~Amyotrophic Lateral Sclerosis (ALS), Part 4 - Protect and Regenerate Neurons

Protect and Regenerate Neurons
  • General Supplements
  • Improve Mitochondrial Function
  • Mineral Deficiency
  • Growth Stimulation
  • Miscellaneous
  • Anecdotal Evidence
  • Therapeutic Approach
General Supplements
  • Vitamin B12 ( Methylcobalamin)
  • Acetyl-L-Carnitine
  • Essential Fatty Acids
  • Pregnenolone and DHEA
  • Genistein
  • Progesterone
Vitamin B12 ( Methylcobalamin). High doses of methylcobalamin have been used to treat degenerative neurological diseases in rodents and humans. People with ALS took 25 mg a day of methylcobalamin for 1 month. In this disease, the neurons that control muscle movements deteriorate. The double-blind, controlled study showed that methylcobalamin improved muscle response after 1 month of treatment (Kaji et al. 1998).

A study investigated the daily administration of 60 mg of methylcobalamin to patients with chronic progressive multiple sclerosis (MS), a disease that has a poor prognosis and widespread demyelination in the central nervous system. Although motor disability did not improve, there were clinical improvements in visual and auditory MS-related disabilities. The scientists stated that methylcobalamin might be an effective adjunct to immunosuppressive treatment for chronic progressive MS. This again suggests a potential benefit, but no clinical studies on ALS patients using methylcobalamin have been conducted (Kira et al. 1994).

The effects of methylcobalamin were studied on an animal model of muscular dystrophy. This study looked at the degeneration of axon motor terminals. In mice receiving methylcobalamin, nerve sprouts were more frequently observed, and the regeneration of motor nerve terminals occurred in sites that had previously been in a degenerating state (Yamazaki et al. 1994).

In a study, scientists postulated that methylcobalamin could regulate protein synthesis and help regenerate nerves. The scientists showed that very high doses of methylcobalamin produced nerve regeneration in laboratory rats. The scientists stated that ultra - high doses of methylcobalamin might be of clinical use for patients with peripheral neuropathies. The human equivalent dose to duplicate this study would be about 40 mg of sublingually administered methylcobalamin (Watanabe et al. 1994).

In humans, a subacute degeneration of the brain and spinal cord can occur by the demyelination of nerve sheaths caused by a folic acid or vitamin B12 deficiency. In a study it was shown that some people have genetic defects that preclude them from naturally producing methylcobalamin. The scientists stated that a deficiency of methylcobalamin directly caused demyelination disease in people with this inborn defect that prevents the natural synthesis of methylcobalamin (Surtees 1993).

An early study showed that the daily administration of methylcobalamin in rats markedly activated the regeneration of mechanically damaged axons of motor neurons (Mikhailov et al. 1983).

An even more pronounced effect was observed in laboratory rats whose sciatic nerves were mechanically crushed. Two studies showed that the administration of methylcobalamin caused significant increases in the in vivo incorporation of the amino acid leucine into the crushed sciatic nerve. This resulted in a stimulating effect on protein synthesis repair and neural regeneration (Yamatsu et al. 1976a; Yamatsu et al. 1976b).

Acetyl-L-Carnitine. Acetyl-L-carnitine has produced dramatic results in protecting neurons in a wide range of disease states. Alzheimer's disease and ALS also respond to higher doses of acetyl-L-carnitine combined with other neuroprotective supplements.

One study of exercise tests in six ALS patients and six matched untrained controls indicated that the exercise-induced increase in plasma free fatty acids, beta-hydroxybutyrate, esterified carnitine, and muscle esterified carnitine was significantly retarded in ALS patients (Sanjak et al. 1987). It is therefore suggested that ALS patients take 3000 mg a day of acetyl-L-carnitine.

Essential Fatty Acids. Neuronal damage can be caused by degeneration of the myelin sheath, a fatty layer that wraps the signal-moving neuronal fibers. Omega-3 and omega-6 fatty acids may help to repair the myelin sheath required for proper neuron conduction. Suggested supplementation regimens include the daily ingestion of 6000 mg of perilla oil (providing 3300 mg of alpha-linolenic acid) and 5200 mg of borage oil (providing 1200 mg of gamma-linolenic acid [GLA]).

