Monday, February 26, 2024

Can Amino Acids Help Parkinson’s

Regulation Of Gut Microbiota On Amino Acid Metabolism And Synthesis

Glutathione Therapy for Parkinson’s Part 1 from David Perlmutter, MD FACN

An enormous number of metabolic pathways, such as glucose, lipid, and amino acid metabolism, are regulated by gut microbiota. The composition of gut microbiota-derived metabolites in the intestinal tract is very complex. The nutrition can be provided by amino acids acquired in the diet or synthesized by the host for the gut microbiota for protein production. Amino acids can be integrated into bacterial cells as amino acid residues in proteins, and further incorporated into the metabolic pathway. Amino acids and peptides are obtained by the hydrolysis of proteins through proteases and peptidases secreted by gut microbiota. Ultimately, amino acids and peptides could be absorbed by microbiota through specific transporters. However, the small bioactive molecules will encounter various consequences under different physiological conditions of humans . Transamination or deamination is the first stage of amino acid catabolism, followed by oxidation or reduction. Biogenic amines are alkaline organic compounds mainly produced by decarboxylation reactions of free amino acids present by the enzyme decarboxylase .

Table 2. Major amino acid-fermenting bacteria in the digestive tract.

Demographics And Clinical Characteristics Of Study Participants

Demographics and clinical characteristics of study participants are summarized in Table . A total of 106 PD patients and 114 controls were enrolled in this study. Age, sex, and body mass index were indistinguishable between PD patients and controls. PD patients had an average Hoehn and Yahr stage of 2.5±0.9, disease duration of 6.5±4.6 years, and Movement Disorder Society-sponsored revision of the Unified Parkinsons Disease Rating Scale total score of 61.9±21.8 points. All PD patients were using antiparkinsonian medications. Dopamine agonists were used by 70 patients, including pramipexole , piribedil , and ropinirole . Monoamine oxidase-B inhibitors, including selegiline and rasagiline , were used by 36 patients. There were no significant differences in age, sex, or BMI between patients with early and advanced PD . The disease duration was longer MDS-UPDRS total and part II, III, and IV scores were higher and levodopa daily dose and levodopa equivalent daily dose was larger in patients with advanced stage. More patients were treated with levodopa in the advanced stage.

Table 1 Demographics and clinical characteristics of study participants.

Roles Of Gut Microbial Dysbiosis And Microbial Products In Pd

The key pathological characteristics of PD are the accumulation of -syn and cell death in the brain’s basal ganglia, affecting an estimated three million people . This damage to dopaminergic neurons is responsible for the distinctive movement disorder and vagal nerve dysfunction associated with PD. Until recently, the NMS including constipation, dysphagia, disrupted sleep architecture, impaired olfaction, and depression were presented in PD patients . A great quantity of studies has shown that constipation is an early manifestation of the neurodegenerative process underlying PD. More importantly, the NMS of GI dysfunction often appears much earlier in PD patients, predating the onset of motor symptoms by as many as 20 years . Many studies found that gut microbiota composition alters in various PD-related NMS, possibly pre-dating motor symptoms . Interestingly, current research studies have illustrated that gut microbial disturbance can damage the intestinal barrier and raise chronic inflammation both in the gut and brain .

The intestinal barrier

Figure 3. A schematic overview of the main cell types and physical defense mechanisms as targets related to intestinal barrier function for therapeutic strategies in PD.

Inflammation of the gut and neuroinflammation of the brain

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What Causes Parkinsons Disease

Though the precise cause of Parkinson’s disease remains unknown, it develops as the result of neurons breaking down or dying. Loss of these neurons decreases levels of dopamine, a neurotransmitter that carries information between brain cells. Dropping dopamine levels, in turn, cause many of the symptoms associated with Parkinson’s to manifest.

In many cases, the underlying stimulus that causes neurons to begin to break down or die cannot be identified. However, genetic mutations as well as environmental triggers such as herbicides and pesticides appear to be instigating factors in some cases. While having a close relative with Parkinson’s does somewhat raise your risk, the likelihood you will develop the condition remains quite low. The more family members who have the disease, the higher the risk a person faces. The increased risk posed by environmental triggers is even slighter and associated only with ongoing exposure. Researchers have also found that men are more likely than women to develop Parkinson’s, though it is not clear why.

