What’s Going On?

NEUROPEPTIDES AND SUPPLEMENTS

 

What biochemical factors might cause a problem with the synthesis of neurotransmitters and hormones in autism?

A deficiency of the intestinal enzyme DPP-IV (dipeptydal peptidase), which acts to catalyze the breakdown of proteins into amino acids, has been hypothesized as a contributing factor to autism. If proteins aren’t being degraded into the amino acid substrates necessary to form hormones and neurotransmitters, the resultant metabolic havoc would be severe indeed, compromising both brain and body function. The proliferation of yeast or toxins in the intestinal tract, yeast induced pancreatic atrophy, and/or problems with the synthesis or activation of the hormone secretin, could also cause a problem with protein catabolism resulting in a deficit of critical polypeptide biochemical catalysts.

These gastrointestinal problems would also cause problems with the synthesis and degradation of the glucose necessary to fuel the electro-chemical processes in the brain. A deficiency or uneven supply of glucose would result in a deficiency or uneven supply of the glucose energy derivative ATP (adenosine triphosphate), which is required for the synthesis, degradation and “firing” of neurotransmitter molecules. ATP is converted to cystic AMP (cAMP), an important messenger system and reaction substrate in the brain and body. An inadequate supply of ATP would result in an inadequate supply of the cAMP required for the phosphorylation of tryptophan hydroxylase into serotonin.

In addition to forming ATP, the breakdown of glucose through glycolysis forms the substrates NAD (nicotinamide dinucleotide) and NADH. The phosphorylated forms of these chemicals, NADP and NADHP are precursors to the coenzymes dihydrobiopterin (BH2) and tetrahydrobiopterin (BH4), necessary for the activation of the enzymes tryptophan hydroxylase and tyrosine hydroxylase, precursors to the neurotransmitters dopamine and serotonin, respectively. As dopamine is catabolized to form norepinephrine and epinephrine, any problem with NAD production would affect the synthesis of all four of these neurochemicals that have been closely linked to autism.

NADHP is also necessary for the formation of progesterone, which is the precursor to all the other steroid hormones, including estrogen, testosterone and adreno-corticotropic hormone or ACTH.

How might certain neurotransmitters cause or contribute to autism?

The brain chemical most commonly linked to autism is serotonin, which is formed from the hydroxylation of the amino acid tryptophan. Serotonin is an excitatory neurotransmitter, meaning its release makes neurons more likely to fire, so an excess of this chemical could account for a lack of modulation of sensory input, leading to overstimulation and anxiety. Some studies have documented a significant elevation of blood serotonin in many autistic children, an abnormality that has been attributed to an alteration in the uptake or storage of serotonin by blood platelets.154 Other studies show, however, that the surge in serotonin levels that normally takes place in a child’s formative years is significantly diminished in children with autism.155

It seems more likely to me that autistic processing problems are caused by a deficit or uneven supply of serotonin. This would slow or impede the impulse or message transmission of serotonin releasing neurons, which have axons distributed throughout the brain from the cerebellum to the cerebral cortex.156 The anterior cingulate gyrus in the limbic system, an area rich in 5-HT (hydroxy tryptophan) receptors, is involved in higher cognitive functions, the expression and recognition of facial emotions, vocalized emotional responses, mother-infant interactions, pain response and the ability to initiate goal directed, context dependent behavior.157 If the 5-HT receptors in this area are not being properly activated these functions would be impaired, as they are in autism. There is also a correlation between repetitive and compulsive behaviors and the level of metabolic activity in the anterior cingulate gyrus.158

The largest amount of serotonin, however, is found not in the brain but in cells of the intestinal mucosa.159 If the functions of these cells have been undermined, due to the proliferation of yeast, bacterial or viral infection, and/or the presence of toxic or opioid microbials, the ability of serotonin to regulate sleep, pain perception, temperature and blood pressure might be compromised, which could account for the sleep problems and elevated pain thresholds experienced by many people with autism.

