Carnosine and Autism

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 transcript
Abstract of study
more carnosine facts
Pangborn letter
Rosemary

CBS News: Autism Breakthrough

 There has been a major breakthrough in the treatment of autism. A supplement that you can get at health food stores has been shown to make 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
                     847-735-0300

http://www.cbs2chicago.com/works/feature_detail.asp?id=000045058214&type=337003

Links

back to top
back to AutismNews

Double-Blind, placebo-controlled Study of L-carnosine supplementation in children with autistic spectrum disorder

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.

 http://www.carn-aware.com/online-store/scstore/abstract.html
http://www.carn-aware.com/online-store/scstore/faq.html

full article with charts and footnotes:
http://smart-nutrition.net/carnosine-autism-research.htm

back to top
back to AutismNews

 Just the Facts

 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)

back to top

Pangborn - a contrary view

  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 Radicals
 http://www.physorg.com/news112976118.html      

 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.
 

back to top
back to AutismNews