Monthly Archives: September 2016

image_pdfimage_print

Why Elephants Rarely Get Cancer: 40 Genes that Code for the p53 Tumor Protein!

Dr. Joshua Schiffman and his colleagues from the Huntsman Cancer Institute (HCI) at the University of Utah and Arizona State University, have studied why elephants rarely get cancer. 

The answer partially lies in the the p53 tumor protein, also known as the p53 tumor suppressor gene.  This protein prevents cancer formation and functions as a tumor suppressor.  1   The p53 tumor suppressor gene has been described as “the guardian of the genome” dues to its ability to prevent genome mutation.

p53tumor

“P53” by Thomas Splettstoesser – Based on atomic coordinates of PDB 1TUP, rendered with open source molecular visualization tool PyMol (www.pymol.org). Licensed under CC BY-SA 3.0 via Commons – https://commons.wikimedia.org/wiki/File:P53.png#/media/File:P53.png

The elephant genome has 40 copies (alleles) of genes that code for the p53 tumor suppressor gene, which is 38 more than humans.  Humans have 2 genes that code for the p53 protein.  The “extra” p53 proteins has explained why elephant’s have enhanced resistance to cancer.   2

In humans, the cancer mortality rate is approximately 11 to 25 percent.  However, in elephants, this mortality rate is 5 percent, despite the fact that elephants can weigh about 10,500 lbs. (4,800 kilograms) and live for up to 65 years. 

The majority of the p53 genes in elephants are so-called retrogenes, which are modified duplicates developed over time through evolution of the species.  3  4

The p53 protein in humans, in particular, has many mechanisms of anticancer function, such as:

  • Inhibition of angiogenesis (Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels)
  • Activates DNA repair proteins when DNA has sustained damage
  • Arrests growth by holding the cell cycle at the G1/S regulation point on DNA damage recognition
  • Initiates apoptosis (i.e., programmed cell death)

Mutations in the p53 protein can result is carcinogenesis.  It has been concluded that Aflatoxin, the fungal carcinogen first identified in 1960, is now recognized as the prototypical laboratory carcinogen. It causes mutations in the p53 tumor-suppressor gene as well as ras mutations, which are involved in the majority of human cancers.   5

It is important to continuously up-regulate and enhance the p53 tumor suppressor gene in humans.  There are certain natural substances identified that are known to up-regulate and enhance the p53 tumor suppressor gene.  They are listed in the Table below:

Natural Substances that Up-Regulate and Enhance p53 Tumor Suppressor Gene

P5 Tumor Suppressor Gene  
SubstanceAbstract of StudyReference
Inositol hexaphosphate (InsP6 or IP6)These data demonstrate that IP6 up-regulates the expression of the tumor suppressor gene p53 and p21WAF1/CIP1 gene and their modulation may be one of the mechanisms of the anti-neoplastic action of IP6. Since loss of p53 function enhances cancer cells' resistance to chemotherapeutic agents, the stimulating function of IP6 on p53 makes it an attractive adjuvant chemotherapeutic agent as well.1
Ellagic AcidThe effects of ellagic acid on cell cycle events and apoptosis were studied in cervical carcinoma (CaSki) cells. We found that ellagic acid at a concentration of 10(-5) M induced G arrest within 48 h, inhibited overall cell growth and induced apoptosis in CaSki cells after 72 h of treatment. Activation of the cdk inhibitory protein p21 by ellagic acid suggests a role for ellagic acid in cell cycle regulation of cancer cells.2
Apigenin (topically applied)The mechanism of p53 protein stabilization is currently being investigated. To determine whether p53 was transcriptionally active, we also performed gel mobility shift assays and transient transfection studies using a luciferase plasmid under the control of the p21/waf1 promoter. Both p53 DNA-binding activity and transcriptional activation peaked after 24 h of exposure to apigenin. These studies suggest that apigenin may exert anti-tumorigenic activity by stimulating the p53-p21/waf1 response pathway.3
Folate (Folic acid)Our data indicate that folate deficiency induces DNA strand breaks and hypomethylation within the p53 gene. Such alterations either did not occur or were chronologically delayed when examined on a genome-wide basis, indicating some selectivity for the exons examined within the p53 gene. Folate insufficiency has been implicated in the development of several human and experimental cancers, and aberrations within these regions of the p53 gene that were examined in this study are thought to play an integral role in carcinogenesis. The aforementioned molecular alterations may therefore be a means by which dietary folate deficiency enhances carcinogenesis.4
CurcuminWe observed that p53 was highly expressed in HT-29 cells and curcumin could up-regulate the serine phosphorylation of p53 in a time- and concentration-dependent manner. An increase in expression of the pro-apoptotic factor Bax and a decrease in expression of the anti-apoptotic factor Bcl-2 were also observed in a time-dependent manner after exposure of 50 microM curcumin, while the expression of the anti-apoptotic factor Bcl-xL was unchanged. Curcumin could also down-regulate the expression of pro-caspase-3 and pro-caspase-9 in a time-dependent manner. These data suggest a possible underlying molecular mechanism whereby curcumin could induce the apoptosis signaling pathway in human HT-29 colon adenocarcinoma cells by p53 activation and by the regulation of apoptosis-related proteins. This property of curcumin suggests that it could have a possible therapeutic potential in colon adenocarcinoma patients.5


