NEUROLOGICAL

In this section we will provide scientific studies related to the ingredients contained in the NMS Neuromuscular Support Formula that deal with Neurological conditions in the body. This is additional information that we feel relates to the efficacy of this amazing product and should also give you an idea of the breadth and scope of the information about the ingredients in the NMS Formula dealing with health conditions other than Pain & Inflammation.

NEUROLOGICAL --- THIAMINE

Thiamine (thye' a min)
Why is this medication prescribed?
Thiamine is a vitamin used by the body to break down sugars in the diet. The medication helps correct nerve and heart problems that occur when a person's diet does not contain enough thiamine.
This medication is sometimes prescribed for other uses; ask your doctor or pharmacist for more information.
How should this medicine be used?
Thiamine comes in tablets to take by mouth. It is usually taken three times a day with meals. If you have a thiamine deficiency, your doctor may prescribe thiamine for 1 month or more. Follow the directions on your prescription label or package label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take thiamine exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.
Thiamine should be taken with meals. If you are taking an extended-release (long-acting) product, do not chew or crush the tablet. There are some tablets that can be crushed and mixed with food.

What special precautions should I follow?
Before taking thiamine,

• tell your doctor and pharmacist if you are allergic to thiamine or any other drugs.
• tell your doctor and pharmacist what prescription and nonprescription medications you are taking, including other vitamins.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking thiamine, call your doctor.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking thiamine.

What special dietary instructions should I follow?
Your doctor may suggest that you eat more potatoes, whole-grain cereals and breads, meats (especially pork and liver), peas, beans, and nuts to increase the thiamine in your diet.
What should I do if I forget a dose?
Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.
What side effects can this medication cause?
Thiamine tablets usually do not cause any side effects.
What storage conditions are needed for this medicine?
Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom). Throw away any medication that is outdated or no longer needed. Talk to your pharmacist about the proper disposal of your medication.
In case of emergency/overdose
In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.
What other information should I know?
Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your response to thiamine.
It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.
Other names
Vitamin B1
Copyright © 2009 American Society of Health-System Pharmacists, Inc. Disclaimer

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Nutr Clin Pract. 2008 Oct-Nov;23(5):487-93.
Characteristics of thiamin and its relevance to the management of heart failure.
Wooley JA.
University of Michigan Health System, Ann Arbor, MI, USA. jenwoole@med.umich.edu

Heart failure (HF) is a major public health problem in the United States that puts a significant burden on both patients and the healthcare system. The prevalence of malnutrition in HF patients is well-known and correlates with a dramatic decline in quality of life and disease progression, and is associated with high morbidity and mortality rates. The implication of HF on micronutrient status is underrecognized in the quest to offer "best practice" medical, device, and surgical interventions to this population. The micronutrient thiamin is of particular interest in the management of HF for several reasons: (a) HF is a disease of the elderly whose micronutrient status is in need of attention; (b) HF patients tend to have inadequate nutrient intake, which has been associated with thiamin deficiency; (c) thiamin deficiency (wet beriberi) impairs cardiac performance and can mimic the signs and symptoms of HF thereby potentially exacerbating the underlying disease; (d) use of loop diuretics to manage fluid and sodium imbalances associated with HF may cause the hyperexcretion of thiamin, thereby increasing the risk of deficiency; and (e) the prevention of thiamin deficiency should be a routine component in the overall management of this disease.

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Hum Exp Toxicol. 2007 Mar;26(3):251-7.
The Neurotoxicity of Alcohol
Harper C.
Department of Pathology, Blackburn Building, D06, University of Sydney, NSW 2006, Australia. cliveh@med.usyd.edu.au

Patterns of drinking are changing throughout the world and in many countries this will be detrimental to the health and welfare of the local population. Even uncomplicated alcoholics who have no specific neurological or hepatic problems show signs of regional brain damage and cognitive dysfunction. Many of these changes are exaggerated and other brain regions damaged in patients who have additional vitamin B1 (thiamine) deficiency (Wernicke-Korsakoff syndrome). Quantitative neuropathology techniques and improvements in neuroimaging have contributed significantly to the documentation of these changes but mechanisms underlying the damage are not understood. A human brain bank targeting alcohol cases has been established in Sydney, Australia and provides fresh and frozen tissue for alcohol researchers. The tissues can be used to test hypotheses developed from structural neuropathological studies or from animal models and in vitro studies. Identification of reversible pathological changes and preventative medical approaches in alcoholism should enhance rehabilitation and treatment efforts, thereby mitigating debilitating morbidities and reducing mortality associated with this universal public health problem.