Pregnenolone and DHEA. DHEA is a hormone primarily made in the adrenal glands. Production peaks around the age of 25-30 and then drops by 85-90% by the age of 70. DHEA has been associated with the ability to stay thin, make muscle, improve memory, resist stress, and produce a sense of "well-being."

Since both pregnenolone and DHEA are involved in the regulation of neurologic al function, supplementation with 50 mg 3 times a day of pregnenolone, and/or 25 mg 2-3 times a day of DHEA should be considered (Faloon 1996).

Genistein. The phytoestrogen genistein, found in soy products, may also help the survival rate in ALS patients, according to research results. Researchers at the Hughes Institute in Minnesota studied the effects of genistein on male and female mice with familial ALS. The researchers propose that the higher incidence of the disease and earlier onset in the male mice could be related to the presence of estrogen in females. Results of the study indicated that the genistein provided neuroprotective effects that were both estrogen-dependent and independent. Genistein warrants further study as a preventive agent against conditions such as ALS and stroke. (Trieu et al. 1999).

Progesterone. Progesterone is synthesized in the peripheral nervous system in glial cells, which comprise the supporting structure of the nervous system. Studies have shown that progesterone stimulates neuron growth, accelerates the maturation of the regenerating axons, and enhances the remyelination of nerve fibers. The progesterone-induced myelination is probably mediated by progesterone receptors, as it is impaired by mifepristone (RU486), a progesterone antagonist (Koenig et al. 2000).

Improve Mitochondrial Function
  • Coenzyme Q10
  • Creatine
Coenzyme Q10 ( CoQ10 ). In a study, W w hen CoQ10 was administered to rats genetically bred to develop ALS, a significant increase in survival time was observed. After only 2 months of CoQ10 supplementation, mitochondrial energy expenditure in the brain increased by 29% compared to the group not getting CoQ10. The human equivalent dose of CoQ10 to achieve these results was 100-200 mg a day. The conclusion by the scientists was "CoQ10 can exert neuroprotective effects that might be useful in the treatment of neurodegenerative diseases" (Matthews et al. 1998).

This study documented that orally supplemented CoQ10 specifically enhanced metabolic energy levels of brain cells. While this effect in the brain has been previously postulated, this study provides hard-core evidence. Based on the types of brain cell injury that CoQ10 protected against, the scientists suggested that it might be useful in the prevention or treatment of Huntington's disease and ALS. It was noted that while vitamin E delays the onset of ALS disease in mice, it does not increase survival time. CoQ10 was suggested as a more effective treatment strategy for neurodegenerative disease than vitamin E because survival time was increased in mice treated with CoQ10.

About 95% of cellular energy is produced from structures in the cell called mitochondria. The mitochondria have been described as the cell's "energy powerhouse," and the diseases of aging are increasingly being referred to as "mitochondrial disorders." When CoQ10 is orally administered, it is incorporated into the mitochondria of cells throughout the body where it facilitates and regulates the oxidation of fats and sugars into energy.

CoQ10 levels decrease with aging. Depletion is caused by reduced synthesis of CoQ10 in the body, along with increased oxidation of CoQ10 in the mitochondria. CoQ10 deficit results in the inactivation of enzymes needed for mitochondrial energy production, whereas supplementation with CoQ10 preserves mitochondrial function.

Further studies at Massachusetts General Hospital demonstrated that CoQ10 could protect against striatal (brain) lesions produced by both malonate and 3-nitropropionic acid. It extended survival in a transgenic mouse model of ALS (Beal 1999a). One study of 30 patients with ALS, however, found that serum CoQ10 levels were unrelated with the risk of ALS (Molina et al. 2000).

Based on this very preliminary research, ALS patients may want to take 300 mg of an oil-based CoQ10 supplement 3 times a day. CoQ10 absorbs best when taken with fat, so oil-based supplements of CoQ10 can markedly improve systemic absorption.