Informational References:

Video – Dr. Schiffman and the elephants who inspired him


Resources:

Curcumin

Ellagic Acid

Folate (as Methyl Folate)

Inositol hexaphosphate (InsP6 or IP6)


    Print This Post Print This Post

Wasabi japonica: A Natural Anti-Cancer Agent

Wasabi (Wasabi japonica) is a member of the Brassica, or cruciferous, family of vegetables. It grows naturally along stream beds in mountain river valleys in Japan.

The Wasabi paste that is often served in Japanese sushi restaurants is typically not pure Wasabi japonica. Most of these restaurants substitute wasabi with less expensive European horseradish. Even though it contains shorter-chain isothiocyanates,  European horseradish does not contain the longer-chain isothiocyanates which has been found beneficial to health and is found in Wasabi japonica.

Wasabi japonica contains the following phytochemicals: [1]

  • 6-(methylsulfinyl)hexyl isothiocyanate (6-MITC or 6-HITC)
  • Monogalactosyl diacylglycerides
  • Isothiocyanates

The naturally occurring compound 6-(methylsulfinyl)hexyl isothiocyanate (6-MITC) has been reported as having specific medicinal activities:

  • Anti-inflammatory [2]
  • Chemopreventive [3]
  • Antimelanoma [4]

A study published in Phytochemistry in March 2006 found that 6-methylsulfinylhexyl isothiocyanate (6-HITC) was able to inhibit cell proliferation in human monoblastic leukemia U937 cells. The abstract of the study concluded that 6-HITC is potentially useful as a natural anti-cancer agent:

“The ethanol extract from Japanese horseradish wasabi was found to inhibit cell proliferation in human monoblastic leukemia U937 cells by inducing apoptotic cell death. Separation by methods including silica gel chromatography and preparative HPLC gave an active compound, which was identified as 6-methylsulfinylhexyl isothiocyanate (6-HITC). Several lines of evidence indicated that 6-HITC induced apoptosis in U937 cells and human stomach cancer MKN45 cells. Thus, 6-HITC is potentially useful as a natural anti-cancer agent.” [5]

Scientists at Japan’s Kanazawa Gakuin College learned that 6-MITC has similar properties against breast cancer and melanoma cells. The authors concluded that because of the low dosages required, 6-MITC has the potential to control cancer cells of all types. [6]


References:

[1] Morimitsu Y, Hayashi K, Nakagawa Y et al. Antiplatelet and anticancer isothiocyanates in Japanese domestic horseradish, Wasabi. Mech Ageing Dev 2000;116 (2-3) : 125-34

Hasegawa K, Miwa S, Tsutsumiuchi K, Miwa J. Allyl isothiocyanate that induces GST and UGT expression confers oxidative stress resistance on C. elegans, as demonstrated by nematode biosensor. PLoS ONE 2010;5 (2) : e9267

[2] T. Uto, D. X. Hou, O. Morinaga, and Y. Shoyama, “Molecular mechanisms underlying anti- inflammatory actions of 6-(methylsulfinyl)hexyl isothiocyanate derived from wasabi (Wasabia japonica),” Advances in Pharmacological Sciences, vol. 2012, Article ID 614046, 8 pages, 2012. View at Publisher · View at Google Scholar

[3] T. Nabekura, S. Kamiyama, and S. Kitagawa, “Effects of dietary chemopreventive phytochemicals on P-glycoprotein function,” Biochemical and Biophysical Research Communications, vol. 327, no. 3, pp. 866–870, 2005. View at Publisher · View at Google Scholar · View at Scopus

Hecht SS. Chemoprevention by isothiocyanates. J Cell Biochem Suppl. 1995;22:195-209.

