Some Interesting Connections

A forum to discuss research on the origins of MS and its development.
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Annesse
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DOPAMINE AND HYPERPROLACTINEMIA

Reduced levels of dopamine can also lead to hyperprolactinemia. Hyperprolactinemia is a condition in which a person has higher-than-normal levels of the pituitary hormone prolactin, named because of its role in lactation (secretion or formation of milk by mammary glands). Dopamine is one of the main regulators of the production of prolactin (Ben-Jonathan, 2001). Thus, in the context of regulating prolactin secretion, dopamine is occasionally called prolactin-inhibiting factor, prolactin-inhibiting hormone, or prolactostatin. Dopamine restrains prolactin production, so the more dopamine there is, the less prolactin is released. In the absence of dopamine, prolactin is secreted continuously.



In the following study published in the Journal of the Neurological Sciences the study authors found that serum prolactin levels were significantly higher in MS patients compared to controls. In addition, the researchers concluded that all relapsing-remitting MS patients showed a rise in prolactin levels in the acute stage of relapse and a decrease during the recovering stage and the following remission phase.


Journal of the Neurological Sciences Volume 102, Issue 1, March 1991, Pages 61–66
Hyperprolactinemia in multiple sclerosis.
Jun-ichi Kira , Mamoru Harada, Yukiko Yamaguchi, Norihiko Shida, Ikuo Goto

“…Serum prolactin levels were found to be significantly higher in MS patients than in healthy controls in both sexes…All relapsing-remitting patients with hyperprolactinemia showed a rise in prolactin levels in the acute stage of the relapse and a decrease during the recovering stage and the following remission phase…”




Prolactin is not only a lactigenic hormone, it is also an important regulator of the immune system. Prolactin plays a central role in MS by stimulating autoimmune B cells. B cells belong to a group of white blood cells known as lymphocytes. Prolactin is involved in lymphocyte survival, activation, and proliferation. There is increasing data implicating prolactin in autoimmunity due to its immuno stimulatory effects on B cells (Peeva, 2004). In the following study the researchers stated that persistently elevated prolactin levels interfere with B cell tolerance, thereby promoting autoreactivity.



Arthritis Rheum. 2009 Jun;60(6):1743-52. doi: 10.1002/art.24500.
Prolactin alters the mechanisms of B cell tolerance induction.
Saha S, Gonzalez J, Rosenfeld G, Keiser H, Peeva E.


“…Persistently elevated serum prolactin levels interfere with B cell tolerance induction…thereby promoting autoreactivity.”





In the following study the researchers also found higher levels of prolactin in MS patients and concluded that prolactin can promote B cell “autoreactivity” in MS.

Biomed Pharmacother. 2004 Jun;58(5):310-9.

The role of prolactin on B cell regulation in multiple sclerosis.
Jorge Correale1, Mauricio Farez2 and María Ysrraelit3

“…Prolactin levels were higher in MS subjects compared to controls...B and T cells isolated from both MS patients and controls expressed prolactin receptor, which were upregulated by estrogens…Moreover, prolactin antagonists blocked these effects, suggesting prolactin may enhance autoreactive B cells survival. Finally, prolactin induced CD40 expression on B cells, suggesting it may rescue autoreactive B cells, possibly through recruitment of T cell support…Prolactin can promote B cell autoreactivity in MS through different mechanisms…”





The prinicipal function of B cells is to make antibodies against antigens. An antibody, also known as an immunoglobulin, is a large Y-shaped protein produced by B-cells that is used by the immune system to identify and neutralize foreign objects, such as bacteria and viruses. As the following study states, B cells and antibodies account for the most prominent immunodiagnostic feature in patients with MS--oligoclonal bands. Oligoclonal bands are bands of immunoglobulins that are seen when a patient's blood serum, gained from blood plasma or cerebrospinal fluid, is analyzed.



Nat Rev Neurol. 2012 Nov 5;8(11):613-23. doi: 10.1038/nrneurol.2012.203. Epub 2012 Oct 9.
B cells and antibodies in multiple sclerosis pathogenesis and therapy.
Krumbholz M, Derfuss T, Hohlfeld R, Meinl E.

“B cells and antibodies account for the most prominent immunodiagnostic feature in patients with multiple sclerosis (MS), namely oligoclonal bands…B cells can increase or dampen CNS inflammation, but their proinflammatory effects seem to be more prominent in most patients, as B-cell depletion is a promising therapeutic strategy. Other therapies not primarily designed to target B cells have numerous effects on the B-cell compartment…”



Atacecept, one of the medications used in the treatment of MS, is designed to inhibit B cells, as the following study confirms.

Ther Adv Neurol Disord. 2010 July; 3(4): 205–216.
Atacicept: targeting B cells in multiple sclerosis.
Hans-Peter Hartung

“Multiple sclerosis (MS) has traditionally been considered to be a T-cell-mediated disease. However, there is an increasing body of evidence for the involvement of B cells and autoantibodies in the pathology of this disease, providing a rationale for treatments directed against B cells. In this paper we summarize evidence for the key role of B cells in the immunopathology of MS and review data supporting the use of a novel B-cell targeted therapy, atacicept, in this condition…”





In addition to promoting B cell autoreactivity, prolactin has been shown to cause the preferential development of CD4+ T cells. The “T cells” (so-called because they develop in a small organ called the thymus gland) are responsible for a variety of immune responses. These responses include: 1) direct attacks on foreign substances such as bacteria, viruses, or foreign tissues; 2) augmenting the B-cell response; and 3) producing substances called cytokines that direct responses and activities in other immune cells. CD4+ T cells are types of T cells that are considered to play an important role in the immunopathogenesis of MS, as the following study states.



Neurol Res. 2006 Apr;28(3):245-9.
The role of CD4+ T-cells in the development of MS.
Delgado S, Sheremata WA.

“Multiple sclerosis (MS) is a chronic, progressive central nervous system (CNS) disease with unknown cause. Considerable evidence supports an autoimmune origin with an important role for cellular immune responses in its pathogenesis…The evidence reviewed supports an important role of CD4+ T-cells in the immunopathogenesis of MS. The successful outcome of blocking CD4 cells entry into the CNS of animals with experimental demyelinating disease and humans with MS is a strong support for other evidence of an important role of these cell populations in the pathogenesis of MS. The understanding of the specific roles of CD4+ T-cells in the development of MS is crucial for better disease management and the prevention of neurological disability.”



In the following study the researchers stated that activated myelin-reactive CD4+T cells are present in the blood and cerebrospinal fluid of MS patients.

Int Rev Neurobiol. 2007;79:43-72.
The role of CD4 T cells in the pathogenesis of multiple sclerosis.
Chitnis T.

“T lymphocytes play a central role in the pathogenesis of multiple sclerosis…Activated myelin-reactive CD4+ T cells are present in the blood and cerebrospinal fluid (CSF) of MS patients…”



In the following study published in The Journal of Clinical Investigation the study authors stated that prolactin has been shown to cause the preferential development of CD4+ T cells.

J. Clin. Invest. 111:275–283 (2003). doi:10.1172/JCI200316530.
Prolactin modulates the naive B cell repertoire.
Elena Peeva,1,2 Daniel Michael,1 James Cleary,1 Jeffrey Rice,1 Xian Chen,1
and Betty Diamond1,2


“…Prolactin has been shown to increase antigen presentation by dendritic cells…Prolactin has been shown to enhance the release of thymocytes from lymphoepithelial complexes in the thymus, to act as growth factors for T cells, to cause preferential development of CD4+ T cells, and to promote a Th1 response…”




THE GENDER BIAS, STRESS, AND PROLACTIN


Estrogens increase prolactin production and inhibit dopamine at the same time, which would be an important factor in explaining why MS and other autoimmune diseases are more common in women. According to the National Multiple Sclerosis Society, “MS is significantly more common (at least 2-3 times) in women than men.”

In the following study the researchers stated that autoimmune diseases are more common in females, and the sex hormones, mainly estrogen and prolactin, which modulate the immune response, play an important role in this “gender bias”.

Autoimmun Rev. 2007 Sep;6(8):537-42. Epub 2006 Dec 1.
Hyperprolactinemia and autoimmune diseases.
Orbach H, Shoenfeld Y.

“The autoimmune diseases are more common in females. The sex hormones have an important role in this gender bias, mainly estrogen and prolactin (PRL) which modulate the immune response…PRL has an immunostimulatory effect and promotes autoimmunity: PRL impairs the negative selection of autoreactive B lymphocytes occurring during B cell maturation into fully functional B cells. PRL has an anti-apoptotic effect, enhances proliferative response to antigens and mitogens and enhances the production of immunoglobulins and autoantibodies. Hyperprolactinemia (HPRL) is observed in multi-organ and organ specific autoimmune diseases like systemic lupus erythematosus (SLE) rheumatoid arthritis (RA), Sjogren's syndrome (SS), Hashimoto's thyroiditis (HT) and multiple sclerosis (MS)…”





As the previous study stated, hyperprolactinemia is observed in autoimmune diseases like rheumatoid arthritis, systemic lupus, and MS. In the following study from Columbia University the researchers stated that data accumulated during the past few years provides striking evidence that hormonal modulation of B cells by estrogen and prolactin can have a profound impact on the survival and maturation of autoreactive B cells, which begins to explain the sex bias associated with the autoimmune disease lupus.

Curr Opin Rheumatol. 2006 Sep;18(5):456-61.
Sex and systemic lupus erythematosus: the role of the sex hormones estrogen and prolactin on the regulation of autoreactive B cells.
Grimaldi CM.