Creatine. A study found the amino acid creatine more effective than Riluzole in extending the survival of mice with an ALS-type disease. The scientists reported that with 1% creatine administration, survival was extended by 13 days, and with 2% administration of creatine, survival doubled to 26 days. These scientists note that Riluzole alone extends survival rate by 13 days (in mice). The supplemented creatine protected the mice from the loss of motor neurons and improved movement. This study proposed that creatine could help reverse the effects of ALS at the cellular level. This is done by stabilizing the enzymes in the mitochondria, the "powerhouses" of the cell that store energy, thus slowing the cell death process (Klivenyi et al. 1999).

After taking creatine, patients with muscular dystrophy also showed a 10% increase in strength, according to a study by Walter et al. 2000.

"Creatine is well-tolerated," explains Leon Charash, M.D., who chairs the medical advisory committee of the Muscular Dystrophy Association. "Harnessing its apparent ability to buffer and stabilize the production and transportation of energy within cells could yield important health benefits for people with ALS and other progressive diseases."

Evidence has demonstrated a neuroprotective effect of creatine monohydrate supplementation in animal models of Parkinson's disease, Alzheimer's disease, ALS, and after ischemia. A low total and phosphocreatine concentration has been reported in human skeletal muscle from aged individuals and those with neuromuscular disorders (Tarnopolsky 2000).

A study showed that creatine significantly increased longevity and motor performance of transgenic mice with a SOD mutation. Creatine also significantly attenuated the increases in glutamate measured with spectroscopy at 75 days of age, but had no effect at 115 days of age. The authors concluded that the beneficial effect of creatine might be due to an improved function of the glutamate transporter, which has a high demand for energy and is susceptible to oxidative stress (Andreassen et al. 2001).

Another study found that oral administration of creatine produced a dose-dependent improvement in motor performance and extended survival in G93A transgenic mice. It also protected mice from loss of both motor neurons and substantia nigra neurons at 120 days of age (Klivenyi et al. 1999).

Creatine monohydrate (10 grams daily for 5 days-5 grams daily for 5 days) was administered to patients with neuromuscular disease in a pilot study (n = 81), followed by a single-blinded study (n = 21). Body weight, handgrip, dorsiflexion, and knee extensor strength were measured before and after treatment. Creatine administration increased all measured indices in both studies. The authors conclude d that short-term creatine monohydrate increased high-intensity strength significantly in patients with neuromuscular disease (Tarnopolsky et al. 1999).

Mineral Deficiency
  • Magnesium
  • Vitamin D and Calcium
Magnesium. Magnesium and glycine play an important role in NMDA receptors, which is a type of glutamate receptor. NMDA receptors permit passage of relatively large amounts of calcium ions. First, glycine binds to it to facilitate its function. Second, the channel is blocked (closed) by a magnesium ion. The channel becomes unblocked when the membrane becomes partially depolarized (Ganong 1995).

Vitamin D and Calcium. Two studies have shown a deficiency of vitamin D in patients with ALS along with decreased intestinal absorption of calcium and a reduction in bone mass (osteopenia) (Yanagihara et al. 1984; Sato et al. 1997).

Growth Stimulation
  • Human Growth Hormone
  • Testosterone
Human Growth Hormone. Growth hormone has multiple functions in the body, including maintaining lean body mass, mobilizing fat, counteracting insulin, enhancing immunity, lowering blood pressure and improving cholesterol levels, increasing energy, and even improving vision (Dean 2000).

Growth hormone (GH) received the Food and Drug Administration's imprimatur in 1996 for use in adults with GH deficiency due to pituitary or hypothalamic disease, injury, surgery, or radiation therapy. This now allows doctors to prescribe growth hormone as an anti - aging treatment for adults with low levels of IGF-I, which indicates a failure of the pituitary gland to produce adequate amounts of growth hormone.

Innovative drug therapies for ALS also might include 10-20 mg a day of Hydergine, 40 mg a day of vinpocetine, and testosterone and human growth hormone replacement therapy.