[4] Y. Fuke, S. Shinoda, I. Nagata et al., “Preventive effect of oral administration of 6-(methylsulfinyl)hexyl isothiocyanate derived from wasabi (Wasabia japonica Matsum) against pulmonary metastasis of B16-BL6 mouse melanoma cells,” Cancer Detection and Prevention, vol. 30, no. 2, pp. 174–179, 2006. View at Publisher · View at Google Scholar · View at Scopus

[5] Identification of 6-methylsulfinylhexyl isothiocyanate as an apoptosis-inducing component in wasabi.

[6] Nomura T, Shinoda S, Yamori T, et al. Selective sensitivity to wasabi-derived 6-(methylsulfiny)hexyl isothiocyanate of human breast cancer and melanoma cell lines studies in vitro. Cancer Detect Prev. 2005;29(2):155-60.


Resources:

Eclectic Institute – Wasabi (Freezed Dried) (pills)

I-Sabi – Health Logics

Planetary Herbs – Wasabi Detox (pills)


    Print This Post Print This Post

 

 

Turn Off Your Body’s Aging “Switch”

“In an important scientific advance, researchers have uncovered a biochemical “switch” that turns on many of the chronic diseases of aging.

The name of this newly identified “switch” is HMGB1, which stands for “High Mobility Group Box-1”.

HMGB1 turns on the release of chemical signals called cytokines that generate inflammation in your body.

The more chronic inflammation you have, the more rapidly your body ages. The tragic consequence of higher levels of inflammation is the acceleration of chronic diseases that cause premature death and disability.

Once scientists uncovered the switch that “turns on” chronic inflammation, they began looking for a safe and effective means of “turning off” that switch.

Researchers have found two natural ingredients that can directly control HMGB1, thus reducing the body’s exposure to chronic inflammation, and ultimately protecting against inflammation-induced disorders.”

Excerpt from article “Turn Off Your Body’s Aging “Switch””, by Morris Eagleton, Life Extension Magazine Winter Edition 2013-2014


References:

Nogueira-Machado JA, de Oliveira Volpe CM. HMGB-1 as a target for inflammation controlling. Recent Pat Endocr Metab Immune Drug Discov. 2012 Sep;6(3):201-9.

Strzelecka M, Bzowska M, Kozieł J, et al. Anti-inflammatory effects of extracts from some traditional Mediterranean diet plants. J Physiol Pharmacol. 2005 Mar;56 Suppl 1:139-56.

Li W, Ashok M, Li J, Yang H, Sama AE, Wang H. A major ingredient of green tea rescues mice from lethal sepsis partly by inhibiting HMGB1. PLoS One. 2007;2(11):e1153.

Zhu S, Li W, Li J, Jundoria A, Sama AE, Wang H. It is not just folklore: The aqueous extract of mung bean coat is protective against sepsis. Evid Based Complement Alternat Med. 2012;2012:498467.


    Print This Post Print This Post

Mozuku Seaweed is a Good Source of Fucoidan

The edible seaweed, Mozuku, is also known by its botanical name Cladosiphon okamuranus.  Mozuku is naturally found in Okinawa Japan and is known by the Japanese name モズク; 水雲; 藻付; 海蘊; 海雲 and is derived from the word “Mo ni tsuku”.

Mozuku is in the brown seaweed family and is harvested from natural populations in the more tropical climate of the southern islands of Japan (Kagoshima and Okinawa Prefectures).  It grows in depths of 1-3 m for 5-6 months from late October to April.  The perfect growing environment for Mozuku is a flat reef in calm waters with continuous and moderate water currents that supply needed nutrients.

Mozuku is dark brown and in Japan is often eaten with vinegar.

The main constituents of Mozuku are:

  • Carbohydrates
    • Alginic Acid
    • Fucoidan
    • Fuco-Oligosaccharide
    • Fucose
    • Xylose
  • Fat-Soluble Components
    • Arachidonic Acid
    • EPA
    • Fucosterol
  • Carotenoids
    • Fucoxanthin

A very important chemical compound in Mozuku is fucoidan which has demonstrated wide and various health benefits.  Fuicodan is a sulfated polysaccharide found mainly in various species of brown algae. 