One of the most significant substances found in these deposits is a protein called alpha-synuclein . Though scientists have not pieced out all the mechanisms by which A-synuclein contributes to Parkinson’s, they believe that targeting its harmful effect could lead to the development of new treatment options.

Amino Acid Unique To Tea Could Help Patients With Parkinson’s

Dopamine Metabolism

Meta-analyses of tea consumption and reduced risk of Parkinson’s disease have thrown light in the pathway of exploring beneficial properties of tea components.

On the basis of dry mass, a typical black or green tea beverage contains approximately 6% of free amino acids, which impart high quality, taste and distinctive aroma to the tea infusion. L-theanine is a non-proteinogenic amino acid of tea that takes part in the biosynthesis of its polyphenols.

Recently discovered neuroprotective effects of L-theanine can be attributed to its structural analogy with glutamate, the principal excitatory neurotransmitter in brain. This unique amino acid also bears a potential to ameliorate the pathophysiological changes associated with Parkinson’s disease as it displays antioxidant and anti-inflammatory properties, improves motor behavioral abnormalities, increases dopamine availability and may cause a favorable downshift in neurodegeneration due to glutamate excitotoxicity.

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Dietary Amino Acids Regulate Pd

Rescue effects of dietary amino acids are retained via late life diet switch. A, Schematic representation of the diet switch study. A set of LRRK2 G2019S flies were aged on 25, 50, or 200N diets for 6 weeks and tested for locomotor function. Another set of mutant LRRK2 flies were fed 50N diet for 5 weeks and then switched to either 25 or 200N amino acid diet for an additional 1 week. B, All flies were reared on standard sugar/yeast food. Switching flies from a 50N diet to either a 25 or 200N diet significantly improved motor function = 7.33 Bonferroni post-tests: *p< 0.05, **p< 0.01 n = 4 replicates of 25 flies/condition). Data are the mean ± SEM.

The Absorption And Metabolization Of Amino Acids In The Intestine

Amino acids perform several crucial functions in the human body, either directly or indirectly. They are the main constituents of protein in bioactive substances and adjust the balance of energy and immunity in organisms. In addition, amino acids can be catalyzed through oxidized, reduced, fissioned, or coupled pathways . Several reactions including transamination, deamination, and decarboxylation are required steps in this process. Lots of work demonstrated that glycine, proline, and arginine usually act as the acceptors of hydrogen, and alanine, leucine, isoleucine, and histidine are hydrogen donors in the metabolic pathways . The metabolisms of relevant amino acids are summarized in Figure 4. The microorganisms are mixed with endogenous proteins, such as mucous proteins, chemicals secreted by the pancreas and gastric gland in the alimentary canal . The nitrogen-containing compounds are broken down into amino acids and peptides and related enzymes are excreted via the exocrine pancreas. The amino acids and peptides are absorbed by bacteria or spread from the intestinal lumen to the portal vein.

Figure 4. The summary of microbiota-derived amino acid metabolism profile.

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Could Something As Simple As Targeted Amino Acid Supplementation Be The Missing Piece To Your Parkinsons Adhd Or Insomnia Healing Regimens

Neurologic issues are some of the most common and complex health challenges we face and the treatments are often worse than the disease itself! When it comes to medications for Parkinsons, ADHD, and insomnia, the side effects can be downright dangerous, ranging from balance issues all the way to suicidal depression. It may surprise you to know that there are safe, natural amino acid therapies that get to the root causes of these complicated illnesses to provide relief from the debilitating symptoms.

Eat Plenty Of Protein But Not With Levodopa Medications

2-Minute Neuroscience: L-DOPA

If youre taking a levodopa medication, your doctor may tell you to avoid protein when taking your meds. Both animal and plant protein can interfere with the absorption of levodopa medications.

But you should still eat plenty of protein. Just be strategic with the timing. Dont take levodopa medications with meals, Dr. Gostkowski says. Its best to take it on an empty stomach either 30 minutes before your meal or an hour after eating.

If you get nauseous from the medication, eat a small amount of starchy food with it, such as crackers. Make sure whatever you eat with your medicine doesnt have protein. Its a misunderstanding that people with Parkinsons should avoid protein, Dr. Gostkowski says. You definitely need protein in your diet. Just dont eat it when youre taking your levodopa medication.