The excitatory neurotransmitter dopamine is formed from the hydroxylation of the amino acid tyrosine. The inability of schizophrenics to filter out incoming sensations is thought to be attributable to raised levels of dopamine in the brain, or to the increased sensitivity of dopamine neural receptors which induce a high state of arousal.160 Autistic brains may be equally susceptible to overstimulation due to the exaggerated effects of dopamine. Uta Frith postulates that the problem could be attributable to dopamine cells not dying back as they should in normal development. The result would be an increased number of dopamine neurons and therefore an overactive system.161

As the major dopamine pathways or projections in the brain originate in tiny structures at the tip of the brain stem and spread out to every cortical lobe, the impact of either an excess or deficiency of this chemical on information processing would be significant. If the dopamine system in the autistic brain is overactive, however, at the very least neural impulses would be routed through all the proper processing channels, so that people with autism would be better able to grasp the “big picture” and be able to base their thoughts and behavior on precise perceptions. As dopamine activity is regulated in the frontal lobe, and as circuits to this lobe are likely to be compromised to some degree in autism, it might be that at times there is too much activity and at other times much too little.

Two other neurotransmitters that may be implicated in causing or contributing to autism are norepinephrine and epinephrine, dopamine derivatives in the same catecholamine family. In the brain, nerve cells that release norepinephrine are clustered in the brain stem with their axons projecting to many brain regions. As a neurotransmitter, norepinephrine is both excitatory and inhibitory and is involved in arousal level as well as in autonomic control of body functions.162

Norepinephrine and epinephrine have important physiologic functions outside the nervous system as well. They act as regulators of carbohydrate and lipid metabolism, increasing the degradation of triacylglycerol and glycogen to glucose as well as increasing heart beat and blood pressure in response to fright, exercise, cold and low levels of blood glucose.163 If there is a shortage of these “fight or flight” molecules in the blood, the

breakdown of carbohydrates to glucose would be slowed, as would the body’s reaction to emergency situations.

Norepinephrine as well as dopamine and serotonin have their effect on receptor cells through a time and energy consuming ‘second messenger’ system, so any irregularity in the supply of the energy source ATP would have a significant negative impact on the ability of these neurotransmitters to function smoothly.

Another brain chemical linked to autism is GABA or gamma-aminbutyric acid. As this neurotransmitter is inhibitory, a deficiency of GABA in people with autism would help explain the poor inhibition that allows their brains to become overaroused, causes them to live in a constant state of anxiety.

Glutamate may also play a role in autism. Formed from glycogenic amino acids, this chemical acts as an excitatory neurotransmitter in the brain, activating some receptors in the hippocampus.164 Any deficit of glutamate would result in decreased activation of receptors in the limbic system that influence emotion, learning, memory and motivation.165 Receptors in the amygdala, located directly atop the hippocampus, might also be affected, further affecting the formation of declarative memories and throwing off the coordination of autonomic and endocrine responses with emotional states.

A deficiency of another neuropeptide, Oxytocin, may also contribute to autism. Oxytocin is a hormone that is intimately involved in social functions, with numerous receptor sites in the limbic system. Oxytocin receptive fields are labile, and significant shifts in receptor density occur in early development. A failure to shift from an infantile to a mature pattern, resulting in decreased central oxytocin receptor function, may contribute to the social impairment in autism.166 The correlation of low plasma oxytocin levels has been found in low functioning or “aloof” autistic children, but the correlation is not found in high functioning or “active-but-odd” children.167

The steroid hormones, progesterone, estrogen, testosterone and adreno-corticotropic hormone or ACTH are also relevant to autism. The production and secretion of ACTH is activated by the hypothalamus when the body is stressed. This hormone stimulates the adrenal cortex to synthesize cortisol, which in turn acts to promote gluconeogenesis in the liver and to stimulate the breakdown of proteins to amino acids in the muscles.168 So, the ingestion of the ACTH precursor, progesterone, in the form of birth control pills, would cause an increase in ACTH, making a person better equipped to handle stress. The resultant increase in cortisol would also activate glucose and amino acid synthesis, helping the brain and body to function better.