“For many decades, it has been speculated that sex hormones play a role in systemic lupus erythematosus. Recent data accumulated during the past few years provide striking evidence that hormonal modulation of B cells can have a profound impact on the survival, maturation and repertoire selection of autoreactive B cells and begin to explain the sex bias associated with the condition…Elevations in the levels of estrogen or prolactin can promote the survival and activation of high affinity autoreactive B cells. These hormones engage different B cell pathways to interfere with B cell tolerance…”





Elevated prolactin would also explain the association research has found between MS and stress. For instance, researchers in the following study stated that “a growing literature reports that stressful life events are associated with exacerbation and the subsequent development of brain lesions in patients with multiple sclerosis.”

Brain Behav Immun. 2006 Jan;20(1):27-36.
A temporal framework for understanding the effects of stressful life events on inflammation in patients with multiple sclerosis.
Mohr DC, Pelletier D.

“A growing literature reports that stressful life events are associated with exacerbation and the subsequent development of brain lesions in patients with multiple sclerosis…”





Stress, both physical and mental, can increase prolactin levels, which would lead to an increase in MS disease activity. In the following study the researchers stated that various situations and laboratory stressors can induce a “significant increase” in prolactin secretion.

Stress Med., 3: 211–216.
Prolactin and stress.
Dr. Maurizio Fava MD1, Gian Paolo Guaraldi MD

“There is evidence that stress influences prolactin secretion in animals and humans. Various situations and laboratory stressors can induce a significant increase in prolactin secretion.”




In the next study the researchers stated that prolactin is a stress hormone, and that prolactin levels rise in response to stresses such as surgery, vigorous exercise, and accidents.

Serum prolactin stress values in patients with systemic lupus erythematosus.
Dostál, C., L. Moszkorzová, L. Musilová, Z. Lacinová, J. Marek, J. Zvárová. 2003. Ann Rheum Dis 62:487-488 doi:10.1136/ard.62.5.487

“Over the past decade we have seen a gradual increase in reports giving more support to the hypothesis that mildly or moderately increased values of serum prolactin have a role in the pathogenesis and clinical activity of systemic lupus erythematosus (SLE). Prolactin is a hormone with a very wide range of action, and its effect on the immune response has been proved in both animal experiments and in humans. It is also one of the stress hormones…Stress, whether mental or physical, acts on prolactin secretion in different ways so that its serum levels rise not only in response to stress such as surgery…but also after vigorous exercise and accidents…”




In the following study the researchers concluded that in rheumatoid arthritis (RA) patients the immune-stimulating hormones, prolactin and estradiol (estrogen), were significantly positively correlated with interpersonal stress and disease activity.

Interpersonal stress, depression, and disease activity in rheumatoid arthritis and osteoarthritis patients.
Zautra, A.J., M.H. Burleson, K.S. Matt, S. Roth, L. Burrows. 1994. Health Psychology Vol 13(2) 139-148.

“The relationships among interpersonal stressors, depression, coping inefficacy, hormones (prolactin, cortisol, and estradiol), and disease activity were examined. In RA…the immune-stimulating hormones prolactin and estradiol were significantly positively correlated with interpersonal conflicts, depression, coping inefficacy, and clinician ratings of disease activity…”
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Elevated levels of prolactin would also account for the association MS, lupus, rheumatoid arthritis, and other autoimmune diseases have to the Epstein-Barr virus (EBV). EBV is a member of the herpesvirus family and according to the National Institutes of Heatlh (NIH) nearly 95 percent of all people between the ages of 35 and 40 have been infected with the virus.

The EBV is responsible for the viral infection known as mononucleosis (or “mono”). Although the symptoms of mono, which include a fever, sore throat, and swollen lymph glands, eventually go away, EBV takes up permanent residence in B cells in the immune system where it can lie dormant for years.


Persistent B cell activation by prolactin would drive the reactivation of EBV. For instance, in the following study the researchers concluded that B cell activation during flares drives frequent EBV reactivation in lupus.

PLoS Pathog. 2011 Oct;7(10):e1002328. doi: 10.1371/journal.ppat.1002328. Epub 2011 Oct 20.
Exhausted cytotoxic control of Epstein-Barr virus in human lupus.
Larsen M, Sauce D, Deback C, Arnaud L, Mathian A, Miyara M, Boutolleau D, Parizot C, Dorgham K, Papagno L, Appay V, Amoura Z, Gorochov G.


“Systemic Lupus Erythematosus (SLE) pathology has long been associated with an increased Epstein-Barr Virus (EBV)…EBV reactivation appears to be an aggravating consequence rather than a cause of SLE immunopathology. We therefore propose that autoimmune B cell activation during flares drives frequent EBV reactivation, which contributes in a vicious circle to the perpetuation of immune activation in SLE patients.”





Stress is also a known predictor of EBV reactivation, and as we have discussed, stress increases levels of prolactin.




Persistent B cell activation by prolactin and the subsequent reactivation of EBV could also eventually deplete the T cells that attack virus infected cells--CD8+T cells. Patients with MS have been shown to have a deficiency of CD8+T cells (Pender, 2011). In the following study published in the Journal of Virology the researchers stated that chronic viral infections often result in ineffective CD8+T cell responses due to functional exhaustion or physical deletion.


J Virol. 2003 Apr;77(8):4911-27.
Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment.
Wherry EJ, Blattman JN, Murali-Krishna K, van der Most R, Ahmed R.


“Chronic viral infections often result in ineffective CD8 T-cell responses due to functional exhaustion or physical deletion of virus-specific T cells…Persistent infection led to a disruption of the normal immunodominance hierarchy of CD8 T-cell responses seen following acute infection and dramatically altered the tissue distribution of LCMV-specific CD8 T cells in lymphoid and nonlymphoid tissues…antigen appeared to be the driving force for this loss of function, since a strong correlation existed between the viral load and the level of exhaustion. Further, epitopes presented at higher levels in vivo resulted in physical deletion, while those presented at lower levels induced functional exhaustion. A model is proposed in which antigen levels drive the hierarchical loss of different CD8 T-cell effector functions during chronic infection, leading to distinct stages of functional impairment and eventually to physical deletion of virus-specific T cells. These results have implications for the study of human chronic infections, where similar T-cell deletion and functional dysregulation has been observed.”
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Prolactin is also associated with breast cancer, which would be another factor, along with dysregulated VEGF, involved in the increased risk of breast cancer found in patients with MS. Research has shown that more than 95 percent of breast cancers express the receptor for prolactin (Reynolds, 1997). In the following study the researchers stated that prolactin can promote cell proliferation and survival, increase cell motility, and support tumor vascularization. In addition, the researchers stated that a recent study of 235 cases reported a “significant positive association” between prolactin levels and breast cancer risk.




Prolactin and breast cancer risk.
Tworoger, S.S., S.E. Hankinson. 2006. Cancer Lett. 243(2):160-9. Epub 2006 Mar 10.

“Prolactin, a hormone involved in normal breast development and lactation, has been hypothesized to be important in the etiology of breast cancer… Experimental evidence indicates that prolactin can promote cell proliferation and survival, increase cell motility, and support tumor vascularization. Animal data suggest that prolactin can increase tumor growth rates and the number of metastases, as well as induce both estrogen receptor +(ER) and ER--tumors in a transgenic mouse model in which ER+ tumors are very rare. Epidemiologic data for premenopausal women are sparse; however a recent study with 235 cases reported a significant positive association between plasma prolactin levels and breast cancer risk. Studies in postmenopausal women have reported a positive association as well, and in the largest study (n=851 cases) the association was strongest for ER+ tumors. Overall, the available data support the hypothesis that prolactin increases risk of breast cancer…”
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LOW DOPAMINE AND BRAIN GRAY MATTER LOSS

Low dopamine can also cause brain gray matter loss.



The gray matter involves regions of the brain concerned with muscle control, emotions, learning and memory, speech, and sensory perception such as seeing and hearing. In the following study published in Neurology the researchers stated that gray matter atrophy is detected even in the earliest stages of MS.



Neurology. 2007 Feb 27;68(9):634-42.

Gray matter involvement in multiple sclerosis.
Pirko I, Lucchinetti CF, Sriram S, Bakshi R.

“Gray matter (GM) involvement is detected even in the earliest stages of multiple sclerosis (MS), and GM atrophy occurs at a faster rate than white matter (WM) atrophy early in the disease course. Studies published to date establish that 1) GM involvement and in particular cortical demyelination can be extensive in MS; 2) GM pathology may occur in part independently of WM lesion formation; 3) a primarily GM-related process may be the earliest manifestation of MS; 4) GM involvement is associated with physical disability, fatigue, and cognitive impairment in MS; and 5) GM disease might help explain the observed dissociation between markers of inflammatory demyelination (relapses, WM gadolinium enhancement, WM lesion burden) and disease progression…”






In the next study the researchers discussed the entensive involvement of the thalmus, which consists of gray matter, in MS. The study authors stated that extensive involvement of gray matter, and particularly of the thalamus, is associated with a wide range of clinical manifestations including cognitive decline, motor deficits, fatigue, painful syndromes, and ocular motility disturbances in MS patients.



Neurology. 2013 Jan 8;80(2):210-9. doi: 10.1212/WNL.0b013e31827b910b.
The thalamus and multiple sclerosis: modern views on pathologic, imaging, and clinical aspects.
Minagar A, Barnett MH, Benedict RH, Pelletier D, Pirko I, Sahraian MA, Frohman E, Zivadinov R.

