Physiological Functions: Manganese is a cofactor for enzymes involved in hydrolysis, phosphorylation, decarboxylation, and transamination. It also promotes activities of transferases such as glycosyltransferase, and of glutamine synthetase and superoxide dismutase. Manganese helps in the production of enzymes used for metabolism of proteins and fat. It supports the immune system, blood sugar balance and is involved in the production of cellular energy, reproduction and bone growth.

Deficiency: Manganese deficiency in humans has not been documented, but has been induced experimentally in animals. Poor growth and abnormal reproduction have been observed in rats and mice.

Toxicity: No reported cases of manganese toxicity resulting from dietary intake have been reported. Manganese toxicity has been observed from inhalation manganese-containing dust by workers in mines and steel mills manifested by adverse effects on the central nervous system. The upper limit of safety for manganese established by the Food and Nutrition Board of the Institute of Medicine is approximately 11 mg daily for adults.

Manganese is a mineral found in large quantities in both plant and animal matter. Only trace amounts of this element can be found in human tissue, however. Manganese is predominantly stored in the bones, liver, kidney, and pancreas. It aids in the formation of connective tissue, bones, blood-clotting factors, and sex hormones and plays a role in fat and carbohydrate metabolism, calcium absorption, and blood sugar regulation. Manganese is also necessary for normal brain and nerve function.

Manganese is a component of the antioxidant enzyme manganese superoxide dismutase (MnSOD). Antioxidants scavenge damaging particles in the body known as free radicals. These particles occur naturally in the body but can damage cell membranes, interact with genetic material, and possibly contribute to the aging process as well as the development of a number of health conditions. Antioxidants such as MnSOD can neutralize free radicals and may reduce or even help prevent some of the damage they cause.

Low levels of manganese in the body can contribute to infertility, bone malformation, weakness, and seizures. Manganese deficiencies are considered rare, however, since it is relatively easy to obtain adequate amounts of manganese through the diet. Interestingly, though, some experts estimate that as many as 37% of Americans do not get the recommended daily amounts of manganese in their diet. This may be due to the fact that whole grains are a major source of dietary manganese, and many Americans consume refined grains more often than whole grains. Refined grains provide half the amount of manganese as whole grains.

Uses: Manganese may be of some benefit for the following illnesses when used in conjunction with conventional medical care. People with rheumatoid arthritis tend to have low levels of MnSOD (an antioxidant that helps protect the joints from damage during inflammation). Manganese supplementation is thought to increase MnSOD activity. In addition, a few studies of people with osteoarthritis suggest that the combination of manganese supplementation taken along with glucosamine and chondroitin can reduce pain associated with the condition.

Osteoporosis: Manganese and other trace elements are necessary for bone health. Therefore, many experts feel that appropriate balance and intake of manganese and these other nutrients may play a role in preserving bone density and preventing osteoporosis.

Diabetes: Although results have been conflicting, some research suggests that people with diabetes have significantly lower levels of manganese in their bodies than people without diabetes. It is not clear, however, whether this is a cause or effect of the condition. In other words, researchers have yet to determine whether diabetes causes levels of manganese to drop or if deficiencies in this trace element actually contribute to the development of the metabolic disorder. In addition, one study found that diabetics with higher blood levels of manganese were more protected from oxidation of LDL ("bad") cholesterol than those with lower levels of manganese. (LDL oxidation contributes to the development of plaque in the arteries which can lead to heart attack and stroke.) Further studies are needed to determine whether supplementation with manganese helps prevent and/or treat diabetes and its associated complications.

Premenstrual Syndrome (PMS): In at least one study, women who ate small amounts of manganese (levels below the recommended daily amount) experienced greater mood swings and cramping pain just prior to their periods than women who ate normal to high amounts of manganese. These results suggest that a manganese-rich diet may help reduce symptoms of PMS.