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Nigrostriatal Dopamine Transporter Availability In Early Parkinsons Disease

also confirms my perspective that PD does not necessarily mean cell death:

These results suggest that in the early stages of the disease dopamine cells are still viable and that, given the correct treatment, it should be possible to restore their function, says Andrea Varrone, senior lecturer in nuclear medicine at Karolinska Institutets Department of Clinical Neuroscience who led the study.

Also, several other papers in the scientific literature, such as

S Rrna Gene Amplification And Sequencing

DNA extraction from thawed fecal samples was performed using the QIAamp DNA Stool Mini Kit following the manufacturers instructions. The V3V4 regions of 16S rRNA genes were amplified by polymerase chain reaction using the barcoded primers 341F 5-CCTACGGGRSGCAGCAG-3 and 806R 5-GGACTACVVGGGTATCTAATC-3. PCR reactions were performed in 30L mixtures containing 15L of 2 × KAPA Library Amplification ReadyMix, 1L of each primer , and 50ng of template DNA and ddH2O. The procedure of PCR was as follows: 95°C for 3min, followed by 30 cycles at 98°C for 20s, 58°C for 15s, and 72°C for 20s, then a final extension at 72°C for 5min. Amplicons were extracted from 2% agarose gels and purified using the AxyPrep DNA Gel Extraction Kit according to the manufacturers instructions and were quantified using Qubit®2.0 . The pooled library was sequenced using an Illumina MiSeq system .

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Modeling Intestinal Absorption Of Levodopa Using A Combined Pbpkcobra Model

Figure 1

The multiscale PBPKCOBRA model used in this study. We combined a spatially and temporally refined PBPK model of the gastrointestinal tract with seven copies of a mechanistically accurate and detailed metabolic model of small intestinal epithelial cells . COBRA, constraint-based reconstruction and analysis PBPK, physiologically based pharmacokinetic WB-ACAT, whole-body advanced compartmental absorption and transit.

Using the WB-ACAT-sIEC model, we predicted that the addition of serine in the systemic circulation could improve the bioavailability of levodopa as shown by the increase of the AUC above the efficacy threshold . The subsequent increase of amino acids concentration in the plasma improved the bioavailability of the next dose through a higher absorption in the basolateral side of the seven compartments of the small intestine. Taken together, we propose that a serine-rich meal after a levodopa dose could improve the brain bioavailability of levodopa.

C Elegans Strains And Maintenance

Levodopa for the Treatment of Parkinson

Worms were maintained at 20 °C on standard nematode growth medium plates or high growth medium plates seeded with OP50 E. coli or HT115 RNAi E. coli, as indicated. The following strains were used in this study: wild-type worms of the N2 Bristol strain, neuron-only RNAi strain CQ511 uIs69 , and the following neuronal RNAi-sensitive strains: CF512 , CQ434 baIn11 vIs69 , and TU3311 uIs60 .

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Icipant Recruitment And Data Collection

One hundred six individuals with PD were recruited from the Movement Disorders Clinic at the Department of Neurology and Institute of Neurology, Ruijin Hospital. PD was diagnosed according to the United Kingdom Parkinsons Disease Society Brain Bank criteria. Exclusion criteria for PD patients were: atypical or secondary parkinsonism, serious chronic illnesses , the use of probiotic or antibiotic supplements for the three months before enrollment, or a high- or low-amino acid diet.

One hundred fourteen controls matched by age, sex, and nutritional status were recruited over the same period. Inclusion criteria for controls were: normal physical exam, no digestive symptoms or disease, no neurodegenerative disease, and avoidance of a high- or low-amino acid diet. Exclusion criteria for controls were the same as for PD patients. This study was approved by the Research Ethics Committee, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. All participants were informed of the purpose of this study and provided written informed consent.

Venous blood samples were taken after an overnight fast of at least 10h from PD patients and controls, and immediately centrifuged at 4°C to obtain plasma, which was further stored at 80°C until analysis. Fecal samples were collected from PD patients in sterile fecal collection containers and stored at 80°C prior to processing.

Dyskinesia Uncontrolled Involuntary Movement

This is the most unpleasant side effect that appears within 2 years of using levodopa therapy, although in some patients, it may appear after 5 years.