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Brain Res. 2007 Mar 30;1139:210-9. Epub 2007 Jan 8
Selective septohippocampal - but not forebrain amygdalar - cholinergic dysfunction in diencephalic amnesia.
Savage LM, Roland J, Klintsova A
Behavioral Neuroscience Program, Department of Psychology, Binghamton University, State University of New York, Binghamton, NY 13902, USA. lsavage@binghamton.edu

A rodent model of diencephalic amnesia, pyrithiamine-induced thiamine deficiency (PTD), was used to investigate diencephalic-limbic interactions. In-vivo acetylcholine (ACh) efflux, a marker of memory-related activation, was measured in the hippocampus and the amygdala of PTD-treated and pair-fed (PF) control rats while they were tested on a spontaneous alternation task. During behavioral testing, all animals displayed increases in ACh efflux in both the hippocampus and amygdala. However, during spontaneous alternation testing ACh efflux in the hippocampus and the alternation scores were higher in PF rats relative to PTD-treated rats. In contrast, ACh efflux in the amygdala was not suppressed in PTD treated rats, relative to PF rats, prior to or during behavioral testing. In addition, unbiased stereological estimates of the number of choline acetyltransferase (ChAT) immunopositive neurons in the medial septal/diagonal band (MS/DB) and nucleus basalis of Meynert (NBM) also reveal a selective cholinergic dysfunction: In PTD-treated rats a significant loss of ChAT-immunopositive cells was found only in the MS/DB, but not in the NBM. Significantly, these results demonstrate that thiamine deficiency causes selective cholinergic dysfunction in the septo-hippocampal pathway.

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Neuroscience. 2007 Feb 9;144(3):1045-56. Epub 2006 Nov 28
Thiamine deficiency induces endoplasmic reticulum stress in neurons.
Wang X, Wang B, Fan Z, Shi X, Ke ZJ, Luo J.
Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, PR China.

Thiamine (vitamin B1) deficiency (TD) causes region selective neuronal loss in the brain; it has been used to model neurodegeneration that accompanies mild impairment of oxidative metabolism. The mechanisms for TD-induced neurodegeneration remain incompletely elucidated. Inhibition of protein glycosylation, perturbation of calcium homeostasis and reduction of disulfide bonds provoke the accumulation of unfolded proteins in the endoplasmic reticulum (ER), and cause ER stress. Recently, ER stress has been implicated in a number of neurodegenerative models. We demonstrated here that TD up-regulated several markers of ER stress, such as glucose-regulated protein (GRP) 78, growth arrest and DNA-damage inducible protein or C/EBP-homologus protein (GADD153/Chop), phosphorylation of eIF2alpha and cleavage of caspase-12 in the cerebellum and the thalamus of mice. Furthermore, ultrastructural analysis by electron microscopic study revealed an abnormality in ER structure. To establish an in vitro model of TD in neurons, we treated cultured cerebellar granule neurons (CGNs) with amprolium, a potent inhibitor of thiamine transport. Exposure to amprolium caused apoptosis and the generation of reactive oxygen species in CGNs. Similar to the observation in vivo, TD up-regulated markers for ER stress. Treatment of a selective inhibitor of caspase-12 significantly alleviated amprolium-induced death of CGNs. Thus, ER stress may play a role in TD-induced brain damage.