How do drugs work to control neurotransmitter function?

All mind-affecting drugs have their action at the synaptic gap. They work by modifying the way neurons communicate across this gap. Some drugs alter the amount of neurotramsmitters released or the rate of release. Others have their effect by either blocking or increasing the availability of receptor sites. Still others work by reducing the action of enzymes that break down neurotransmitters, rendering them inactive.169 The catecholamines (dopamine, norepinephrine and epinephrine) and serotonin are inactivated by oxidative deamination, catalyzed by the enzyme monoamine oxidase (MAO). MAO inhibitor drugs (antidepressants) serve to inactivate this enzyme, permitting neurotransmitter molecules to escape degradation and to activate dormant receptor systems.

Some neurotransmitters are reabsorbed into axons from fluid surrounding the nerve cells for reuse (endocytosis). Selective serotonin reuptake inhibitor drugs (SSRIs), including fluoxetine (Proxac), sertraline (Zoloft), fluvoxamine (Luvox), paroxetine (Paxil) and venlafaxine (a serotonin and norepinephrine reuptake inhibitor) work by blocking the re-uptake or recycling of serotonin and norepinephrine, thereby reducing their excitatory effect on the brain. The use of these drugs can be effective in curbing the restrictive, repetitive and obsessive behaviors associated with autism.

In attempting to curb or control the symptoms of autism, is it better to use drugs or dietary supplements?

Its better to use whatever works! As autism has a biochemical basis, pharmacological intervention is certainly warranted and often effective. In my daughter’s case, we've used both at different junctures in Meg's life. If there are no severe symptoms or medically warranted reason to resort to seizure medication, antidepressants or SSRIs, I would recommend supplements to begin with, as nutrients are part of the body’s normal physiology and given to facilitate normal functioning, while drugs are blocking agents, foreign to the body and given to interfere with normal processes.”170

How do specific supplements work to make the brain and body function better?

Quite simply, supplements work by building up or activating the biochemicals in the body responsible for normal functioning. If we are deficient in any nutrient, or if the nutritional value of the foods we eat is compromised by over-cooking and over- processing, whole chains of metabolic processes may go awry.

The following is a brief list of the supplements that act as coenzymes (or precursors to coenzymes) in the synthesis, activation or metabolism of some neuropeptides that have been causally linked to autism.

B-complex vitamins:

- Riboflavin is needed for synthesis of the amino acid tryptophan (precursor to serotonin).

- Niacin is needed for activation of the enzymes tryptophan hydroxylase and tyrosine hydroxylase (to form serotonin and the catecholamines: dopamine, norepinephrine and epinephrine)

- Niacin and Pantothenic Acid are needed for synthesis of the steroid/adrenal hormones.

- B6 is needed for synthesis of the amino acids cysteine, taurine and tryptophan and, along with Folic Acid, synthesis of the nucleic acids RNA and DNA.

Choline (needed for the proper transmission of nerve impulses) and Inositol are needed for synthesis of many hormones and of lecithin, a component of all cell membranes.

Vitamin C is needed for synthesis of anti-stress hormones and the metabolism of folic acid, tyrosine and phenylalanine.

Calcium is needed for the synthesis of RNA and DNA and for the activation of digestive enzymes like lipase that break down fats.

Magnesium is a vital catalyst in of enzymes involved in energy production. It assists in calcium and potassium uptake.

Potassium is needed for hormone secretion and for catalyzing chemical reactions within cells.

Amino acids as a group are necessary for the synthesis of all protein substances, so I will only list a few specific examples.

- Arginine stimulates the pancreas to produce insulin.

- Glycine forms RNA and DNA and the amino acid serine.

- DMG helps to produce choline and the amino acid methionine.

- Serine forms transferase enzymes and pyruvate (the substrate for gluconeogenesis). It can also be converted into the amino acids cysteine and glycine (as long as the vitamin B6 is present).

- Cysteine, the main source of free sulfur in the body, is needed for the synthesis of taurine and undergoes desulfurization to yield pyruvate.