Other than Mozuku, fucoidan is also found in the following brown algae’s:

  • Bladderwrack
  • Hijiki
  • Kombu
  • Wakame

A number of in vitro studies have shown that fucoidan has the following health benefits:

  • Anti-arthritic  1 
  • Anti-inflammatory effects to protect against various organ injuries  2  3  4
  • Antitumor and antiangiogenic  5  6  7  8
  • Antiulcer  9
  • Antiviral  10  11
  • Immunomodulatory  12
  • Neuroprotective  13  14
  • Radioprotective  15

    Print This Post Print This Post

 

 

 

 

Vinpocetine Enhances Brain Circulation

Vinpocetine is a semi-synthetic derivative of the periwinkle (Vinca minor) plant. Developed more than three decades ago, vinpocetine has been hailed as an important neuroprotective agent with several key mechanisms of action. [75] It has been widely used to treat symptoms of cognitive decline throughout Europe, where it is available only by prescription. Vinpocetine’s ability to increase blood circulation and enhance glucose utilization in the brain is one of its most powerful effects. [76-79] This is particularly helpful to the aging brain, given that blood flow in the brain (and thus, oxygenation) tends to diminish with advancing age.

Vinpocetine’s therapeutic effects include its ability to enhance the electrical conductivity of cells composing the neural network. It protects the brain from damage caused by the excessive release of calcium ions intracellularly. Vinpocetine improves cerebral blood flow by inhibiting an enzyme that degrades cyclic GMP, a cellular metabolite. Degradation of cyclic GMP causes blood vessel constriction. Preventing degradation, therefore, allows cerebral arteries to relax, improving blood flow. [76-78,80-82]

Scientists have studied vinpocetine’s effects on human subjects under controlled conditions in various clinical trials. Three studies of older adults with memory problems associated with poor brain circulation or dementia-related disease have shown that vinpocetine confers significantly more improvement than a placebo in performance on comprehensive cognitive tests reflecting attention, concentration, and memory. [83]

Vinpocetine has even been studied in newborn babies who suffered brain damage due to birth trauma. Vinpocetine significantly reduced or eradicated seizures and elicited a decrease in abnormally high pressure within the brain. [84]

These studies reveal that vinpocetine’s therapeutic effects compare favorably with acetylcholinesterase inhibitor drugs such as Aricept®, which is used extensively in the US and abroad to treat Alzheimer’s symptoms and vascular dementia. Human trials and others using rodent models reveal that vinpocetine is safe, effective, and well tolerated. [81,85-87]

There have been some reports that vinpocetine in combination with the prescription drug Coumadin® (warfarin) may slightly influence prothrombin time, a measure of the clotting time of blood plasma. [88,89]

Although vinpocetine is unlikely to have a clinically meaningful effect on prothrombin time in patients who are also taking Coumadin®, please consult with your doctor if you plan to use a vinpocetine-containing supplement concomitantly with Coumadin® (warfarin).

Excerpt from Preserving and Restoring Brain Function By Dale Kiefer (Life Extension)


References:

75. Kiss B, Karpati E. Mechanism of action of vinpocetine. Acta Pharm.Hung. 1996 Sep;66(5):213-24.

76. Bonoczk P, Gulyas B, Adam-Vizi V, et al. Role of sodium channel inhibition in neuroprotection: effect of vinpocetine. Brain Res Bull. 2000 Oct;53(3):245-54.

77. Szilagyi G, Nagy Z, Balkay L, et al. Effects of vinpocetine on the redistribution of cerebral blood flow and glucose metabolism in chronic ischemic stroke patients: a PET study. J Neurol Sci. 2005 Mar 15;229-230:275-84.

78. Szapary L, Horvath B, Alexy T, et al. Effect of vinpocetin on the hemorheologic parameters in patients with chronic cerebrovascular disease. Orv Hetil. 2003 May 18;144(20):973-8.

79. Gabryel B, Adamek M, Pudelko A, Malecki A, Trzeciak HI. Piracetam and vinpocetine exert cytoprotective activity and prevent apoptosis of astrocytes in vitro in hypoxia and reoxygenation. Neurotoxicology. 2002 May;23(1):19-31.

80. Ukraintseva SV, Arbeev KG, Michalsky AI, Yashin AI. Antiaging treatments have been legally prescribed for approximately thirty years. Ann NY Acad Sci. 2004 Jun;1019:64-9.