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Eur J Neurosci. 2006 Mar;23(5):1172-88.
Gene expression changes in thalamus and inferior colliculus associated with inflammation, cellular stress, metabolism and structural damage in thiamine deficiency.
Vemuganti R, Kalluri H, Yi JH, Bowen KK, Hazell AS.
Department of Neurological Surgery, University of Wisconsin, Madison, USA.

Identification of gene expression changes that promote focal neuronal death and neurological dysfunction can further our understanding of the pathophysiology of these disease states and could lead to new pharmacological and molecular therapies. Impairment of oxidative metabolism is a pathogenetic mechanism underlying neuronal death in many chronic neurodegenerative diseases as well as in Wernicke's encephalopathy (WE), a disorder induced by thiamine deficiency (TD). To identify functional pathways that lead to neuronal damage in this disorder, we have examined gene expression changes in the vulnerable thalamus and inferior colliculus of TD rats using Affymetrix Rat Genome GeneChip analysis in combination with gene ontology and functional categorization assessment utilizing the NetAffx GO Mining Tool. Of the 15 927 transcripts analysed, 125 in thalamus and 141 in inferior colliculus were more abundantly expressed in TD rats compared with control animals. In both regions, the major functional categories of transcripts that were increased in abundance after TD were those associated with inflammation (approximately 33%), stress (approximately 20%), cell death and repair ( approximately 26%), and metabolic perturbation (approximately 19%), together constituting approximately 98% of all transcripts up-regulated. These changes occurred against a background of neuronal cell loss and reactive astro- and microgliosis in both structures. Our results indicate that (i) TD produces changes in gene expression that are consistent with the observed dysfunction and pathology, and (ii) similar alterations in expression occur in thalamus and inferior colliculus, brain regions previously considered to differ in pathology. These findings provide important new insight into processes responsible for lesion development in TD, and possibly WE.

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NEUROLOGICAL --- VITAMIN B6

Indian J Physiol Pharmacol. 2004 Jul;48(3):304-1
Effect of pyridoxine deficiency on the structural and functional development of hippocampus.
Krishna AP, Ramakrishna T.
Department of Physiology, K. S. Hegde Medical Academy, Nithyananda Nagar, Deralakatte, Mangalore-575 018.

In this study it was attempted to understand the effect of pyridoxine deficiency on the structural and functional development of the hippocampus. Hippocampus has been closely associated with complex neuroendocrine control of physiological activities as well as behavioural responses including learning process and memory retention. Prenatal, preweanling and weanling deficiency of pyridoxine was induced in the experimental rats by feeding dams with diet deficient in pyridoxine during pregnancy and lactation. The general growth profile for pyridoxine deficient (PD) rats is compared with control ones. The structural changes in the hippocampus of pyridoxine deficient rats was investigated using the histological techniques. Hippocampal electrical activity was recorded from in vitro brain slice preparation. The study clearly showed the structural impairment in the hippocampus of PD rats. These anatomic anomalies might be related to poor neurointegrative development and neurophysiological deficits that occur in young one. The electrical activity recorded from hippocampal slices of PD rats showed significant variation when compared to controls. Pyridoxine deficiency is common in pregnant women who used anovulatory steroids before pregnancy. The pyridoxine deficiency of the mother may result in permanent behavioural abnormality and intellectual deficit in the progeny.

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J Nutr. 2004 Dec;134(12):3350-4.
Vitamin B-6 deficiency prolongs the time course of evoked dopamine release from rat striatum.
Tang FI, Wei IL.
School of Nursing, National Yang-Ming University, Taipei 112, Taiwan.