“The paired thalamic nuclei are gray matter (GM) structures on both sides of the third ventricle that play major roles in cortical activation, relaying sensory information to the higher cortical centers that influence cognition. Multiple sclerosis (MS) is an immune-mediated disease of the human CNS that affects both the white matter (WM) and GM. A number of clinical observations as well as recent neuropathologic and neuroimaging studies have clearly demonstrated extensive involvement of the thalamus, basal ganglia, and neocortex in patients with MS. Modern MRI techniques permit visualization of GM lesions and measurement of atrophy. These contemporary methods have fundamentally altered our understanding of the pathophysiologic nature of MS. Evidence confirms the contention that GM injury can be detected in the earliest phases of MS…extensive involvement of GM, and particularly of the thalamus, is associated with a wide range of clinical manifestations including cognitive decline, motor deficits, fatigue, painful syndromes, and ocular motility disturbances in patients with MS…”




In the following study, published in The Journal of Pain, researchers found a strong correlation between dopamine metabolism and gray matter density.


Changes in gray matter density in fibromyalgia: correlation with dopamine metabolism.
Wood, P.B., M.F. Glabus, R. Simpson, J.C. Patterson 2nd. 2009. J Pain 10(6):609-18. Epub 2009 Apr 23.

“Fibromyalgia is associated with reductions in gray matter density within brain regions ostensibly involved in phenomena related to the disorder, including enhanced pain perception, cognitive dysfunction, and abnormal stress reactivity. Given mounting evidence of abnormal dopaminergic neurotransmission associated with the disorder, the strong correlation between dopamine metabolism and gray matter density provides insight as to the pathophysiology that might contribute to these changes.”



Dopamine regulates prolactin, so we should find elevated levels of prolactin in patients with fibromyalgia. 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.”




We should also find brain gray matter loss in the other diseases we have been discussing that have high prolactin. As the previous studies posted confirm, high levels of prolactin are also found in rheumatoid arthritis, lupus, Sjogren's syndrome, Hashimoto's thyroiditis, diabetes, and celiac disease. In the following study the researchers concluded their results suggest that rheumatoid arthritis is associated with changes in the subcortical gray matter.

Structural changes of the brain in rheumatoid arthritis.
Wartolowska, K., M.G. Hough, M. Jenkinson, J. Andersson, B.P. Wordsworth, I. Tracey. 2012. Arthritis Rheum. 64(2):371-9. doi: 10.1002/art.33326.

“…Our results suggest that RA is associated with changes in the subcortical gray matter…”





Researchers in the following study discovered that the gray matter (GM) was “particularly affected” in patients with neuropsychiatric lupus (NPSLE).

Selective gray matter damage in neuropsychiatric lupus.
Steens, S.C., F. Admiraal-Behloul, G.P. Bosma, G.M. Steup-Beekman, H. Olofsen, S. Le Cessie, T.W. Huizinga, M.A. Van Buchem. 2004. Arthritis Rheum. 50(9):2877-81.

“…This is the first study to demonstrate… that in SLE patients with a history of NP symptoms …the GM is particularly affected. These findings support the hypothesis that neuronal injury may underlie central nervous system manifestations in NPSLE.”




In the following study the researchers concluded that patients with Sjögren's syndrome had decreased brain gray matter.


CNS involvement in primary Sjögren’s syndrome: assessment of gray and white
matter changes with MRI and voxel-based morphometry.
Tzarouchi, L.C., N. Tsifetaki, S. Konitsiotis, A. Zikou, L. Astrakas, A. Drosos, M.I. Argyropoulou. 2011. AJR Am J Roentgenol. 197(5):1207-12. doi: 10.2214/AJR.10.5984.


“…In comparison with the controls, patients with primary Sjögren syndrome had decreased gray matter volume in the cortex, deep gray matter, and cerebellum…”




In our next study researchers found an association with reduced brain grey matter in children with Hashimoto’s thyroiditis and low performance in attention testing.

Low performance in attention testing is associated with reduced grey matter density of the left inferior frontal gyrus in euthyroid patients with Hashimoto’s thyroiditis.
Leyhe, T., T. Ethofer, J. Bretscher, A. Künle, A.L. Säuberlich, R. Klein, B. Gallwitz, H.U. Häring, A. Fallgatter, S. Klingberg, R. Saur, K. Müssig. 2013. Brain Behav Immun. 27(1):33-7. doi: 10.1016/j.bbi.2012.09.007. Epub 2012 Sep 23.


“…Recently we found an increased occurrence of weaknesses in sustained attention and response inhibition in a subgroup of euthyroid patients with HT as obtained by the d2 attention test…GM density was significantly reduced when comparing HT patients with control patients that scored in the lower third during d2 attention testing…Particularly low achievement was associated with reduced GM density of this brain region suggesting an influence of autoimmune processes on the frontal cortex in this disease…”




In the following study published in Diabetologia the researchers concluded that type 2 diabetes was associated with a smaller volume of brain grey matter.



Automated measurement of brain and white matter lesion volume in type 2 diabetes
mellitus.
Jongen, C., J. van der Grond, L.J. Kappelle, G.J. Biessels, M.A. Viergever, J.P. Pluim. Utrecht Diabetic Encephalopathy Study Group. 2007. Diabetologia. 50(7):1509-16. Epub 2007 May 11.


“Type 2 diabetes mellitus has been associated with brain atrophy and cognitive decline, but the association with ischaemic white matter lesions is unclear…Type 2 diabetes was associated with a smaller volume of grey matter… and with larger white matter lesion volume…The combination of atrophy with larger WML volume indicates that type 2 diabetes is associated with mixed pathology in the brain.”




Here is some information on celiac disease and brain gray matter damage.
http://celiacdisease.about.com/b/2013/0 ... isease.htm





As we have discussed, low dopamine can also lead to restless legs syndrome (RLS). Due to reduced levels of dopamine, patients with RLS also have brain gray matter damage. In the following study the researchers concluded that patients with RLS had significant regional decreases of gray matter volume.


Cortical gray matter alterations in idiopathic restless legs syndrome: An optimized voxel-based morphometry study.
Unrath, A., F.D. Juengling, M. Schork, J. Kassubek. 2007. Mov Disord. Sep 15;22(12):1751-6.

“…The comparison of the RLS patients versus controls yielded significant regional decreases of gray matter volume...All clusters correlated both with the severity of RLS symptoms and with disease duration. These results, for the first time, give in vivo evidence to structural neocortical gray matter alterations in RLS patients…”
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PROTEASE AND IRON METABOLISM

The protease that digest dietary proteins belong to a class of protease called "serine protease".

In addition to breaking down dietary proteins, serine protease are also responsible for regulating iron absorption in the body. Without these enzymes, the body would not be able to properly metabolize iron. The following study entitled “New insights into intestinal iron absorption” concludes that protease are an essential component of a pathway that detect iron deficiency and regulate iron absorption in the body.



New insights into intestinal iron absorption.
Hörl WH. 2008. Nephrol. Dial. Transplant. 23(10):3063-3064.

“Take home message: Iron deficiency activates the serine protease TMPRSS6. The protease then inhibits hepcidin transcription and thereby allows intestinal iron absorption and cellular iron release.”



As the previous study confirmed, protease are essential for iron absorption and cellular iron release. A lack of protease could lead not only to low serum iron, it could also lead to iron overload within the cells. In the following studies the researchers stated that iron overload has been demonstrated in MS lesions.


Anomalous venous blood flow and iron deposition in multiple sclerosis.
Singh AV, Zamboni P. 2009. Journal of Cerebral Blood Flow & Metabolism 29, 1867–1878; doi:10.1038/jcbfm.2009.180; published online 2 September 2009

“…Iron overload has been demonstrated in MS lesions…”



Cellular iron overload would be another factor in the increased risk of cancer found in patients with MS. Numerous studies have shown that cellular iron overload plays a major role in stimulating cancer. In the study entitled “The role of iron in cancer” the researchers stated, “The metal is carcinogenic due to its catalytic effect on the formation of hydroxyl radicals, suppression of the activity of host defense cells and promotion of cancer cell multiplication. In both animals and humans, primary neoplasms develop at body sites of excessive iron deposits” (Weinburg, 1996).




In the following study the researchers concluded that the serine protease Tmprss6 is an essential regulator of iron homeostasis.

Blood. 2008 Sep 15;112(6):2539-45. doi: 10.1182/blood-2008-04-149773. Epub 2008 Jun 3.
Membrane-bound serine protease matriptase-2 (Tmprss6) is an essential regulator of iron homeostasis.

Here we show that matriptase-2 (Tmprss6), a recently described member of the TTSP family, is an essential regulator of iron homeostasis..."





In the following study the researchers discussed the evidence for abnormal iron homeostasis in patients with MS.

Iron and neurodegeneration in multiple sclerosis.
Khalil M, Teunissen C, Langkammer C. 2011. Mult Scler Int. 2011:606807. doi: 10.1155/2011/606807. Epub 2011 Feb 10.


“…Evidence for abnormal iron homeostasis in MS comes also from analyses of iron and iron-related proteins in CSF and blood and postmortem MS brain sections…”







In the next study the researchers discussed the importance of iron in the production of myelin and concluded that disruptions in iron availability or intracellular management may be integral in decreased oligodendrocyte survival and/or myelin production.