Testosterone. The link between testosterone and ALS has been proposed but discounted in research conducted in the 1980s. Testosterone was explored because of the male-to-female ratio of the disease, the age of onset, and the sparing of neurons of cranial nerves III, IV, and VI that coincidentally lack androgen receptors. The hypothesis is that ALS may be due to a loss of androgen receptors that results in an inability to respond to a variety of insults including axonal damage (Weiner 1980). The hypothesis was discounted by a study in which four men with ALS were treated with 200 mg of testosterone weekly. Lab tests indicated the expected degree of suppression of pituitary luteinizing hormone and follicle-stimulating hormone production. These data suggest that testosterone's (androgen) interaction with its receptors in the hypothalamic-pituitary axis is normal in patients with ALS (Jones et al. 1982).

Testosterone is an anabolic steroid. It stimulates the body to grow. Testosterone is responsible for the development of masculine characteristics. The role of testosterone in ALS is unclear, but the evidence presented indicates that it may have a role with other growth factors in some patients.

  • Thiamin
  • Ginseng
  • Branched-Chain Amino Acids
  • Hydergine
  • Vinpocetine
  • Trimethylglycine
  • Sphingolin
Thiamin. Several studies have proposed that a deficiency of thiamin (Vitamin B1) may be associated with ALS. Thiamin and its esters are present in axonal membranes, and electrical stimulation of nerves a e ffects the hydrolysis and release of thiamin diphosphate and triphosphate. Thiamin deficiency causes dry beriberi, a neurologic al disease characterized by "burning" feet, peripheral neuropathy, and Wernicke-Korsakoff syndrome that causes the neurological problems common in alcoholism (staggering gait, confusion, problems with coordination, etc.). The histological lesion of thiamin deficiency is a non - inflammatory degeneration of myelin sheaths.

A study published by Poloni et al. (1982) measured free thiamin and thiamin monophosphate levels in plasma and cerebral spinal fluid of patients with ALS, alcoholics, and controls. In plasma of patients with ALS, as well as in plasma and cerebrospinal fluid (CSF) of alcoholics, both thiamin and thiamin monophosphate concentrations were decreased. In CSF of patients with ALS, however, thiamin monophosphate values decreased much more than thiamin levels. The selective impairment of thiamin monophosphate production by nerve cells is likely to result from the reduction of the activity of thiamin pyrophosphatase, an enzyme synthesized and highly concentrated in the Golgi complex, a component of the cell where complex molecules such as proteins are synthesized and packaged for use in the body. Thiamin pyrophosphatase is known to diminish in ALS, as well as in experimental motor neuronal degeneration or axotomy. Thus, the thiamin to thiamin monophosphate ratio could be taken as an index of the impairment of neuronal protein synthesis in ALS (Poloni et al. 1982).

In a follow-up study, thiamine and thiamine monophosphate levels were measured in the CSF of patients with typical sporadic ALS (50 cases), in other motor neuron diseases (MND) (14 cases), and in patients with upper and/or lower motor neuron lesions of varying origin (disseminated sclerosis, polyneuropathy, spondylotic myelopathy). The thiamin to thiamin monophosphate ratio was greater than or equal to 1 in a high percentage of patients with typical sporadic ALS (94%), in 35.7% of cases with other MND, while it was below one in all the other patients. The decrease of thiamin monophosphate with the inversion of the thiamin to thiamin monophosphate ratio is a finding highly specific to typical sporadic ALS (Poloni et al. 1986).

Other researchers measured the enzymes involved in thiamin synthesis: thiamin pyrophosphatase (TPPase) and thiamin monophosphatase (TMPase) in brain tissue obtained at autopsy from ALS and Parkinsonism-dementia patients from Guam and from Guamanian patients who died from other diseases (controls). TPPase content, chemically determined at pH 9.0, was found to be significantly reduced in the frontal cortex of ALS and Parkinsonism-dementia patients compared to controls. TMPase content, on the contrary, was unchanged (Laforenza et al. 1992).