Vitamin B-6-deficient animals exhibit motor abnormalities. To investigate the possible physiologic alterations in the dopaminergic nervous system in vitamin B-6 deficiency, dopamine release in the striatum of vitamin B-6-deficient rats was determined using in vivo electrochemistry. Male Sprague-Dawley rats, 3 wk old, weighing 50-60 g, were randomly assigned to a control (7 mg pyridoxine HCl/kg diet), vitamin B-6-deficient (0 mg pyridoxine HCl/kg diet), or pair-fed (7 mg pyridoxine HCl/kg diet) group. After 8 wk of dietary treatment, plasma concentrations of pyridoxal 5'-phosphate as well as the striatal pyridoxal 5'-phosphate and pyridoxamine 5'-phosphate were significantly lower in the vitamin B-6-deficient group than in the control and pair-fed groups. The dopamine concentrations of the striatum and the magnitude of the dopamine release after local application of KCl did not differ among the groups. However, the time required for KCl-evoked dopamine release to reach its peak level was significantly longer for the vitamin B-6-deficient rats than for controls. In addition, the decay time from the peak to one-half of the KCl-evoked dopamine release was also significantly prolonged in vitamin B-6-deficient rats compared with the control group. The results indicate that the cellular content of dopamine does not reflect the functional state of dopaminergic neurons in vitamin B-6 deficiency. The time course for release of dopamine and decay of the released dopamine is prolonged by vitamin B-6 deficiency, which might contribute to the motor abnormalities of the deficient rats.

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Psychother Psychosom. 2004 Nov-Dec;73(6):340-3.
Vitamin B6 level is associated with symptoms of depression.
Hvas AM, Juul S, Bech P, Nex� E.
Department of Clinical Biochemistry, Aarhus University Hospital, AKH, Aarhus, Denmark. am.hvas@dadlnet.dk

BACKGROUND: A low level of vitamin B6 might theoretically cause depression as vitamin B6 is a cofactor in the tryptophan-serotonin pathway. In the present study, we examined the association between depression and the phosphate derivative of vitamin B6 in plasma, pyridoxal phosphate (PLP). METHODS: In 140 individuals, symptoms of depression were evaluated by the Major Depression Inventory, and biochemical markers of vitamin B deficiency were measured. RESULTS: We found that 18 (13%) individuals were depressed. A low plasma level of PLP was significantly associated with the depression score (p=0.002). No significant association was found between depression and plasma vitamin B12 (p=0.13), plasma methylmalonic acid (p=0.67), erythrocyte folate (p=0.77), and plasma total homocysteine (p=0.16). CONCLUSION: Our study suggests that a low level of plasma PLP is associated with symptoms of depression. Randomized trials are now justified and needed in order to examine whether treatment with vitamin B6 may improve symptoms of depression.

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NEUROLOGICAL --- CURCUMIN

Am J Hum Genet. 2007 Sep;81(3):438-53. Epub 2007 Aug 3.
Oral curcumin mitigates the clinical and neuropathologic phenotype of the trembler-j mouse: a potential therapy for inherited neuropathy.
Khajavi M, Shiga K, Wiszniewski W, He F, Shaw CA, Yan J, Wensel TG, Snipes GJ, Lupski JR.
From the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.

Mutations in myelin genes cause inherited peripheral neuropathies that range in severity from adult-onset Charcot-Marie-Tooth disease type 1 to childhood-onset Dejerine-Sottas neuropathy and congenital hypomyelinating neuropathy. Many myelin gene mutants that cause severe disease, such as those in the myelin protein zero gene (MPZ) and the peripheral myelin protein 22 gene (PMP22), appear to make aberrant proteins that accumulate primarily within the endoplasmic reticulum (ER), resulting in Schwann cell death by apoptosis and, subsequently, peripheral neuropathy. We previously showed that curcumin supplementation could abrogate ER retention and aggregation-induced apoptosis associated with neuropathy-causing MPZ mutants. We now show reduced apoptosis after curcumin treatment of cells in tissue culture that express PMP22 mutants. Furthermore, we demonstrate that oral administration of curcumin partially mitigates the severe neuropathy phenotype of the Trembler-J mouse model in a dose-dependent manner. Administration of curcumin significantly decreases the percentage of apoptotic Schwann cells and results in increased number and size of myelinated axons in sciatic nerves, leading to improved motor performance. Our findings indicate that curcumin treatment is sufficient to relieve the toxic effect of mutant aggregation-induced apoptosis and improves the neuropathologic phenotype in an animal model of human neuropathy, suggesting a potential therapeutic role in selected forms of inherited peripheral neuropathies.