Relationship of iron to oligodendrocytes and myelination.
Connor JR, Menzies SL. 1996. Glia. 17(2):83-93

“Oligodendrocytes are the predominant iron-containing cells in the brain…The only known function of oligodendrocytes is myelin production, and both a direct and indirect relationship exists between iron acquisition and myelin production. Iron is directly involved in myelin production as a required co-factor for cholesterol and lipid biosynthesis and indirectly because of its requirement for oxidative metabolism (which occurs in oligodendrocytes at a higher rate than other brain cells). Factors (such as cytokines) and conditions such as iron deficiency may reduce iron acquisition by oligodendrocytes and the susceptibility of oligodendrocytes to oxidative injury may be a result of their iron-rich cytoplasm. Thus, the many known phenomena that decrease oligodendrocyte survival and/or myelin production may mediate their effect through a final common pathway that involves disruptions in iron availability or intracellular management of iron…”









In the following study the researchers discussed the importance of iron, folate, and vitamin B12 in the regeneration of myelin.


Iron and the folate-vitamin B12-methylation pathway in multiple sclerosis.
Van Rensburg SJ, Kotze MJ, Hon D, Haug P, Kuyler J, Hendricks M, Botha J, Potocnik FC, Matsha T, Erasmus RT. 2006. Metab Brain Dis. 21(2-3):121-37. Epub 2006 May 26.


“…Myelin is regenerated continually, but prerequisites for this process are iron and a functional folate-vitamin B12-methylation pathway..."





The inability to properly metabolize vitamin B12 and iron would also be associated with anemia in MS. Here is some good information on this.



J of IMAB 2011; 17(1):203-205
MULTIPLE SCLEROSIS ASSOCIATED WITH ANAEMIC SYNDROME: A RETROSPECTIVE ANALYSIS AND LITERATURE REVIEW
Nadezhda S. Deleva, Alexandra J. Tzoukeva, Ara G. Kaprelyan, Kalina V. Drenska.


"An association of MS with different anaemic syndromes has been reported. Most common are states of B12 deficiency and pernicious anaemia,occurring before or during the development of MS. The aetiology of vitamin B12 deficiency in MS remains not always specified, but it is assumed that disorders are possible, both in absorption or in the transport of vitamin B12. Despite the unexplained nature of the association of vitamin B12 deficiency and MS, a similarity of the pathogenetic mechanisms is assumed. In addition to the well known role of vitamin B12 as a cofactor in the formation of myelin, of myelin, the significant immunomodulatory and neurotrophic effects are discussed. On the other hand, the epidemiological picture of pernicious anaemia shows significant similarity to that of MS. Accordingly, the coincidence of anaemia with MS has been considered to impact seriously on clinical presentation, therapeutic strategy and patient’s quality of life.


Objective: To perform a retrospective analysis of 18 cases with anaemic syndrome as a factor of comorbidity in patients with MS.

Results: The study group included patients with pernicious (n=8), Vitamin B12 (n=6), and iron (n=3) deficiency anaemia, as well as with β-thalassemia (n=1). In 12 patients anaemic syndrome proceeded MS and in 6 evolved during the course of the desease.

Conclusion: Our own notices and literature review suggests a possible causative relation between MS and anaemic syndrome..."
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Vitamin B12 and iron are also needed to produce steroid hormones.


LOW HORMONE LEVELS-TESTOSTERONE, ESTROGEN, AND DHEA

In the following study the researchers found that women with MS had significantly lower serum testosterone.

J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):272-5.
Sex hormones modulate brain damage in multiple sclerosis: MRI evidence.
Tomassini V, Onesti E, Mainero C, Giugni E, Paolillo A, Salvetti M, Nicoletti F, Pozzilli C.

“…Serum testosterone was significantly lower in women with MS than in controls…”



Male MS patients also have low testosterone. In the next study the researchers found significantly lower levels of testosterone (TES) in male MS patients.

Iranian Journal of Neurology 2006. 5(2):.
Serum testosterone level study in multiple sclerosis patients.
M.A Shafa, A.R Vakilian, A.R Pourebrahimi, Jafar Ahmadi Kohanali

“…male patients had lower level of TES than controls significantly…”




Here is a link to the following study on MS and low testosterone that was previously posted on this site.
http://www.thisisms.com/forum/general-d ... c2227.html

Decreased Serum Testosterone Levels in Multiple Sclerosis
Elena V. Simon, Ilir Topalli, Amir Touray, Saud A. Sadiq, New York, NY

"...Low testosterone levels occur in approximately 50% of patients with MS. In patients with low hormone levels, a relationship with increased disease activity was seen and needs to be confirmed for significance in a larger study."




In the next study the researchers concluded that about half of the MS patients had low estrogen.

Endocrinological findings in patients with multiple sclerosis.
Poser S, Kreikenbaum K, König A, Poser W, Evers P, Wikström J.

“about half of the patients showed decreased…estrogen values in the urine…”




In the following study the researchers found that MS patients with fatigue had significantly lower DHEA levels.

Mult Scler. 2006 Aug;12(4):487-94.
Fatigue in progressive multiple sclerosis is associated with low levels of dehydroepiandrosterone.
Téllez N, Comabella M, Julià E, Río J, Tintoré M, Brieva L, Nos C, Montalban X.

“…Analysis of…DHEA over time showed significantly lower hormone levels in patients with fatigue…”




Our bodies have an essential enzyme pathway for homone synthesis called “cytochrome P450”. The cytochrome P450 enzyme system converts cholesterol into pregnenolone, which then gets converted into other hormones like estrogen, testosterone, and DHEA. An inability to properly metabolize hormones, due to a disruption in the cytochrome P450 enzyme system, would account for the low hormone levels found in patients with MS.


The cytochrome P450 enzyme system is also our bodies’ first line of defense against chemicals and environmental pollutants. The cytochrome P450 system detoxifies all sorts of different chemicals that we eat and breathe, including drugs, carcinogens formed in cooking, and poisonous compounds in plants (Guengerich, 2008). For instance, cytochrome P450 is the reason doctors tell you not to drink grapefruit juice when taking certain medications. Grapefruits contain a flavinol molecule that inhibits cytochrome P450 enzymes. This would slow down the detoxification of the drug and might cause it to have a stronger effect than intended. A disruption in the cytochrome P450 enzyme system can cause multiple chemical sensitivities because even small amount of toxins can result in damage throughout the body.





The lack of bioavailable iron and vitamin B12 found in MS patients would lead to a disruption in the cytochrome P450 enzyme system.

The active site of cytochrome P450 contains a heme center, and therefore, cytochrome P450 enzymes are hemoproteins. Heme is made up of a squarish molecule--called a porphyrin--with an iron atom in the center. A molecule of iron is needed to make heme.

Vitamin B12 is also essential in the production of heme. The process of making heme is called the “heme biosynthetic pathway”. Each step of the process is controlled by one of eight enzymes. If any one of the eight enzymes is deficient, the pathway is disrupted.

As we previously discussed, vitamin B12 helps maintain the myelin sheath due to its role as a cofactor in the conversion of methylmalonyl coenzyme A into succinyl coenzyme A. Succinyl-coenzyme A is also the first component in the heme biosynthetic pathway. Therefore, a lack of vitamin B12 would lead to a failure in the entire heme pathway.


Following is a link from Wiki with a picture of a heme molecule showing the iron atom in the center (2nd picture). Also a quote on the biosynthesis of heme: "The committed step for porphyrin biosynthesis is the formation of δ-aminolevulinic acid (δ-ALA, 5-ALA or dALA) by the reaction of the amino acid glycine with succinyl-CoA from the citric acid cycle."

http://en.wikipedia.org/wiki/Porphyrin




LOW BILIRUBIN

Evidence that the heme biosynthetic pathway is disrupted in MS can be found in the following study. As the study confirms, the end product of normal heme catabolism is the yellow-colored substance, bilirubin. Bilirubin, which is excreted in bile and urine, has long been thought just to be a waste product, but it is now recognized as an antioxidant. The study authors found that patients with MS had significantly lower levels of serum bilirubin.



J Clin Neurosci. 2011 Oct;18(10):1355-9. doi: 10.1016/j.jocn.2011.02.023. Epub 2011 Jul 22.
Serum bilirubin concentrations and multiple sclerosis.
Peng F, Deng X, Yu Y, Chen X, Shen L, Zhong X, Qiu W, Jiang Y, Zhang J, Hu X.


“Bilirubin is the end product of heme catabolism by heme oxygenases. Although bilirubin has long been considered as a toxic waste product, it is now recognized as an endogenous antioxidant. It has been reported that bilirubin is an effective treatment in both acute and chronic experimental autoimmune encephalomyelitis (EAE) disease models. However, the relationship between bilirubin and multiple sclerosis (MS) has not been fully explored. The serum bilirubin concentrations were measured in 340 individuals comprising 88 healthy subjects, 133 patients with MS and 119 patients with cerebral infarction. Serum total bilirubin (Tbil), direct bilirubin (Dbil) and indirect bilirubin (Ibil) concentrations were significantly lower in patients with MS than in either patients with cerebral infarction or healthy controls …The correlation identified between bilirubin and MS was still highly significant when the effect of gender was eliminated…Our results suggest that there are reduced serum bilirubin concentrations in patients with MS.”





In the following study the researchers discussed the importance of the heme biosynthetic pathway and iron in the production of myelin. The researchers stated, “ Interestingly, myelin expresses the pathway of heme synthesis, hence of cytochromes, that rely on heme group, in turn depending on Fe [iron] availability…a lack of essential metals such as iron produces dramatic myelin decrease. “

Med Hypotheses. 2012 Jun;78(6):707-10. doi: 10.1016/j.mehy.2012.02.015. Epub 2012 Mar 6.
Impairment of heme synthesis in myelin as potential trigger of multiple sclerosis.
Morelli A, Ravera S, Calzia D, Panfoli I.