- Glutamine can be converted to Glutamic Acid or GABA.

- Methionine can be converted to cysteine and/or taurine (as long as the B6 is present).

- Phenylalanine converts to tyrosine, which converts to the neurotransmitter dopamine.

- 5-HTP (5- Hydroxytryptophan) converts to tryptophan, which converts to the neurotransmitter serotonin.

Thiamine, B6, Vitamin C, Iron, Lysine and Methionine are needed to synthesize Carnitine, a transferase enzyme that functions to transport long chain fatty acids across cell membranes so that they can be broken down and metabolized into energy.

Omega 3 and 6 essential fatty acids form prostaglandins, hormone-like substances that act as chemical messengers and regulators of various body processes. They are also precursors to the plasmologens that form myelin.

How might specific supplements help people with autism to feel and function better?

I’ve grouped the supplements below according to the specific roles they may play in remediating autistic biochemistry.

1. Supplements that regulate mood; reduce anxiety and hyperactivity

Vitamins: B-complex (particularly Niacin, Pantothenic acid (B5) B6 and Inositol. Minerals: Calcium and Magnesium. Amino Acids: GABA, Glycine, Taurine, Phenylalanine, Tyrosine, Tryptophan (5-HTP)

2. Supplements that enhance digestion and energy metabolism, resulting in the delivery of more glucose (ATP) to brain cells:

Vitamins: B-complex (particularly Thiamine, Riboflavin, Niacin, Biotin, B6 and Folic Acid) Choline, Inositol and Coenzyme Q10. Minerals: Calcium, Potassium and Magnesium. Amino Acids: Alanine, Serine, Taurine, Glutamine, Glycine and DMG. Enzymes: Bromelain, Papain, Pancreatin and Pepsin.

3. Supplements that help maintain a healthy, gastrointestinal tract and acid/base balance of digestive fluids: 

Vitamins: B-complex (particularly Thiamine, Riboflavin, Niacin and B6). Minerals: Potassium and Sodium. Amino Acids: Glutamine, Glycine and Taurine. “Friendly” bacteria: Acidophilus and Bifudus supplements.

4. Supplements that stimulate blood circulation and oxygen delivery to the brain, thereby boosting cognitive function: 

Vitamins: B-complex (particularly Thiamine), Vitamin E and Coenzyme Q10. Amino Acids: Methionine. Herbal: Kyolic Garlic and Ginkgo Biloba.

5. Supplements that abet the transmission of neural messages to and within the brain, thereby enhancing learning and memory: 

Vitamins: B-complex (particularly Thiamine, Niacin, B6, Folic Acid) and Choline. Minerals: Calcium, Potassium and Magnesium. Amino Acids: Glutamine, Phenylalanine, Tyrosine. Fatty Acids: DHA, Evening Primrose Oil, Ultimate Oil and Phosphatidylserine/choline.

6. Supplements that promote neural cell development, fatty acid metabolism and myelin formation: 

Vitamins: Vitamin A, B-complex (particularly B12, Biotin, B6 and Folic Acid), Lecithin (formed from Choline and Inositol) and Vitamin C. Amino Acids: Serine, Taurine, Methionine and DMG. Omega-3 and Omega-6 Fatty Acids, Carnitine and Phosphatidlyserine complex.

7. Supplements that bolster immune system function by promoting red or white blood cell and antibody production: 

Vitamins: B-complex (particularly Riboflavin, B6 and Folic acid) Vitamin C, Coenzyme Q10 and DMG. Minerals: Iron and Sulfur. Amino Acids: Arginine and Serine. Herbal: Kaolic Garlic

8. Supplements that aid in protecting the body and brain from the harmful effects of toxic substances: 

Amino Acids: Aspartic acid, Glutamine (removes ammonia from the brain and intestinal mucosal cells), Cysteine and Methionine.

9. Supplements that lessen allergies by reducing histamine levels:

Vitamins: Coenzyme Q10. Amino Acids: Methionine and Taurine.

 

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