This month (October 2002), CBS news in Chicago ran a special about Carnosine, a nutritional supplement which may help children with autism. If you missed the show, here are a few sources about it. The AutismNews takes no postion on its efficacy.
CBS transcript2006 update: Currently Dr. Chez is initiating a study to test if carnosine in combination with anti-inflammatory substances such as tumeric (or curcumin) can reduce the symptoms of autism. Many studies show autism can result from an inflammation of the brain. Prednisone is the best known anti-inflammatory medication, and its effect in treating autism is powerful; however, it is a steroid with side effects. After the patient makes the powerful initial gains in speech, behavior and motor skills, it is phased out to avoid side effects. Tumeric is an over the counter spice, common in middle eastern or Indian cuisine.
Abstract of study
more carnosine facts
There has been a major breakthrough in the treatment of
A supplement that you can get at health food stores has been shown to
a major difference. Dr. Michael Breen reports the details. Parents with
autistic children are saying that a natural compound in a person’s body
called carnosine have helped their kids.
Carnosine combines with transmitters deep in the brain.
Rose Stodola a mother of autistic child said, “Almost immediately within the first week I noticed a change.”
“The gym teacher came up to me and said my gosh he's like a different child,” added Maureen Sieger.
Four-year-old Nicholas Stodola would not talk to anybody. But then he took carnosine and there was a noticeable change. (Nick shakes Dr. Breen’s hand.)
Dr. Charles Chez found that kind of change was typical for 80 percent of these and other autistic children. Some jumped eight months in their reading scores and their behavior also changed. He said, “Response time, and eye contact and social awareness improved, play skills improved as a general rule.”
What's really exciting is because carnosine works by stabilizing and protecting brain cells and helping patients like Nicholas may be just the beginning.
Carnosine may help patients with Alzheimer's, an illness similar to autism and it has already helped some Alzheimer patients.
Carnosine's also helped some other children. Dr. Chez said, “We've had parents report improved reading skills with dyslexic tendencies...just improved test scores with kids who've had borderline attention disorder.”
Soon other parents may have the same reaction Nicholas' have. “Carnoware and Dr. Chez have given us our son back,” said Stodola.
Dr. Michael Breen says some non-autistic adults claim carnosine makes them more alert and improves their memory.
Dr. Michael Chez
Autism and Epilepsy Center
Lake Bluff, IL
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Michael G. Chez, M.D., Cathleen P. Buchanan, Ph.D.,
Jamie L. Komen, M.A., Marina Becker, R.N.
Objective: L-Carnosine is an amino acid dipeptide that may enhance frontal lobe function. We therefore sought to investigate whether L-Carnosine supplementation for children with Autistic Spectrum Disorders (ASD) results in observable, objective changes in language and/or behavior in contrast to placebo.
Design/Methods: Thirty-one children (21 M, mean age= 7.45; range = 3.2-12.5 yrs )meeting inclusion criteria were enrolled in an 8 week blinded trial of either 400 mg BID powdered L-Carnosine or placebo. Children were assessed at a pediatric neurology clinic with the Childhood Autism Rating Scale (CARS), the Gilliam Autism Rating Scale (GARS), the Expressive and Receptive One-Word Picture Vocabulary tests (E/ROWPVT), and biweekly parental Clinical Global Impression of Change (CGI), at baseline and 8 week endpoint.
Results: Children who were on placebo (n=17) did not show statistically significant changes on any of the outcome measures. After 8 weeks on L-Carnosine, children (n=14) showed statistically significant improvements on the GARS total score, GARS Behavior, Socialization, and Communication subscales, and the ROWPVT (all p’s<.05). EOWPVT and CARS showed trends in improvements, which were supported by parental CGI.
Conclusions: Oral supplementation with L-Carnosine resulted in demonstrable improvements in autistic behaviors as well as increases in language comprehension that reached statistical significance. Although the mechanism of action of the amino acid is not well understood, it is believed that it acts to modulate neurotransmission and affect metal ion transfer of zinc and copper in the entorhinal cortex. This may enhance neurological function or act in a neuroprotective fashion.
full article with charts and footnotes:
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Carnosine is a substance that protects and extends the functional life of the body’s key building blocks-cells, proteins, DNA, and lipids and can be fairly called an agent of longevity.
What is most exciting is the ability of carnosine to reverse the signs of aging in cells approaching senescence restoring normal appearance and extending cellular life span. Studies show that carnosine is effective against all forms of protein modification.