“…An unexpected role in energizing the axon has been reported for myelin, supposed to be the site of consumption of most of oxygen in brain…Interestingly, myelin expresses the pathway of heme synthesis, hence of cytochromes, that rely on heme group, in turn depending on Fe availability…a lack of essential metals such as iron…produces dramatic myelin decrease. Myelin is a primary target, of iron shortage, indicating that in myelin Fe-dependent processes are more active than in other tissues.”
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CYTOCHROME P450 AND VITAMIN D

A disruption in the cytochrome P450 enzyme system would also interfere with the metabolism of vitamin D. The enzymes in cytochrome P450 (which depend on heme), are key enzymes of vitamin D metabolism. Vitamin D from the diet or skin synthesis is biologically inactive and requires enzymatic conversion to active metabolites.



The following study confirms the importance of the cytochrome P450 enzyme system in the metabolism of vitamin D. The researchers concluded that the cytochrome P450 enzyme CYP7A1 catalyzes “multiple reactions” involved in the metabolism of vitamin D3.

Front Biosci. 2005 Jan 1;10:119-34. Print 2005 Jan 1.
Metabolism of vitamin D3 by cytochromes P450.
Sakaki T, Kagawa N, Yamamoto K, Inouye K.

“The vitamin D3 25-hydroxylase (CYP27A1), 25-hydroxyvitamin D3 1alpha-hydroxylase (CYP27B1) and 1alpha,25-dihydroxyvitamin D3 24-hydroxylase (CYP24A1) are members of the cytochrome P450 superfamily, and key enzymes of vitamin D3 metabolism…These results indicated that human CYP27A1 catalyzes multiple reactions involved in the vitamin D3 metabolism…”


Here are a few additional studies.



J Lipid Res. 2013 Apr 6. [Epub ahead of print]
Cytochrome P450-mediated metabolism of vitamin D.
Jones G, Prosser DE, Kaufmann M.

"The vitamin D signal transduction system involves a series of cytochrome P450-containing sterol hydroxylases to generate and degrade the active hormone..."




Int J Mol Med. 2001 Feb;7(2):201-9.
Cytochrome P450 enzymes in the bioactivation of vitamin D to its hormonal form (review).
Wikvall K.

"The formation of 1alpha,25-dihydroxyvitamin D3 requires a 25-hydroxylation followed by a 1alpha-hydroxylation catalyzed by cytochrome P450 (CYP) enzymes in liver and kidney."




Front Biosci. 2004 Sep 1;9:3007-18.
Eight cytochrome P450s catalyze vitamin D metabolism.
Ohyama Y, Yamasaki T.

"At present, six cytochrome P450s (CYP2C11, 27A1, 2D25, 2R1, 3A4, and 2J3) are found to exhibit vitamin D 25-hydroxylation activities..."






HEME AND CATALASE

Heme is also necessary to produce one of the most important antioxidant enzymes in oligodendrocytes-catalase. In the following study the researchers stated, “If the catalase antioxidant system fails, oligodendroglial cell death may follow.” In addition, the researchers stated, “Furthermore, the hydroxylations that produce 1,25(OH)2 D3 (active vitamin D) from cholesterol are carried out by a cytochrome P450 enzyme called CYP27B1.”



Metab Brain Dis. 2012 Sep;27(3):239-53. doi: 10.1007/s11011-012-9290-1. Epub 2012 Mar 17.
The conundrum of iron in multiple sclerosis-time for an individualised approach.
van Rensburg SJ, Kotze MJ, van Toorn R.

“…Catalase, one of the foremost antioxidant enzymes in oligodendrocytes contains 4 haem groups; its production and maintenance is therefore dependent on a constant supply of iron. If the catalase antioxidant system fails, oligodendroglial cell death may follow…Futhermore, ingestion of medication or toxic substances causes the induction of cytochrome P450 which would suddenly have to be mass-produced to metabolize these chemicals. Iron deficiency could inhibit this process since each cytochrome P450 molecule contains a haem group…Furthermore, the hydroxylations that produce 1,25(OH)2 D3 (active vitamin D) from cholesterol are carried out by a cytochrome P450 enzyme called CYP27B1…”

LOW CATALASE

In the following study the researchers found that catalase (CAT) was decreased by about 7.7 percent in patients with MS.

Pol J Pharmacol. 1996 Jul-Aug;48(4):441-5.
Red blood cell superoxide dismutase and catalase activities in patients suffering from multiple sclerosis treated with adrenocorticotropic hormone.
Kopff M, Zakrzewska I, Czernicki J, Klem J, Strzelczyk M, Chmielewski H.

“…while that of CAT-by about 7.7% …in comparison to the normal control.
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CHOLESTEROL AND CYTOCHROME P450 ENZYMES

Cytochrome P450 enzymes also play an important role in cholesterol "homeostasis", as the following studies confirm. In the first study the researchers stated, "These P450s plsay central critical roles in cholesterol metabolism."


Biochem Soc Trans. 2012 Jun 1;40(3):587-93. doi: 10.1042/BST20120077.
Cholesterol, an essential molecule: diverse roles involving cytochrome P450 enzymes.
McLean KJ, Hans M, Munro AW.


"Cholesterol is an essential molecule for eukaryotic life and is an important precursor for a wide range of physiological processes. Biosynthesis and homoeostasis of cholesterol are complex mechanisms that are tightly regulated and interlinked with activities of a number of cytochrome P450 enzymes.These P450s play central critical roles in cholesterol metabolism. Key roles include a rate-limiting reaction in the synthesis of cholesterol itself, and in the oxidative transformations of cholesterol into steroid hormones and bile acids..."




Pharmacol Ther. 2006 Dec;112(3):761-73. Epub 2006 Jul 26.
Cytochrome P450s and cholesterol homeostasis.
Pikuleva IA.


"By participating in pathways of cholesterol biosynthesis and elimination, different cytochrome P450 (P450 or CYP) enzymes play an important role in maintenance of cholesterol homeostasis. CYP51 is involved in cholesterol biosynthesis, whereas CYP 7A1, 27A1, 46A1, 7B1, 39A1, and 8B1 are the key enzymes in cholesterol catabolism to bile acids, the major route of cholesterol elimination in mammals. Cholesterol transformations to steroid hormones are also initiated by the P450 enzyme CYP11A1. Finally, one of the major drug-metabolizing P450s CYP3A4 seems to contribute to bile acid biosynthesis as well..."




In the following study the researchers concluded that cholesterol homeostasis was disturbed in patients with MS and that cholesterol synthesis was related to neurodegenerative pathological processes as seen on the MRI. In addition, the researchers stated, "The data seem to be in line with the recently reported observation that high dose statins may have a positive effect on clinical disability in secondary progressive MS."



Mult Scler. 2013 Aug 19. [Epub ahead of print]
Oxysterols and cholesterol precursors correlate to magnetic resonance imaging measures of neurodegeneration in multiple sclerosis.


Cholesterol homeostasis is important for formation and maintenance of myelin and axonal membranes in the central nervous system (CNS). The concentrations of the brain specific cholesterol metabolite 24S-hydroxycholesterol (24OHC) and cholesterol precursors have been shown to be altered in multiple sclerosis (MS)...We found decreased serum 24OHC and 27-hydroxycholesterol (27OHC) and increased CSF lathosterol in MS patients compared to control patients (p=0.018, p=0.002 and p=0.002, respectively). Subgroup analysis showed that serum 24OHC levels were negatively correlated to normalized brain volume measurements in relapse-onset MS patients (r= -0.326, p=0.004)...These results confirm that cholesterol homeostasis is disturbed in MS and suggest that changes in cholesterol synthesis are related to neurodegenerative pathological processes as seen on the MRI. The data seem to be in line with the recently reported observation that high dose statins may have a positive effect on clinical disability in secondary progressive MS.





In the following study from Johns Hopkins the researchers discuss the vital functions performed by cytochrome P450 enzymes in the brain.


Curr Drug Metab. 2004 Jun;5(3):225-34.
Cytochrome P450 in neurological disease.
Liu M, Hurn PD, Alkayed NJ.


"Advances in a multitude of disciplines support an emerging role for cytochrome P450 enzymes and their metabolic substrates and end-products in the pathogenesis and treatment of central nervous system disorders, including acute cerebrovascular injury, such as stroke, chronic neurodegenerative disease, such as Alzheimer's and Parkinson's disease, as well as epilepsy, multiple sclerosis and psychiatric disorders, including anxiety and depression. The neural tissue contains its own unique set of P450 genes that are regulated in a manner that is distinct from their molecular regulation in peripheral tissue. Furthermore, brain P450s catalyze the formation of important brain signaling molecules, such as neurosteroids and eicosanoids, and metabolize substrates as diverse as vitamins A and D, cholesterol, bile acids, as well as centrally acting drugs, anesthetics and environmental neurotoxins. These unique characteristics allow this family of proteins and their metabolites to perform such vital functions in the brain as neurotrophic support, neuroprotection, control of cerebral blood flow, temperature control, neuropeptide release, maintenance of brain cholesterol homoeostasis, elimination of retinoids from CNS, regulation of neurotransmitter levels and other functions important in brain physiology, development and disease.





As the previous study stated, cytochrome P450 enzymes are involved in the metabolism of vitamin A (retinol), as well as vitamin D, so we should be able to find evidence of an association between vitamin A and MS. The following studies confirm this association.



Expert Rev Clin Immunol. 2013 Feb;9(2):113-5. doi: 10.1586/eci.12.105.
Vitamin A: yet another player in multiple sclerosis pathogenesis?Filippi M, Preziosa P, Rocca MA.