81. Szatmari SZ, Whitehouse PJ. Vinpocetine for cognitive impairment and dementia. Cochrane Database Syst Rev. 2003;(1):CD003119.

82. Hagiwara M, Endo T, Hidaka H. Effects of vinpocetine on cyclic nucleotide metabolism in vascular smooth muscle. Biochem Pharmacol. 1984 Feb 1;33(3):453-7.

83. McDaniel MA, Maier SF, Einstein GO. “Brain-specific” nutrients: a memory cure? Nutrition. 2003 Nov;19(11-12):957-75.

84. Dutov AA, Gal’tvanitsa GA, Volkova VA, et al. Cavinton in the prevention of the convulsive syndrome in children after birth injury. Zh Nevropatol Psikhiatr m SS orsakova. 1991;91(8):21-2.

85. Vas A, Gulyas B, Szabo Z,et al. Clinical and non-clinical investigations using positron emission tomography, near infrared spectroscopy and transcranial Doppler methods on the neuroprotective drug vinpocetine: a summary of evidences. J Neurol Sci. 2002 Nov 15;203-204:259-62.

86. Balestreri R, Fontana L, Astengo F. A double-blind placebo controlled evaluation of the safety and efficacy of vinpocetine in the treatment of patients with chronic vascular senile cerebral dysfunction. J Am Geriatr Soc. 1987 May;35(5):425-30.

87. Feigin VL, Doronin BM, Popova TF, Gribatcheva EV, Tchervov DV. Vinpocetine treatment in acute ischaemic stroke: a pilot single-blind randomized clinical trial. Eur J Neurol. 2001 Jan;8(1):81-5.

88. Available at: http://www.pdrhealth.com/…/nmdru…/nutsupdrugs/vin_0259.shtml. Accessed July 29, 2005.

89. Hitzenberger G, Sommer W, Grandt R. Influence of vinpocetine on warfarin-induced inhibition of coagulation. Int J Clin Pharmacol Ther Toxicol. 1990 Aug;28(8):323-8.


    Print This Post Print This Post

Serotonin: Enhancing this Important Neurotransmitter

Approximately 90% of the human body’s total serotonin is located in the Enterochromaffin (EC) cells in the gastrointestinal tract, where it is used to regulate intestinal movements. The remainder is synthesized in serotonergic neurons of the central nervous system, where it has various functions. 1

Serotonin is related to the brain synchrony and is popularly thought to be a contributor to feelings of well-being and happiness.

Serotonin System

SystemSerotonin
SystemSerotonergic
TypeInhibitory
Lobe of the BrainOccipital lobes
BrainwaveDelta
Brain MeasurementSynchrony (Rest)
CharacteristicsHealing
BalancedNourishment
Satisfied feelings
Sleep deeply
Think rationally
CharacteristicDepression
DeficiencySleep disorders
Eating disorders
Sensory processing
disfunction
Diettryptophan-rich: turkey; chicken; sausage; avocados; cheese; cottage cheese; ricotta; eggs; granola; oat flakes; luncheon meats; wheat germ; whole milk; yogurt.
Supplementstryptophan; calcium; fish oil; 5-HTP; magnesium; melatonin; passionflower; pyridoxine; SAM-e; St. John’s Wort; zinc.

The average adult human possesses only 5mg to 10mg of serotonin, 90% of which is in the intestine and the rest in blood platelets and the brain. 

As a neurotransmitter, serotonin allows for  allowing numerous functions in the human body including:

  • behavior
  • cardiovascular function
  • control of appetite
  • depression
  • endocrine regulation
  • learning
  • memory
  • mood
  • muscle contraction
  • sleep
  • temperature regulation

The neurons in the brain that release serotonin are found in small dense collections of neurons called Raphe Nuclei.  The Raphe Nuclei are found in the medulla, pons and midbrain which are all located at the top of the spinal cord.  Serotonergic neurons have axons which project to many different parts of the brain, therefore serotonin affects many different behaviors.