Epilepsy: Several studies suggest that manganese levels may be lower in people with seizure disorders. It is not known, however, whether seizures reduce manganese levels or if low manganese levels make a person more susceptible to convulsions. It is also unclear at this time whether manganese supplements would help reduce the number of seizures in people with epilepsy. In fact, at least one animal study suggests that manganese supplementation does not alter the severity or frequency of seizures in rats.

Other: Low levels of manganese have also been associated with muscle disorders that involve lack of coordination, irregular menstrual cycles, tinnitus (ringing in the ears), hearing loss (even in infants), and poor milk production in lactating women.

Dietary Sources: Rich dietary sources of manganese include nuts and seeds, wheat germ and whole grains (including unrefined cereals, buckwheat, bulgur wheat, and oats), legumes, and pineapples.

The nutritional importance of manganese was discovered in 1936-37, when A. H. Norris and his co- workers and T. P. Lyons and Insko reported the development of bony malformation in poultry fed on a manganese­free diet. Studies of L. S. Hurley and G.J. Everson and their associates in 1961 threw more light on the relationship of manganese to growth, bone development, reproduction, and the functioning of the central nervous system.

Manganese is found in the body as a trace element and is essential for life. The human body contains 10 to 20 mg of this element which is widely distributed throughout the tissues. It is found in high concentration in the mitochondria of cells.

Manganese is a hard, brittle, greyish-white metallic element. It is readily oxidized and forms an important component of certain alloys. If manganese is breathed in excess, in the form of dust or fumes, it can lead to a condition very much like Parkinson's disease wherein tremors develop in the hands and fingers.

Only three to four percent of the manganese present in the diet is absorbed from the intestine and reaches the blood. It is stored in the blood and liver. Serum manganese levels are almost always elevated following a myocardial infarction. Manganese is excreted in the feces. The urine contains only traces of this element. High calcium intakes have been shown to increase the fecal excretion of manganese.

Manganese Benefits: Manganese is an important component of many enzyme systems which are involved in the metabolism of carbohydrates, fats, and proteins. In combination with choline, it helps in the digestion and utilization of fat. Manganese helps to nourish the nerves and brain and assists in the proper coordinative action between the brain, nerves and muscles in every part of the body. It is also involved in normal reproduction and the function of mammary glands.

Manganese Rich Food Sources: nuts, whole grains, and dried legumes are excellent sources of manganese.

Manganese Deficiency Symptoms: a prolonged deficiency of manganese may cause retarded growth, digestive disorders, abnormal bone development, and deformities. It may also cause male and female sterility and sexual impotence in men. However, the human body obtains sufficient manganese through normal dietary intake, so a deficiency syndrome is rare.

Manganese Side Effects: toxic symptoms have been reported to occur in mine workers due to inhalation of dust from manganese ores. The symptoms are blurred speech, tremors of the hands, and a spastic gait.

1. Crow JP, Calingasan NY, Chen J, Hill JL, Beal MF. Manganese Porphyrin Given at Symptom Onset Markedly Extends Survival of ALS Mice. Ann Neurol. 2005 Aug;58 (2):258-65.

Mice that overexpress the human Cu,Zn superoxide dismutase-1 mutant G93A develop a delayed and progressive motor neuron disease similar to human amyotrophic lateral sclerosis (ALS). Most current studies of therapeutics in these mice to date have involved administration of agents long before onset of symptoms, which cannot currently be accomplished in human ALS patients. We examined the effects of the manganese porphyrin AEOL 10150 (manganese [III] tetrakis[N-N'-diethylimidazolium-2- yl]porphyrin) given at symptom onset and found, in three separate studies, that it extended the survival after onset up to 3.0-fold. Immunohistochemical analysis of spinal cord for SMI-32, an abundant protein in motor neurons, indicated better preservation of motor neuron architecture, less astrogliosis (glial fibrillary acidic protein), and markedly less nitrotyrosine and malondialdehyde in porphyrin-treated spinal cords relative to vehicle-treated mice. These results show that the catalytic antioxidant AEOL 10150 provides a pronounced therapeutic benefit with onset administration and is, therefore, a promising agent for the treatment of ALS.