Ginseng. Ginseng (Panax quinquefolium) was given to transgenic mice with a defect in SOD1-G93A. Compared to controls there was a prolongation in onset of signs of motor impairment and survival. These experiments lend support to the use of ginseng root in ALS (Jiang et al. 2000).

Branched-Chain Amino Acids. Nutritional supplements called branched-chain amino acids can slow weight loss and muscle decline. There is, however, controversy in using branched-chain amino acids with ALS patients, and one research group reported higher than usual normal mortality rates, which caused the cessation of the clinical trial (Beghi 1993).

Hydergine. Hydergine is a drug approved by the FDA for persons over 60 who manifest signs and symptoms of an idiopathic decline in mental capacity. Studies have shown that it increases stores of the universal energy molecule, adenosine triphosphate (ATP), stabilizes the intracellular messenger molecule cyclic adenosine monophosphate (cAMP) content of nerve cells, improves utilization of glucose in the brain, and enhances cerebral microcirculation.

A study showed that Hydergine causes an increase of SOD and catalase in the brain. SOD and catalase are the body's natural antioxidants and are among the most effective free radical scavengers (Sozmen et al. 1998).

What was interesting about this study is that Hydergine was administered for only 20 days, but its effects on the brains of the lab rats were dramatic. Hydergine specifically increased catalase levels in the brain, as well as SOD in the hippocampus and in the corpus striatum regions. Those regions of the brain suffer severe oxidative damage from hydrogen peroxide and other free-radical generating agents. Orally ingested SOD and catalase have not proven efficacious because these antioxidant enzymes are broken down in the stomach, so scientists have concentrated on ways of prompting the body to produce its own cellular SOD and catalase. This study showed that Hydergine could increase brain levels of SOD and catalase after only short-term administration (Faloon 1998a).

Vinpocetine. Vinpocetine is produced by slightly altering the v V incamine molecule, an alkaloid extracted from the periwinkle plant, Vinca minor. Vinpocetine has been shown to enhance cerebral metabolism and selectively vasodilate cerebral arteries. Vinpocetine has also been shown to enhance oxygen and glucose uptake from blood by brain neurons, and to increase neuronal ATP bio-energy production, even under hypoxic (low oxygen) conditions (Biro et al. 1976; Solti et al. 1976; Szobor et al. 1976; Vamosi et al. 1976). Studies demonstrate that vinpoce-tine offers significant and direct protection against neuro-logical damage caused by aging. The molecular evidence indicates that the neuroprotective action of vinpocetine is related to its ability to maintain brain cell electrical conductivity and to protect against damage caused by excessive intracellular release of calcium. Vinpocetine also has been documented to partially protect against excitotoxicity induced by a wide range of glutamate-related neurotoxins (Faloon 1998b).

Trimethylglycine (TMG). Remethylation nutrients such as folic acid and TMG are being studied as possible therapies to treat Alzheimer's disease, and the same mechanism of action might have a beneficial effect against ALS.

Sphingolin. Sphingolin, from Ecological Formulas, is an extract of bovine myelin sheath and is a rich source of myelin protective proteins. Use of this product may benefit those with myelin diseases such as MS and ALS.

Anecdotal Evidence. Nutritionist Carmen Fusco reported that, while under her care for ALS, Senator Jacob Javits seemed to improve enough to reduce his hospital admissions and recommended the following nutrients: octacosanol as it occurs in raw wheat germ oil; high doses of pantothenic acid (vitamin B5, the "stress vitamin"); and DMG sublingual. Fusco also has used the branch-chain amino acids and sublingual vitamin B12. Dr. Benjamin Frank recommended the coenzyme form of the B vitamins, which was administered intramuscularly by injection.

Physical, occupational and speech therapies are important to the patients with ALS to make it easier to live their lives. Wheelchairs, foot braces, and other devices that can make it easier to use the telephone and computer are helpful in making the patient as independent as possible.

Certain medications may be prescribed as the disease progresses. These include Baclofen to relieve stiffness in limbs and throat; tizanidine as a muscle relaxant; Riluzole to reduce the presynaptic release of glutamate; and Hydergine to increase brain levels of SOD and catalase.

Continued . . .

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