The limited capacity of the cell to perpetuate itself through division is called the Hayflick Limit. (Hayflick L et al., 1961; Hayflick L, 1965)
Carnosine levels decline with age. Muscle levels decline 63% from ages 10 to 70, which may account for the normal age-related decline in muscle mass and function. (Stuerenberg, 1999)
In a remarkable series of experiments, scientists at an Australian research institute have shown that carnosine rejuvenates cells as they approach senescence. (McFarland GA, 1999; McFarland GA, 1994)
Carnosine enables the heart muscle to contract more efficiently through enhancement of calcium response in heart myocytes. (Zaloga GP et al., 1997)
Carnosine eye drops have been shown to delay vision senescence in humans, being effective in 100% of cases of primary senile cataract and 80% of cases of mature senile cataract. (Wang AM et al., 2000)
Another Japanese study showed that carnosine enhances granulation, a healing process in which proliferating fibroblasts and blood vessels temporarily fill a tissue defect. (Nagai K et al., 1986)
Carnosine inhibits MDA(malondialdehyde), a noxious product of lipid peroxidation which causes protein carbonylation, cross-linking, glycation and AGE formation (Burcham PC et al., 1997). Carnosine inhibits MDA from carbonylating albumin (the main serum protein) and crystallin (eye lens protein) in a concentration-dependent manner.
Glycation, a destructive process that carbonylates proteins, is itself recognized as a major cause of aging and degenerative diseases. Glycation occurs when proteins react with sugars. Then, through a series of reactions including oxidation, advanced glycation (aptly called AGEs) form. AGE formation in the body is the chemical equivalent of the browning of food in the oven and equally irreversible. When proteins accumulate “AGEs”, they do in fact turn brown. The “slow oven” of AGE formation turns proteins fluorescent, and cross-links them to a point where the body cannot break them down. As AGEs build up, tissues lose tone and resiliency and organ systems degenerate. For example, AGEs are now recognized as an important factor in atherosclerosis (Bierhaus A et al., 1998), cataracts, Alzheimer’s disease (Munch G et al., 1998), and loss of skin elasticity. It could be compared to iron oxide, rust, or oxidized iron, which is, incidentally brown. High levels of carnosine in the brain and cell membranes may serve as natural protection against protein cross-linking and glycation, and especially oxidation of cell membranes.
An interesting Russian study showed that rat cerebellar cells incubated in carnosine were resistant to excitotoxic cell death from the glutamate analogs NMDA and kainite. (Boldyrev A et al., 1999)
Alzheimer’s disease tends to create an acidic environment with concomitant inflammation and disturbed energy metabolism associated with the disease which are now thought to increase copper and zinc levels. New research show that copper and zinc toxicity in the brain can be buffered by carnosine. (Horning MS et al., 2000)
“It is well known that physiological processes such as muscle performance and electrical conduction along nerve fibers involve free radical lipid peroxidation in biological membranes, and that skeletal muscle and brain are two of the tissues which have the most active oxidative metabolism.” (Vladimirov and Archakov, 1972; Evans, 1993)
The relation of high concentrations of carnosine in muscle and brain, especially in the sensory organs, with particular research identifying olfactory (sense of smell) and the retina (sight) is quite interesting since a large body of research comes from Russia. Equally interesting is the Russians’ use of carnosine for improved athletic performance with a strong emphasis on the Olympics. It suggests that they engaged in carnosine research almost like a secret Olympic weapon.
Carnosine is safe, with no toxicity even at dosages above 500 mg per kilogram of body weight in animal studies. (Quinn PJ et al., 1992)
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While I've been busy preparing my half of the new DAN! Consensus Report (2002 Edition), lots of Internet talk about the peptide carnosine has evidently occurred. While I have no desire or intention to engage those who are enamored with this latest magic bullet for autism, I do find itappropriate to point out some of the concerns and pitfalls of carnosine use in autism.
Carnosine is a dipeptide composed of the amino acids histidine and beta-alanine. It seems that it gets dragged out of the closet every decade for some use or other. In the 1970s it was muscular dystrophy. In thediet, it comes from incomplete digestive proteolysis of beef, pork, tuna and salmon - as you can see in the amino acid analyses on the urine of autistics and other patients with maldigestion. Carnosine is elevated in the urine of 20 to 40% of autistics. In the 1980s, Bernie Rimland and I discussed thisfinding and considered it to be another facet of the maldigestion and peptideexcess per the findings of Karl Reichelt, et al.
In body tissues, carnosine is split into histidine and beta-alanine. Beta-alanine can be a real troublemaker, and I'll get to that shortly. Histidine is the Dr. Jekyll and Mr. Hyde part. Histidine becomes FIGlu and FIGlu pushes the formation of 5-formiminotetrahydrofolate. This is good, even though it often raises FIGlu levels in the urine and blood of autistics. It's good because: (a) it helps remove a potential folate trap, and (b) itleads to two forms of folate that are required for purine and purine nucleotide synthesis. One of these forms, 10-formyltetrahydrofolate, comes in just after the adenylosuccinase step and helps "pull" the process along at adocumented sticking point for some forms of autism.