2. Takeda A. Manganese Action in Brain Function. Brain Res Rev. 2003 Jan;41(1):79-87.

Manganese, an essential trace metal, is supplied to the brain via both the blood- brain and the blood-cerebrospinal fluid barriers. There are some mechanisms in this process and transferrin may be involved in manganese transport into the brain. A large portion of manganese is bound to manganese metalloproteins, especially glutamine synthetase in astrocytes. A portion of manganese probably exists in the synaptic vesicles in glutamatergic neurons and the manganese is dynamically coupled to the electrophysiological activity of the neurons. Manganese released into the synaptic cleft may influence synaptic neurotransmission. Dietary manganese deficiency, which may enhance susceptibility to epileptic functions, appears to affect manganese homeostasis in the brain, probably followed by alteration of neural activity. On the other hand, manganese also acts as a toxicant to the brain because this metal has prooxidant activity. Abnormal concentrations of manganese in the brain, especially in the basal ganglia, are associated with neurological disorders similar to Parkinson's disease. Understanding the movement and action of manganese in synapses may be important to clarify the function and toxicity of manganese in the brain.

3. Zhao Y, Oberley TD, Chaiswing L, Lin SM, Epstein CJ, Huang TT, St Clair D. Manganese Superoxide Dismutase Deficiency Enhances Cell Turnover Via Tumor Promoter-induced Alterations in Ap-1 and P53-mediated Pathways in a Skin Cancer Model. Oncogene. 2002 May 30;21(24):3836-46.

Previous studies in our laboratories demonstrated that overexpression of manganese superoxide dismutase (MnSOD) suppressed both the incidence and multiplicity of papillomas in a DMBA/TPA multi-stage skin carcinogenesis model. The activity of activator protein-1 (AP-1), which is associated with tumor promotion, was reduced in MnSOD transgenic mice overexpressing MnSOD in the skin, suggesting that MnSOD may reduce tumor incidence by suppressing AP-1 activation. In the present study, we report that reduction of MnSOD by heterozygous knockout of the MnSOD gene (Sod2 -/+, MnSOD KO) increased the levels of oxidative damage proteins and the activity of AP-1 following TPA treatment. RNA levels of ornithine decarboxylase (ODC) were also increased, suggesting an increase in cell proliferation in the KO mice. Histological examination confirmed that the number of proliferating cells in DMBA/TPA-treated mouse skin were higher in the KO mice.

Interestingly, histological examination also demonstrated greater numbers of apoptotic cells in the KO mice after DMBA/TPA treatment. Evidence of apoptosis, including DNA fragmentation, cytochrome c release from mitochondria, and caspase 3 activation were also observed by biochemical assays of the skin tissues. Apoptosis was associated with an increase in nuclear levels of p53 as determined by Western analysis. Quantitative immunogold ultrastructural analysis confirmed that p53 immunoreactive protein levels were increased to a greater level in the nuclei of epidermal cells from MnSOD KO mice compared to epidermal nuclei from wild type mice similarly treated. Moreover, p53 levels further increased in the mitochondria of DMBA/TPA treated mice, and this increase was much greater in the MnSOD KO than in the wild type mice, suggesting a link between MnSOD deficiency and mitochondrial-mediated apoptosis. Pathological examination reveals no difference in the incidence and frequency of papillomas comparing the KO mice and their wild type littermates. Taken together, these results suggest that: (1) MnSOD deficiency enhanced TPA-induced oxidative stress and AP-1 and p53 levels, consistent with the increase in both proliferation and apoptosis events in the MnSOD KO mice, and (2) increased apoptosis may negate increased proliferation in the MnSOD deficient mice during an early stage of tumor development.

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