"A combination of genetic and environmental factors probably plays a role in determining an increased susceptibility to multiple sclerosis (MS). Among these factors, vitamin D and A metabolites are likely to play a role given their immunomodulatory properties. Decreased serum vitamin D levels have been associated with clinical and MRI activity of MS. Løken-Amsrud et al. evaluated the association of retinol concentration with clinical and MRI measures of disease activity in MS patients over a 2-year period. Serum retinol levels correlated with MRI metrics of disease activity, but not with clinical findings. Following IFN-β-1a treatment, the association with MRI metrics was lost. These results support a role of vitamin A metabolites in influencing disease activity in MS."



Mult Scler. 2013 Apr;19(4):451-7. doi: 10.1177/1352458512457843. Epub 2012 Aug 20.
Retinol levels are associated with magnetic resonance imaging outcomes in multiple sclerosis.
Løken-Amsrud KI, Myhr KM, Bakke SJ, Beiske AG, Bjerve KS, Bjørnarå BT, Hovdal H, Lilleås F, Midgard R, Pedersen T, Benth JS, Torkildsen Ø, Wergeland S, Holmøy T.


"Vitamin A has immunomodulatory properties and may regulate the transcription of genes involved in remyelination...Each 1 µmol/L increase in serum-retinol reduced the odds (95% confidence interval) for new T1 gadolinium enhanced (Gd(+)) lesions by 49 (8-70)%, new T2 lesions by 42 (2-66)%, and combined unique activity (CUA) by 46 (3-68)% in simultaneous MRI scans, and 63 (25-82)% for new T1Gd(+) lesions, 49 (3-73)% for new T2 lesions and 43 (12-71)% for CUA the subsequent month. Serum-retinol also predicted new T1Gd(+) and T2 lesions six months ahead. The associations were not affected by HLA-DRB1*15, or serum levels of 25-hydroxyvitamin D, eicosapentaenoic acid or docosahexaenoic acid...Serum retinol is inversely associated with simultaneous and subsequent MRI outcomes in RRMS."
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DENDRITIC CELLS

A lack of DNase1 is associated with activation of immune system cells called "dendritic cells". I made a post on this and some additional information on dendritic cells on another thread. Here is a link to the information.
http://www.thisisms.com/forum/general-d ... 23128.html


I posted the following study on the other thread concerning dendritic cells and MS. The researchers stated that emerging evidence indicates that dendritic cells play a “critical role” in the initiation and progression of MS.

Targeting dendritic cells to treat multiple sclerosis.
Comabella, M., X. Montalban, C. Münz, J.D. Lünemann. 2010. Nat Rev Neurol. 6(9):499-507. doi: 10.1038/nrneurol.2010.112. Epub 2010 Aug 17.

“Multiple sclerosis (MS) is considered to be a predominantly T-cell-mediated disease, and emerging evidence indicates that dendritic cells have a critical role in the initiation and progression of this debilitating condition…”




Dendritic cells release proinflammatory cytokines such as interferon-gamma (IFN-gamma), tumor necrosis factor (TNF), and interleukin-6 (IL-6).




In the following study the researchers concluded that patients with MS had high levels of IFN-gamma, TNF, and IL-6 secreting dendritic cells (DC).

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. In multiple sclerosis (MS), autoreactive T cells are proposed to play a pathogenic role by secreting pro-inflammatory cytokines, but studies on DC are lacking…Patients with MS had higher levels of IFN-gamma, TNF-alpha and IL-6 secreting DC than healthy subjects..."





Researchers in the following study found an increase of TNF production preceding clinical symptoms and concluded that IFN-gamma and TNF may trigger exacerbations at a very early stage.

Acta Neurol Scand. 1988 Oct;78(4):318-23.
Increased production of interferon gamma and tumor necrosis factor precedes clinical manifestation in multiple sclerosis: do cytokines trigger off exacerbations?

Beck J, et al.

.“…Before exacerbations, however, we found an increase of…TNF production preceding clinical symptoms by a maximum of 2 weeks. In benign cases, the increase disappeared rapidly, even before the appearance of symptoms, whereas we found sequelae whenever the increase persisted during weeks. In chronic progressive patients, we frequently found intervening increases. It may be that IFN-gamma and TNF trigger off exacerbations at a very early stage and that these cytokines may also play a role in maintaining disease in chronic progressive and invalidating forms.”
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TUMOR NECROSIS FACTOR (TNF)

In the following study published in the New England Journal of Medicine the researchers concluded that the level of TNF in cerebrospinal fluid correlated with the severity and progression of MS.


N Engl J Med. 1991 Aug 15;325(7):467-72.
Association between tumor necrosis factor-alpha and disease progression in patients with multiple sclerosis.
Sharief MK, Hentges R.

“Tumor necrosis factor-alpha (TNF-alpha), is a principal mediator of the inflammatory response…These data provide evidence…of TNF-alpha in multiple sclerosis and suggest that the level of TNF-alpha in cerebrospinal fluid correlates with the severity and progression of the disease…”



Researchers in the next study discovered TNF in MS lesions and concluded that the presence of TNF in MS lesions suggests a significant role for cytokines and the immune response in disease progression.

J Exp Med. 1989 Aug 1;170(2):607-12.
Tumor necrosis factor identified in multiple sclerosis brain.
Hofman FM, Hinton DR, Johnson K, Merrill JE.

“Frozen brain specimens from patients with multiple sclerosis (MS) and other neurologic diseases were analyzed using immunocytochemical techniques for the presence of TNF…TNF+ cells were demonstrated. At the lesion site in MS, TNF+ staining is associated with both astrocytes and macrophages…The presence of TNF in MS lesions suggests a significant role for cytokines and the immune response in disease progression.”



High levels of TNF will produce such symptoms as malaise, night sweats, sore throat, swollen glands, and low-grade fevers. Elevated TNF may be the reason why some MS patients say they feel as if they always have the flu. This is the same part of the immune system that would be activated if you actually did have the flu.

Tumor necrosis factor kicks off a process called an “acute phase response”. This can show up in your blood work as elevated CRP or C-reactive protein. Locally, TNF can cause heat, redness, swelling, and pain--as seen in joints affected by rheumatoid arthritis.


CACHEXIA

Elevated tumor necrosis factor can also lead to a serious condition in MS patients known as cachexia (Kamalian, 1975). Cachexia is a clinical wasting syndrome characterized by unintended and progressive weight loss, weakness, and low body fat and muscle. Cachexia is not caused by nutritional intake, but is rather a metabolic state in which a "breaking down" rather than "building up" occurs in bodily tissues, no matter how much nutritional intake occurs. Cachexia is a positive risk factor for death, meaning if someone has cachexia, the chance of death from the underlying condition is increased dramatically.



In the following study the researchers stated that tumor necrosis factor, also known as “cachectin” for its role in cachexia, induces cachexia.

J Exp Med. 1988 Mar 1;167(3):1211-27.
Cachectin/tumor necrosis factor induces cachexia, anemia, and inflammation.
Tracey KJ, Wei H, Manogue KR, Fong Y, Hesse DG, Nguyen HT, Kuo GC, Beutler B, Cotran RS, Cerami A, et al.

“Cachexia is a potentially lethal syndrome of unknown etiology characterized by anorexia [loss of appetite], weight loss, and protein wasting that frequently complicates the treatment of chronic inflammation and cancer…These data suggests that the exposure of the normal host to cachectin is capable of inducing a pathophysiological syndrome of cachexia, anemia, and inflammation…”


PSORIASIS

Tumor necrois factor is also implicated in another another chronic disease research has found to be associated with MS—psoriasis (Wu, 2012). Psoriasis is a chronic autoimmune disease that appears on the skin. It occurs when the immune system sends out faulty signals that speed up the growth cycle of cells. The most common form, plaque psoriasis, is often seen as red and white hues on the top first layer of the skin. Psoriasis can also cause inflammation of the joints, which is known as psoriatic arthritis.


In the following study from the University of Utah School of Medicine the study authors concluded that TNF plays a major role in the pathogenesis of psoriasis and psoriatic arthritis (PsA).


Potential of tumor necrosis factor inhibitors in psoriasis and psoriatic arthritis.
Krueger, G., K. Callis. 2004. Arch Dermatol.140:218-225.

“Aberrant regulation of TNF is involved in the development of psoriasis and PsA...Tumor necrosis factor plays a major role in the pathogenesis of psoriasis and PsA…”



ALLODYNIA

Elevated TNF can also lead to a painful condition experienced by MS patients known as allodynia (Sakai, 2004). Allodynia is pain, generally on the skin, and is an exaggerated response to stimuli that normally doesn’t cause pain. Someone with allodynia may experience pain from a light touch or fabric brushing against the skin. It is often described as a burning sensation.

Specialized nerve cells, called nociceptors, are the cells involved in allodynia. Nociceptors sense information involving skin pain and temperature and transmit it to the spinal cord. Tumor necrosis factor binds to receptors expressed on nociceptors and leads to the exaggerated pain response found in allodynia (Wei, 2007).
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INFLAMMATORY BOWEL DISEASE, MS, and TNF

An excess of TNF can also lead to inflammatory bowel disease (an umbrella term for ulcerative colitis and Crohn’s disease). One of the drugs used to treat Crohn's disease is Humira. The Humira website states, “Many patients with Crohn’s disease produce too much of a protein called tumor necrosis factor (TNF) in their body. This excess attacks the intestines and other parts of the gastrointestinal (GI) tract, and can cause them to become inflamed. This can result in the pain, diarrhea, and other symptoms of Crohn’s disease. Humira belongs to a class of biologics known as TNF blockers” (Humira.com).