It refers to the abnormal uncontrolled involuntary movements that mostly affect the arms, legs, and face. In this condition, the tremor becomes more aggressive and results in the wiggly movement.

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Studies Of Ochratoxin A

David then suggested I looked up Malassezia and L-Dopa.

Malassezia is a genus of fungi, naturally found on the skin surfaces of many animals, including humans. Allergy tests for this fungus are available.

Moreover,

Investigations show that the Malassezia species causing most skin disease in humans, including the most common cause of dandruff and seborrhoeic dermatitis. As the fungus requires fat to grow, it is most common in areas with many sebaceous glands: on the scalp, face, and upper part of the body. When the fungus grows too rapidly, the natural renewal of cells is disturbed, and dandruff appears with itching .

This is interesting, because such skin issues are very prevalent in Parkinsons Disease. Indeed, David makes one more extremely important connection. Malassezia feeds on L-Dopa,

Human Trials Are Still Needed

3. Structures of Amino Acids, Peptides, and Proteins

If these results can be replicated in patients, it will be a major breakthrough in the treatment of this devastating neurological disorder, concludes Kalipada Pahana, who led the study which was published in Nature Communications. There are drugs that slow the progression of Parkinsons disease, such as levodopa, which replenishes the dopamine deficiency caused by neuronal death. It slows the loss of motor skills but does not prevent the death of dopaminergic neurons. For patients with the most severe impairments, deep brain stimulation may be an alternative.

Scientists are currently working on several lines of research, such as immunotherapy and gene therapy, to cure this disease, which we so far can only slow down.

References

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Parkinsons And The Protein Redistribution Diet

A protein redistribution diet is another way to make levodopa more effective and to help reduce the feeling of sickness. It involves concentrating your protein into a certain time of the day.

This could mean:

  • Reducing the amount of protein you eat early in the day. This may help to increase your bodys response to medication and avoid unpredictable motor fluctuations
  • Eating your main protein meal in the evening as a slower response to medication may not be as important at this time

The Parkinsons NICE guidelines highlight the importance of discussing a protein redistribution diet with a specialist.

How Is Parkinson’s Disease Treated

There is currently no cure for Parkinsons disease, which always gets worse over time. Death is usually because of complications, including pneumonia or falling-related injuries.

Parkinsons disease changes the quality of life for patients and their families. In order to make the most worthwhile treatment decisions, education is imperative. Some prescription drugs and surgical procedures may drastically improve symptoms.

Treatment plans for Parkinson’s depend on symptoms, other health issues and medications used to treat them, metabolism, and age. Because most Parkinson’s symptoms result from a lack of dopamine in the brain, many drugs attempt to replenish proper levels of dopamine or mimic the action of dopamine. Termed dopaminergic medications, these treatments target muscle rigidity, speed and coordination of movement, and tremors.

Though these medications can decrease symptoms for some Parkinson’s patients, they do come with side effects, some of which can be severe. The list of reported side effects for top Parkinson’s drugs includes:

Confusion
Difficult or painful urination

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How Much Protein Do I Need

For optimal health, you need about a half gram of protein per pound of body weight every day. Take your weight in pounds and divide it by two to determine the grams of protein you need. For example, if you weigh 140 pounds, you should eat about 70 grams of protein. Since seniors are less efficient at processing protein, spreading protein consumption evenly throughout the day can improve absorption. If you eat three meals a day, divide the 70 grams by three. You should eat about 23 grams of protein in each meal. Of course, if you weigh more, eat more protein. If you weigh less, eat less protein.

You may think 20-25 grams of protein is a lot in one meal however, if you plan ahead, incorporating the amount of protein you need is easy.

Breakfast

Breakfast is the time that most people dont eat enough protein. Just eating oatmeal or cereal with milk isnt enough. Add Greek yogurt, a slice of cheese, peanut butter on your whole-grain toast, an egg, or turkey sausage to increase protein.

Lunch

For lunch, two cups of chili with beans provide 20 grams of protein. Add some cornbread with some honey, and a half cup of milk or a dairy alternative, such as soy milk and you have met your protein requirement for lunch. A grilled cheese sandwich with tomato soup and carrots sticks is another balanced meal idea.

Dinner

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