loss from quinolinic acid: a neurotoxin in middle ear effusions.
Yellon RF, Rose E, Kenna MA, Doyle WJ, Casselbrant M, Diven WF, Whiteside TL, Swarts JD, Heyes MP.

“Quinolinic acid (QUIN) is an endogenous metabolite that exerts a neurotoxic effect by binding to specific neuronal receptors. Studies involving a broad spectrum of infectious and inflammatory central nervous system diseases have suggested a role for QUIN in causing neuronal injury. Since there is evidence for presence of the QUIN receptor in mammalian cochleas, QUIN was measured in middle ear effusions (MEEs)…We conclude that QUIN is present in MEEs and that QUIN in the middle ear has the potential to cross the RWM and cause sensorineural hearing loss, possibly by binding to specific neuronal receptors in mammalian cochleas.”
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Re: Some Interesting Connections

Postby Annesse » Thu Oct 17, 2013 7:35 am

MS, LOW GABA, ANXIETY, EPILEPSY (SEIZURES), AND THE KYNURENINE PATHWAY


In the following study published in Archives of Neurology the researchers found significant reductions of GABA in the cerebrospinal fluid (CFS) of patients with epilepsy and MS.

Arch Neurol. 1980;37(6):352-355. doi:10.1001/archneur.1980.00500550054006.
Levels of γ-aminobutyric acid in cerebrospinal fluid in various neurologic disorders.
N. V. Bala Manyam, MD; Leonard Katz, MD; Theodore A. Hare, PhD; Joseph C. Gerber, PhD; Mark H. Grossman, PhD

“significant reductions of the GABA level in CSF were seen in patients with Huntington's disease, dementias, cerebellar cortical atrophy, multiple sclerosis, epilepsy, and Parkinson's disease.”





Researchers in the following study, published in Multiple Sclerosis, concluded MS patients had “diffuse GABAergic alteration in neurons.”

Mult Scler. 2012 Nov;18(11):1633-5. doi: 10.1177/1352458512440207. Epub 2012 Mar 14.
Inflammation inhibits GABA transmission in multiple sclerosis.
Rossi S, Studer V, Motta C, De Chiara V, Barbieri F, Bernardi G, Centonze D.

“…Our results provide evidence that focal inflammation in MS perturbs the cytokine milieu within the circulating CSF, resulting in diffuse GABAergic alteration in neurons.”





GABA (gamma-aminobutyric acid) is the major inhibitory neurotransmitter in the brain. Excitation in the brain must be balanced with inhibition. Too much excitation can lead to anxiety, insomnia, impulsivity, inability to focus attention, and even seizures. Anti-anxiety medications, such as benzodiazepines and barbiturates work by binding to GABA receptors to increase its inhibitory effect and relieve anxiety. The significantly lower levels of GABA found in patients with MS would explain the association MS has to anxiety and seizures.


In the following study the researchers stated that anxiety disorders are “quite common” in patients with MS.

Semin Clin Neuropsychiatry. 1999 Apr;4(2):103-13.
Anxiety in patients with multiple sclerosis.
Riether AM.

“Anxiety disorders are quite common, and frequently overlooked, in patients with multiple sclerosis (MS)…”



In the following study the researchers stated there is a large body of evidence describing the clinical presentation of seizures with MS.


Epilepsia. 2011 May;52 Suppl 3:12-7. doi: 10.1111/j.1528-1167.2011.03030.x.
Systemic and neurologic autoimmune disorders associated with seizures or epilepsy.
Vincent A, Crino PB.

“…There is a large body of evidence describing the clinical presentation of seizures with MS and SLE, and showing that refractory epilepsy can complicate these already challenging disorders…”





Researchers in the following study discovered that the tryptophan metabolite “kynurenine” was able to induce convulsions by displacing GABA. The researchers concluded, “The data suggest that the convulsant activity of L-kynurenine might be due to interaction with GABA receptors.”


Kynurenine may directly interact with GABA receptors in rat brain.
Pinelli, A., S. Govoni, C. Ossi, F. Battaini, B.R. Caimi, S. Trivulzio. 1985. Pharmacology 30(5):255-8.

“Previous studies have shown that kynurenine may have convulsant activity…kynurenine was able to displace 3H-GABA from rat brain membrane preparations. The data suggest that the convulsant activity of L-kynurenine might be due to an interaction with GABA receptors…”




The tryptophan metabolite "quinolinic acid" is also associated with seizures and low GABA, as the following studies confirm.

Epilepsia. 1990 Mar-Apr;31(2):172-7.
Quinolinic acid concentrations in brain and cerebrospinal fluid of patients with intractable complex partial seizures.
Heyes MP, Wyler AR, Devinsky O, Yergey JA, Markey SP, Nadi NS.

Quinolinic acid (QUIN) is a neurotoxin and convulsant when injected directly into the brains of experimental animals and as such has been implicated in the etiology of human seizure disorders…”




Brain Res. 2004 Aug 20;1018(1):48-54.
Quinolinic acid promotes seizures and decreases glutamate uptake in young rats: reversal by orally administered guanosine.
de Oliveira DL, Horn JF, Rodrigues JM, Frizzo ME, Moriguchi E, Souza DO, Wofchuk S.


"Quinolinic acid (QA) has been used as a model for experimental overstimulation of the glutamatergic system. Glutamate uptake is the main mechanism involved in the maintenance of extracellular glutamate below toxic levels. Guanosine systemically administered prevents quinolinic acid-induced seizures in adult mice and increases basal glutamate uptake by cortical astrocyte culture and slices from young rats..."
http://www.ncbi.nlm.nih.gov/pubmed/15262204



In the next study the researchers discovered that quinolinic acid reduced GABA in a dose-dependent manner.


Modulation of striatal quinolinate neurotoxicity by elevation of endogenous brain kynurenic acid.
Harris, C.A., A.F. Miranda, J.J. Tanguay, R.J. Boegman, R.J. Beninger, K. Jhamandas. 1998. Br J Pharmacol. 124(2):391-9.

“…Intrastriatal infusion of quinolinic acid also produced a dose-dependent reduction in striatal GABA content…”
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Re: Some Interesting Connections

Postby PointsNorth » Thu Oct 17, 2013 10:01 am

Albany 2010. Brooklyn 2011
Hurry up and wait.
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Re: Some Interesting Connections

Postby PointsNorth » Thu Oct 17, 2013 1:27 pm

BTW- taking a digestive enzyme gelcap (DigeZyme by Alpha Science Laboratories Toronto) that lists Protease I, II, II, IV .... 70mg/18,000 USP units as one of the ingredients.
Also contains Bromelain, Amylase, Lipase, Lactase, Sucrase, Maltase & Cellulase.

PN
Albany 2010. Brooklyn 2011
Hurry up and wait.
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