Tumor necrosis factor is also involved in the pathogenesis of ulcerative colitis. Ulcerative colitis (UC) is a form of inflammatory bowel disease that causes ulcers or open sores in the colon (large intestine). In the study entitled “Tumor necrosis factor in ulcerative colitis and diverticular disease associated colitis” the study authors stated, “In particular, the role of tumor necrosis factor alpha (TNF-a) in UC pathogenesis has been clarified by serological and immunohistochemical studies in humans and by experimental models” (Hassan, 2007).




Due to the elevated levels of TNF found in patients with MS, we would expect to see an increased prevalence of inflammatory bowel disease (IBD). In the following study published in Neuroepidemiology the researchers concluded that the prevalence of IBD is increased in patients with MS.


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.


“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.”





In the following study published in Gastroenterology the researchers concluded that demyelinating diseases, such as MS, occur more commonly among patients with IBD.

Gastroenterology. 2005 Sep;129(3):819-26.
Increased risk for demyelinating diseases in patients with inflammatory bowel disease.
Gupta G, Gelfand JM, Lewis JD.

“…In the cohort study, the incidence of MS/D/ON was higher in patients with Crohn's disease and ulcerative colitis compared with their matched controls…Demyelinating diseases occur more commonly among patients with IBD than among non-IBD patients…”





RECURRENT APHTHOUS ULCERATIONS

If TNF can cause ulcers in the colon, then logically, it could also be responsible for ulcers in oral mucosal tissue. Recurrent aphthous ulcerations (canker sores) are a common occurrence in patients with MS (Chemaly, 2000).


In the study entitled “Salivary interleukin-6 and tumor necrosis factor-alpha in patients with recurrent aphthous ulceration” the researchers stated, “Recurrent aphthous ulceration (RAU) is a well-known oral disease which seems to be mediated principally by the immune system” (Boras, 2006). The researchers found significant differences in salivary TNF between healthy controls and patients with acute RAU. No differences in salivary interleukin-6 between the groups could be found.





Tumor necrosis factor is also implicated in chronic urticaria (hives), which can be experienced by patients with MS. As the following study states, the primary cell involved in chronic urticaria is likely the mast cell, which releases tumor necrosis factor.

Treatment of refractory chronic urticaria with tumor necrosis factor–alfa inhibitors.
Wilson, L.H., Eliason, M.J., Leiferman, K.M., Hull, C.M., Powell, D.L. 2011. Journal of the American Academy of Dermatology Volume 64, Issue 6 , Pages 1221-1222.

“The pathogenic mechanisms of chronic urticaria are not well understood, but the primary effector cell is likely the mast cell. Activated mast cells release mediators, including tumor necrosis factor–alfa (TNF-α), that recruit other immune cells and play a role in perpetuating an urticarial response. TNF-α is known to exist preformed in mast cells and to be newly synthesized upon mast cell activation. Several preclinical investigations have shown an upregulation of TNF-α in patients with chronic urticaria.”
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Researchers in the following study concluded their results point to TNF as a primary neurotoxic molecule in progressive forms of MS.

Mult Scler. 2013 Jul 25.
Tumor necrosis factor is elevated in progressive multiple sclerosis and causes excitotoxic neurodegeneration.
Rossi S, Motta C, Studer V, Barbieri F, Buttari F, Bergami A, Sancesario G, Bernardini S, De Angelis G, Martino G, Furlan R, Centonze D.

“The objective of this paper is to investigate the synaptic mechanism of inflammatory neurodegeneration in progressive forms of MS…Our results point to TNF as a primary neurotoxic molecule in progressive forms of MS.”





Research has shown that TNF also induces oligdendrocyte (cell that synthesizes and maintains myelin) apoptosis (cell death). In the following study the researchers found that oligodendrocyte numbers were reduced by approximately 40% when exposed to TNF. The researchers concluded their data supported the hypothesis that TNF can mediate oligodendrocyte and myelin damage.

Endocrinology. 1999 Jul;140(7):3063-72.
Insulin-like growth factor I protects oligodendrocytes from tumor necrosis factor-alpha-induced injury.
Ye P, D'Ercole AJ.

“Tumor necrosis factor-alpha (TNF-alpha) has been causally implicated in several demyelinating disorders, including multiple sclerosis. Because insulin-like growth factor I (IGF-I) is a potent stimulator of myelination, we investigated whether it can protect oligodendrocytes and myelination from TNF-alpha-induced damage…TNF-alpha decreased oligodendrocyte number by approximately 40% and doubled the number of apoptotic oligodendrocytes and their precursorsSimultaneous addition of IGF-I to TNF-alpha-treated cultures negated these TNF-alpha effects nearly completely…IGF-I abrogated TNF-alpha-induced reductions in a dose- and time-dependent manner…These data support the hypothesis that TNF-alpha can mediate oligodendrocyte and myelin damage, and indicate that IGF-I protects oligodendrocytes from TNF-alpha insults by blocking TNF-alpha-induced apoptosis, and by promoting oligodendrocyte and precursor proliferation/differentiation and myelin protein gene expression.”



In the previous study the researchers found that insulin-like growth factor I (IGF-I) protected oligodendrocytes from TNF. The researchers discovered that simultaneous addition of IGF-I to TNF treated cultures nearly completely negated TNF-induced damage.

IGF-1 is a hormone similar in structure to insulin. In the following study the researchers concluded that IGF-I is a potent inducer of oligodendrocyte development.


Proc Natl Acad Sci U S A. 1986 Feb;83(3):822-6.
Insulin-like growth factor I/somatomedin C: a potent inducer of oligodendrocyte development.
McMorris FA, Smith TM, DeSalvo S, Furlanetto RW.

"results indicate that IGF-I is a potent inducer of oligodendrocyte development..."




REDUCTION IN BIOACTIVE INSULIN-LIKE GROWTH FACTOR I (IGF-1) AND GROWTH HORMONE (GH) DEFICIENCY

In the next study published in the European Journal of Neurology the researchers concluded that MS and higher disability seemed to be associated with a reduction in bioavailability of IGF-1.

Eur J Neurol. 2011 Dec;18(12):1402-6. doi: 10.1111/j.1468-1331.2011.03433.x. Epub 2011 May 18.
Insulin-like growth factor (IGF)-I and IGF-binding protein-3 serum levels in relapsing-remitting and secondary progressive multiple sclerosis patients.
Lanzillo R, Di Somma C, Quarantelli M, Ventrella G, Gasperi M, Prinster A, Vacca G, Pivonello C, Orefice G, Colao A, Morra VB.

“Insulin-like growth factor (IGF)-I has a role in remyelination…Therefore, MS and higher disability seem to be associated with a reduction in bioavailability of IGF-I…”



In the following study the researchers found that TNF markedly reduced IGF-1 and increased IGF binding proteins, likely leading to a reduction in bioactive IGF-1.


Circulation. 2002 Mar 12;105(10):1220-5.
Tumor necrosis factor-alpha regulates insulin-like growth factor-1 and insulin-like growth factor binding protein-3 expression in vascular smooth muscle.
Anwar A, Zahid AA, Scheidegger KJ, Brink M, Delafontaine P.

"...TNF-alpha markedly decreased IGF-1 mRNA (85% reduction at 24 hours) and increased IGFBP-3 mRNA and protein (300% increase at 24 hours)...TNF-alpha, a cytokine that is upregulated in atherosclerotic plaques, reduces IGF-1 and increases IGFBP-3 in VSMCs, likely leading to a reduction in bioactive IGF-1..."



Researchers in the following study stated that the process of remyelination depends on numerous interactive factors, including the presence of various growth factors, the most important of which is IGF-1. In addition, the study authors stated that the most powerful regulator of IGF-I is growth hormone (GH). The researchers concluded that patients with MS had a deficiency of GH in the cerebrospinal fluid.


Clin Neurol Neurosurg. 2006 Mar;108(3):255-8. Epub 2006 Jan 18.
Growth hormone and insulin growth factor-I levels in plasma and cerebrospinal fluid of patients with multiple sclerosis.
Poljakovic Z, Zurak N, Brinar V, Korsic M, Basic S, Hajnsek S.

“Multiple sclerosis (MS) has several clinically different forms. Whereas the illness progresses slowly in most of the patients, 10% have an aggressively progressive course with fatal outcome without signs of remyelination capability. The process of remyelination depends on numerous interactive factors, including the presence of various growth factors, the most important of which in the adult is insulin growth factor-I (IGF-I). On the other hand, the most powerful postnatal regulator of IGF-I is growth hormone (GH), which also acts as a neuroprotective and an antiapoptotic agent, and has direct influence on myelination…positive finding was a deficiency of GH in the CSF of MS patients…”



Growth hormone (GH) is the most abundant hormone produced by the pituitary gland and the body’s foremost anti-ageing hormone. Growth hormone stimulates growth, cell reproduction, and regeneration. It is essential for normal muscle metabolism and repair. Growth hormone also regulates the amount of sugar in the blood and promotes the breakdown of fat.


Many people believe that as we age the amount of GH in our body decreases. In fact, the difference, generally, in growth hormone levels between adults and adolescents is not in the amount of GH, but in its release. For instance, adequate amounts of blood protein levels will stimulate the release of GH from the pituitary gland. The inability to digest proteins, due to a lack of protease, would result not only in a reduction of the amount of GH, but also a reduction in the release of GH from the pituitary. In the following study researchers concluded that dietary protein restriction not only reduced the amount of GH, it also blunted the release of GH from the pituitary.



Dietary protein restriction impairs both spontaneous and growth hormone-releasing factor-stimulated growth hormone release in the rat.
Harel, Z. and G.S. Tannenbaum. 1993. Endocrinology 133(3):1035-43.