Low serotonin levels are believed to be the cause of many cases of mild to severe depression which can lead to symptoms such as:

  • anxiety
  • apathy
  • fatigue
  • fear
  • feelings of worthlessness
  • insomnia

Serotonin is synthesized from the amino acid L-tryptophan by a short metabolic pathway consisting of two enzymes:

  • tryptophan hydroxylase (TPH)
  • amino acid decarboxylase (DDC)

Pyridoxal phosphate is a required cofactor during decarboxylase enzymatic synthesis from 5-hydroxytyortophan to 5-hydroxytyptamine (5-HT) or serotonin.

wps_clip_image-16816

Figure 1:  Serotonin Bio-pathway

The enzymes and required cofactors for serotonin are listed in the Table below:

Serotonin Required Enzymes and Cofactors

Amino Acid/NeurotransmitterEnzymeCofactor(s)
L-tryptophantryptophan hydroxylase (TPH) Tetrahydrobiopterin (folic acid is the precursor of Tetrahydrobiopterin)
Iron
Magnesium and Vitamin B6 enhances the function of tryptophan hydroxylase (TPH)
5-hydroxytyortophanamino acid decarboxylase (DDC) 5-HTP Decarboxylase
pyridoxal phosphate (active form of Vitamin B6)

Serotonin is the neurotransmitter that provides your brain with synchrony which is defined as the brains electricity moving in waves.   There are 4 types of brain waves: 

  • Beta
  • Alpha
  • Theta
  • Delta

Synchrony is achieved when all 4 brains waves are coordinated throughout the day and night.  If this coordination is in balance, then your brain is synchronous with the cycles of life. 

If these brain waves are out of synchrony at night, you will have restless sleep.  If these brain waves are out of synchrony during the day, your mind will wander and you will have less concentration.

Brain Waves

Brain WaveFrequency RateAssociated Feeling
Beta wave12 - 16 cycles per secondAlertness
Alpha wave8 - 12 cycles per secondCreative
Theta wave4 - 8 cycles per secondDrowsy
Delta wave1 - 4 cycles per secongSleep

There are a number of natural substances that are precursors to the synthesis of serotonin as well as natural substances that may enhance the production of serotonin.  These natural substances are listed in the Table below:

Nutraceuticals and Herbs that Enhance Serotonin

CategoryNutraceuticals and HerbsReference
Amino Acids
5-HTP1
Tryptophan2
Herbs
St. John’s Wort3
Valerian4
Organic Acids
Hydroxycitric Acid (HCA)5
Polyphenols
Resveratrol6
Proteins
Whey Protein7
Vitamins
Folic Acid8
Vitamin B69


    Print This Post Print This Post

Dopamine: Enhancing this Important Neurotransmitter

Dopamine is an important catecholamine monoamine neurotransmitter.  Dopamine plays important roles in motor control, motivation, arousal, cognitive control, reinforcement, and reward.  It is considered a stimulatory neurotransmitter.

Dopamine controls the brains voltage or power. The brains power determines the ability to:

  • Stay focused
  • Stay on task
  • Concentrate
  • Accomplish a job or task

A deficiency of dopamine results in not enough maintenance of brain voltage, which is generally manifested as the brain slowing down and losing energy.

After age 45, the brain’s dopaminergic neurons age rapidly, causing a decline in dopamine levels of 13% per decade. [ [i] ] A drop in brain dopamine to 30% of the normal level leads to Parkinson’s, and a plummet to 10% results in death.

Dopamine - Voltage Change and Impact on Cognitive Abilities

Voltage Change 
VoltageConditions
20Superior energy and concentration
10Normal energy and concentration
9Fatigue, mild memory loss and cognitive deficit
8Insomnia, panic disorder
7Obesity, moderate obsessive-compulsive disorder, mild depression
6Moderate addiction, major depression
5Borderline personality disorder, chronic fatigue
4Chronic depression, violent behavior
3Attention deficit disorder
2Alzheimer’s disease
1Schizophrenia
0Coma

The following physical manifestations are apparent with a deficiency of dopamine:

  • Loss of mental intensity
  • More time and effort needed to complete a task
  • Less concentration (wandering mind)
  • Decision making is not as fast
  • Work intensity is diminished and slowed

Dopamine Deficiency

Dopamine Deficiency 
Overall SymptomsPhysical Symptoms
Confusion/Loss of AttentionAddiction
Anemia
Bone density loss
Constipation
Diabetes
Difficulty achieving orgasm
Digestion problems
Excessive sleep
High blood pressure
Hypoglycemia
Impotence
Inability to lose weight
Involuntary movements
Joint pain
Kidney problems
Lack of quickness
Low sex drive
Narcolepsy
Obesity
Parkinson’s disease
Poor blood sugar stability
Poor physical strength
Poor walking
Shuffling gait
Slow metabolism
Slow or rigid movements
Thyroid disorders
Wide-based gait

Dopamine Precursors and Biosynthesis

There are three precursors to the neurotransmitter dopamine:

  • L-Tyrosine
  • L-Phenylalanine
  • L-DOPA

N-Acetyl-L-Tyrosine (NALT) can be substituted for L-Tyrosine and has better bioavailability while being able to cross the blood brain barrier better than L-Tyrosine.