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Brain Res. 2007 Aug 8;1162:9-18. Epub 2007 Jun 21.
Curcumin reverses impaired hippocampal neurogenesis and increases serotonin receptor 1A mRNA and brain-derived neurotrophic factor expression in chronically stressed rats.
Xu Y, Ku B, Cui L, Li X, Barish PA, Foster TC, Ogle WO.
Department of Biomedical Engineering, University of Florida, Gainesville, FL, 32611, USA.

Curcuma longa is a major constituent of Xiaoyao-san, the traditional Chinese medicine, which has been used to effectively manage stress and depression-related disorders in China. As the active component of curcuma longa, curcumin possesses many therapeutic properties; we have previously described its antidepressant activity in our earlier studies using the chronic unpredictable stress model of depression in rats. Recent studies show that stress-induced damage to hippocampal neurons may contribute to the phathophysiology of depression. The aim of this study was to investigate the effects of curcumin on hippocampal neurogenesis in chronically stressed rats. We used an unpredictable chronic stress paradigm (20 days) to determine whether chronic curcumin treatment with the effective doses for behavioral responses (5, 10 and 20 mg/kg, p.o.), could alleviate or reverse the effects of stress on adult hippocampal neurogenesis. Our results suggested that curcumin administration (10 and 20 mg/kg, p.o.) increased hippocampal neurogenesis in chronically stressed rats, similar to classic antidepressant imipramine treatment (10 mg/kg, i.p.). Our results further demonstrated that these new cells mature and become neurons, as determined by triple labeling for BrdU and neuronal- or glial-specific markers. In addition, curcumin significantly prevented the stress-induced decrease in 5-HT(1A) mRNA and BDNF protein levels in the hippocampal subfields, two molecules involved in hippocampal neurogenesis. These results raise the possibility that increased cell proliferation and neuronal populations may be a mechanism by which curcumin treatment overcomes the stress-induced behavioral abnormalities and hippocampal neuronal damage. Moreover, curcumin treatment, via up-regulation of 5-HT(1A) receptors and BDNF, may reverse or protect hippocampal neurons from further damage in response to chronic stress, which may underlie the therapeutic actions of curcumin.

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Pharmacol Biochem Behav. 2005 Sep;82(1):200-6.
Antidepressant effects of curcumin in the forced swim test and olfactory bulbectomy models of depression in rats.
Xu Y, Ku BS, Yao HY, Lin YH, Ma X, Zhang YH, Li XJ.
Department of Pharmacology, School of Basic Medical Science, Peking University, China.

Curcuma longa is a major constituent of Xiaoyao-san, the traditional Chinese medicinal formula, which has been used to effectively manage stress and depression-related disorders in China. Curcumin is the active component of curcuma longa, and we hypothesized that curcumin would have an influence on depressive-like behaviors. The purpose of the present study was to confirm the putative antidepressant effect of chronic administrations of curcumin (1.25, 2.5, 5 and 10 mg/kg, p.o.) in the forced swimming test and bilateral olfactory bulbectomy (OB) models of depression in rats. In the first study, chronic treatment with curcumin (14 days) reduced the immobility time in the forced swimming test. In the second experiment, curcumin reversed the OB-induced behavioral abnormalities such as hyperactivity in the open field, as well as deficits in step-down passive avoidance. In addition, OB-induced low levels of serotonin (5-HT), noradrenaline (NA), high 5-hydroxyindoleacetic acid (5-HIAA) and 4-dihydroxyphenylacetic acid (DOPAC) in the hippocampus were observed, and were completely reversed by curcumin administration. A slight decrease in 5-HT, NA and dopamine (DA) levels was found in the frontal cortex of OB rats which was also reversed by curcumin treatment. These results confirm the antidepressant effects of curcumin in the forced swim and the OB models of depression in rats, and suggest that these antidepressant effects may be mediated by actions in the central monoaminergic neurotransmitter systems.

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