“These results demonstrate that lack of dietary protein blunts spontaneous pulsatile GH release…and reduces pituitary GH content and size.”
grandsons4
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Re: Some Interesting Connections

Post by grandsons4 »

A couple of articles detailing calcitriol's effect on production of TNF-alpha:

Calcitriol inhibits TNF-alpha-induced inflammatory cytokines in human trophoblasts.
These data show that calcitriol prevents TNF-alpha induction of inflammatory cytokines through a process likely to be mediated by the vitamin D receptor.
http://www.ncbi.nlm.nih.gov/pubmed/19501915

Vitamin D has a direct immunomodulatory effect on CD8+ T cells of patients with early multiple sclerosis and healthy control subjects.
We assessed the cytokine profile of EBV-specific CD8+ T cells of 10 early MS patients and 10 healthy control subjects with or without 1,25(OH)(2)D(3) and found that, with 1,25(OH)(2)D(3), these cells secreted less IFN-γ and TNF-α and more IL-5 and TGF-β.
http://www.ncbi.nlm.nih.gov/pubmed/21186064
Annesse
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Posts: 238
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Re: Some Interesting Connections

Post by Annesse »

Thank you grandsons4~I was going to post the first study you posted in the next few days. As the first study you posted states, calcitriol is a "secosteroid". Steroids have strong anti-inflammatory and immunosuppressive properties.



Methylprednisolone (a corticosteroid) has also been shown to decrease TNF. For example, in the following study the researchers concluded that methylprednisolone pulse therapy had a "striking effect" on the production of TNF.

Zhonghua Nei Ke Za Zhi. 1994 Dec;33(12):827-9.
[Effects of methylprednisolone pulse therapy on TNF alpha levels in chronic nephritis].
[Article in Chinese]
Bai LQ, Chen XM, Mao J.
SourceDepartment of Nephrology, General Hospital of PLA Beijing.


"We examined the tumor necrosis factor (TNF alpha) bioactivity in patients with chronic glomerulonephritis (CGN) treated with methylprednisolone (MP) pulse therapy (1 course of 1 g/day x 3 days)...These results indicated that TNF alpha levels in serum, urine and supernatant of lymphocyte were markedly higher in chronic nephritis, the MP pulse therapy possessed a striking effect on inhibiting the production of TNF alpha in peripheral lymphocytes."
http://www.ncbi.nlm.nih.gov/pubmed/7768142




Collen E Hayes, one of the authors of the recent study posted on the board on MS and calcitriol, also authored the following study (funded by Northern Lights Pharmaceuticals) on the use of vitamin D compounds for inflammatory bowel disease. The study states that interferon-gamma and tumor necrosis factor synthesis correlate with IBD.


Vitamin D Compounds for Inflammatory Bowel Disease
Northern Lights Pharmaceuticals
MADISON, WI 53713
Principal Investigator
COLLEEN E HAYES

"The key pathological mechanism in IBD may involve a dysregulated immune response to GI tract antigens or infections. Inflammatory Th1 responses characterized by interferon-gamma and tumor necrosis factor-alpha synthesis correlate with IBD..."http://sbirsource.com/sbir/awards/87294 ... el-disease#
Annesse
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Posts: 238
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Re: Some Interesting Connections

Post by Annesse »

DECREASED SOMATOSTATIN AND TUMOR NECROSIS FACTOR


Somatostatin is a peptide hormone that has a large range of functions in the human body.


In the following study the researchers stated that somatostatin exerts systemic anti-inflammatory and analgesic effects, diminishes neurogenic inflammation, and decreases the release of pro-inflammatory neuropeptides.

Pharmacol Ther. 2006 Nov;112(2):440-56. Epub 2006 Jun 9.
Inhibitory effect of somatostatin on inflammation and nociception.
Pintér E, Helyes Z, Szolcsányi J.

"These data demonstrate that somatostatin is released from capsaicin-sensitive, peptidergic sensory nerve endings in response to noxious heat and chemical stimuli such as vanilloids, protons or lipoxygenase products. It reaches distant parts of the body via the circulation and exerts systemic anti-inflammatory and analgesic effects. Somatostatin binds to G-protein-coupled membrane receptors (sst(1)-sst(5)) and diminishes neurogenic inflammation by prejunctional action on sensory-efferent nerve terminals, as well as by postjunctional mechanisms on target cells. It decreases the release of pro-inflammatory neuropeptides from sensory nerve endings and also acts on receptors of vascular endothelial, inflammatory and immune cells. Analgesic effect is mediated by an inhibitory action on peripheral terminals of nociceptive neurons, since circulating somatostatin cannot exert central action."
http://www.ncbi.nlm.nih.gov/pubmed/16764934




In the following study the researchers found that the somatostatin level was "significantly decreased" in the cererospinal fluid of patients with MS.


Brain Res Bull. 1990 Sep;25(3):411-3.
Lumbar cerebrospinal fluid concentrations of somatostatin and neuropeptide Y in multiple sclerosis.
Vécsei L, Csala B, Widerlöv E, Ekman R, Czopf J, Pàlffy G.


"The cerebrospinal fluid (CSF) concentrations of somatostatin and neuropeptide Y were investigated by use of radioimmunoassay in patients suffering from chronic progressive multiple sclerosis. The somatostatin level was significantly decreased in the CSF of patients with multiple sclerosis compared to the control group. The magnitude of this change was more pronounced in patients with severe clinical symptoms of the illness. The CSF neuropeptide Y concentration did not differ from the control values. These findings suggest a selective involvement of somatostatin neurotransmission in multiple sclerosis."
http://www.ncbi.nlm.nih.gov/pubmed/1981332



In the following study the researchers concluded that their data indicated that decreased levels of somatostatin contributed to the failure of the blood brain barrier in MS. In addition the researchers found that most of the MS cerebrospinal fluid samples studied had lower somatostatin and higher TNF in comparison to non-MS patients.


Biochem Pharmacol. 2013 Aug 15;86(4):497-507. doi: 10.1016/j.bcp.2013.06.001. Epub 2013 Jun 13.
Somatostatin preserved blood brain barrier against cytokine induced alterations: possible role in multiple sclerosis.
Basivireddy J, Somvanshi RK, Romero IA, Weksler BB, Couraud PO, Oger J, Kumar U.
Sour

"Most of the cerebrospinal fluid (CSF) samples studied from definite MS patients exhibited lower somatostatin (SST)-like immunoreactivity and higher expression of TNF-α in comparison to non-MS patients....These data indicate that decreased levels of SST contribute to failure of the BBB in MS.
http://www.ncbi.nlm.nih.gov/pubmed/23770458



In the following study the researchers found that TNF significantly reduced somatostatin (SST) in a dose-dependent fashion.

J Surg Res. 2005 Feb;123(2):294-301.
TNF-alpha decreases expression of somatostatin, somatostatin receptors, and cortistatin in human coronary endothelial cells.
Yan S, Li M, Chai H, Yang H, Lin PH, Yao Q, Chen C.

"The objective of this study was to determine the expression of somatostatin (SST) and its receptors (SSTRs) and their regulation by TNF-alpha as well as cell proliferation in response to SST in human endothelial cells...After treatment with TNF-alpha, the mRNA levels of SST, SSTR-1, SSTR-2, and SSTR-5 were significantly reduced in a dose-dependent fashion. TNF-alpha (1 ng/ml) reduced SST, SSTR-1, SSTR-2, and SSTR-5 by 93, 51, 85, and 99%, respectively, compared to controls (P < 0.001, t test). ...TNF-alpha treatment decreased SST inhibitory potential in cell proliferation...Furthermore, treatment with exogenous SST significantly reduces cell proliferation, and this inhibitory effect is also decreased by TNF-alpha."
http://www.ncbi.nlm.nih.gov/pubmed/15680393


In the previous study the researchers stated that TNF also decreased somatostatin "inhibitory potential in cell proliferation". Somatostatin and its analogues have been shown to have direct inhibitory effects on the growth of human breast cancer cells, as the following studies confirms. The decreased levels of somatostatin would likely be one of the factors involved in the increased risk of breast cancer found in patients with MS.


Cancer Res. 1987 Mar 15;47(6):1566-70.
Direct inhibitory effects of somatostatin (analogues) on the growth of human breast cancer cells.
Setyono-Han B, Henkelman MS, Foekens JA, Klijn GM.

"Various hormones and growth factors are involved in the growth regulation of breast (tumor) cells. In this report we show for the first time that an analogue of the neuropeptide somatostatin (Sandostatin) can also influence the proliferation of human breast cancer cells (MCF-7), namely, in an inhibitory fashion...These results, together with the observation that high affinity binding sites for an iodinated derivative of Sandostatin are present in MCF-7 cells, support the conclusion that somatostatin and analogues act directly on breast cancer cells."



Mol Cell Endocrinol. 2008 May 14;286(1-2):251-61. doi: 10.1016/j.mce.2008.01.006. Epub 2008 Jan 20.
Biology of somatostatin in breast cancer.
Watt HL, Kharmate G, Kumar U.


"The biological effects of the neuropeptide somatostatin (SST) are mediated via a family of five somatostatin receptors (SSTRs) belonging to a family of G-protein-coupled receptors (GPCRs). SSTR regulate the secretion of hormones, growth factors, neurotransmission and cell growth in receptor-specific manner. In addition, SST plays an inhibitory role in several mammary cancer models. These effects are mediated both indirectly through inhibition of hormones and growth factors which promote tumor growth as well as directly via SSTRs present on tumor cells to inhibit mitogenic signaling of growth factor receptor kinases leading to growth arrest and induction of apoptosis..."
http://www.ncbi.nlm.nih.gov/pubmed/18308465
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