D,L-Phenylalanine can be substituted for L-Phenylalanine.

L-DOPA is the direct precursor to dopamine and is able to cross the blood brain barrier.   A natural high-yielding source of L-DOPA is Mucuna pruriens (Velvet Bean).  The seeds of the plant contain about 3.1–6.1% L-DOPA and the leaves contain about 0.5% L-DOPA.

The sequence of the biosynthesis of dopamine is as follows:

image

L-Phenylalanine is converted into L-tyrosine by the enzyme phenylalanine hydroxylase (PAH), with molecular oxygen (O2) and tetrahydrobiopterin (THB) as cofactors.

L-Tyrosine is converted into L-DOPA by the enzyme tyrosine hydroxylase (TH), with tetrahydrobiopterin (THB), O2, and ferrous iron (Fe2+) as cofactors.

L-DOPA is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase (AADC; also known as DOPA decarboxylase (DDC)), with pyridoxal phosphate (PLP) as the cofactor.

Dopamine itself is also used as precursor in the synthesis of the neurotransmitters norepinephrine and epinephrine.

Dopamine is converted into norepinephrine by the enzyme dopamine β-hydroxylase (DBH), with O2 and L-ascorbic acid as cofactors.

Norepinephrine is converted into epinephrine by the enzyme phenylethanolamine N-methyltransferase (PNMT) with S-adenosyl-L-methionine (SAM) as the cofactor..

Deficiency in any required amino acid or cofactor will result in subsequent dopamine, norepinephrine, and epinephrine biosynthesis impairment and deficiency.

DopamineSynthesis

Dopamine Biosynthesis

There are a few natural cofactors that assist in the biosynthesis of dopamine and are required by the various enzymes:

  • Vitamin C (Ascorbic acid)
  • Vitamin B6 (Pyridoxal phosphate (PLP, pyridoxal 5′-phosphate, P5P))
  • S-Adenosyl methionine (SAMe)

Dopamine: Required Enzymes and CoFactors

Dopamine - Enzymes and CoFactors  
Amino Acid/NeuroTEnzymeCofactor(s)
L-Phenylalaninephenylalanine hydroxylase (PAH)
molecular oxygen (O2)
tetrahydrobiopterin (THB)
L-Tyrosinetyrosine hydroxylase (TH)
tetrahydrobiopterin (THB)
O2
ferrous iron (Fe2+)
L-DOPAaromatic L-amino acid decarboxylase (AADC; also known as DOPA decarboxylase (DDC))
pyridoxal phosphate (PLP)
Dopaminedopamine β-hydroxylase (DBH)
L-ascorbic acid (Vitamin C)
O2
Norepinephrinephenylethanolamine N-methyltransferase (PNMT)
S-adenosyl-L-methionine (SAM)

Other than the three precursors that assist in the production of dopamine, namely, L-Phenylalanine, L-Tyrosine and L-DOPA, there are also certain natural substances that are recognized to enhance the production and function of dopamine.

Substances that May Enhance the Production and Function of Dopamine

Dopamine  
CategoryNootropics/Nutraceuticals/Foods/HerbsReference
Amino Acids
Acetyl-L-Carnitine (ALCAR)1
Theanine2
Herbs
Ginko Biloba3
Korean Ginseng4
Siberan Ginseng5
St. John’s Wort6
Lipids
DHA7
Phosphatidylserine8
Minerals
Copper9
Magnesium10
Manganese11
Nootropics
CDP-Choline12
Deprenyl13
Vinpocetine14
Nucleic Compounds
NADH15
Uridine16
Quinones
Coenzyme Q1017
Vitamins
Alpha-GPC18
Vitamin B619
Vitamin C20


References:

[i] Knoll J. (-)Deprenyl-medication: a strategy to modulate the age-related decline of the striatal dopaminergic system. J Am Geriatr Soc. 1992 Aug;40(8):839-47.


    Print This Post Print This Post