However, histidine and carnosine are powerful carriers of copper. They transport copper from the intestinal milieu into the portal blood and from there to organs and tissues in the body. And don't think you can displace copper with zinc once the copper is on histidine - you cannot. The equilibrium constant for copper II chelated to histidine is 18.3; for zinc it is 6.7 to 12.9, depending on chelate structure (Ref. Chaberek and Martell, Organic Sequestering Agents, John Wiley & Sons, p.549). Because these are exponential relationships, the real difference in the constants is 10 tothe 5th up to 10 to the 11th. Only glutathione, cysteine and thionein can intercept this carnosine-copper transport, but that's one of the big problems in autism, isn't it? These sulfur players have gone AWOL, and copper is excessive at the expense of zinc. Dr. Bill Walsh has made excellent presentations on this. You might think that carnosine plus zinc will act to put zinc in and take copper out. With these equilibrium constants and with the natural copper content of food, that's very unlikely. You need a million or more zinc atoms for each copper atom to be competitive in this game!
Histidine/carnosine-copper wisdom has graduated into medical textbooks. We're not talking about research papers; we're talking what you should and shouldn't do per medical texts. Copper homeostasis with histidine and histidine-albumin complexes are well discussed by David Danks, Chapter 58 of Stanbury et al, The Metabolic Basis of Inherited Disease, 5th Ed, p.1252-1254. For carnosine, the publicity is a bit worse. Carnosine is a threat to worsened Wilson's disease because it and its sister anserine are such good importers of copper to body tissues. Ref: Scriver CR and TLPerry, Chapt 26 in Scriver et al eds, The Metabolic Basis of Inherited Disease6th ed McGraw-Hill (1989) 765.
Now, let's go to the really bad guy here, beta-alanine. To be concise: beta-alanine blocks renal conservation of taurine and causeshypertaurinuria - loss of taurine in the urine. This, in turn, causes urinary loss of magnesium, which worsens sulfotransferase activity as well as lots ofother necessary enzymatic processes. If you give carnosine, you lose taurine and magnesium. There are lots of references, but you can start with Dr.Charles Scriver's work referenced above, because all of this biochemistry (carnosine, beta-alanine, taurine, etc.) is closely related.
Did you know that, years ago, Monsanto had a R&D project to replace Aspartame with a beta-alanine dipeptide, because of patent expiration? Chemical and Engineering News published a notice, and the project was canned shortly thereafter. I'd like to think that it was because chemists, including me, wrote them letters about beta-alanine. The public can be grateful that product never made it into circulation.
Oh, I forgot to tell you why FIGlu sometimes goes up in autism. A bunch of credit on this goes to Dr. Sid Baker who observed it. Give folate andFIGlu goes up, not down, in some autistics. After some quick library work Ifound that the FIGlu -to-formiminoTHF enzyme requires pyridoxal 5-phosphate.This needs more study, a lot more, but with Dr. Tapan Audhya's finding of very slow P5P formation in autistics, it fits.
In summary, giving carnosine to the average autistic will at first cause perceived improvement - probably due to the FIGlu-push effect. After some weeks, taurine loss, copper accumulation, magnesium loss, etc. can, unfortunately, reverse the trend and may leave you with a worsenedcondition to deal with.
Jon B. Pangborn,
Ph.D. Fellow, American Institute of Chemists
Rosemary Protects Your Brain From Free
Rosemary not only tastes good in culinary dishes such as Rosemary chicken and lamb, but scientists have now found it is also good for your brain. A collaborative group from the Burnham Institute for Medical Research (Burnham Institute) in La Jolla, CA and in Japan, report that the herb rosemary contains an ingredient that fights off free radical damage in the brain. The active ingredient in rosemary, known as carnosic acid (CA), can protect the brain from stroke and neurodegeneration that is due to injurious chemical free radicals. These radicals are thought to contribute not only to stroke and neurodegenerative conditions such as Alzheimer's, but also to the ill effects of normal aging on the brain.
In two expedited publications by The Journal of Neurochemistry and Nature Reviews Neuroscience, the scientists report for the first time that CA activates a novel signaling pathway that protects brain cells from the ravages of free radicals. In animal models, the scientific group, led by Drs. Takumi Satoh (Iwate University, Japan) and Stuart Lipton (Burnham Institute), found that CA becomes activated by the free radical damage itself, remaining innocuous unless needed, exactly what is wanted in a drug. The scientists call this type of action a "pathological-activated therapeutic" or PAT drug. A "pat" represents a gentle tap and not the heavy sledge hammer that some drugs produce, including significant side effects in areas of the body where their effects are not needed and not wanted. "This new type of drug works through a mechanism known as redox chemistry in which electrons are transferred from one molecule to another in order to activate the body's own defense system," said Stuart A. Lipton, MD, PhD, the senior author on the paper and Director, Professor, and Senior Vice President at the Burnham's Del E. Webb Neuroscience, Aging, and Stem Cell Research Center. "Moreover, unlike most new drugs, this type of compound may well be safe and clinically tolerated because it is present in a naturally-occurring herb that is known to get into the brain and has been consumed by people for over a thousand years." Dr. Lipton is also a practicing neurologist at the University of California, San Diego, and therefore knows first-hand that such drugs are critically needed for care of the aging and neurologically-ill patients.
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