STTT Jiang Jiandong/Cao Xuetao/Wang Yan proved for the first time that oral berberine can improve Parkinson's disease

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The iNature phenylalanine-tyrosine-dopa-dopamine pathway provides dopamine to the brain
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In this process, tyrosine hydroxylase (TH) is the rate-limiting enzyme, which can hydroxylate tyrosine and use tetrahydrobiopterin (BH4) as a coenzyme to produce levodopa (L-dopa)
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Recently, the Chinese Academy of Medical Sciences/Peking Union Medical College Jiang Jiandong, Cao Xuetao and Wang Yan jointly published an online communication titled "Oral berberine improves brain dopa/dopamine levels to ameliorate Parkinson's disease by regulating gut microbiota" in Signal Transduction and Targeted Therapy (IF=18.
19).
"The research paper shows that oral berberine (BBR) may provide H• and promote BH4 produced by dihydrobiopterin through dihydroberberine (reducing BBR produced by bacterial nitrification reductase)
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The increased BH4 enhances TH activity, thereby accelerating the production of L-dopa by intestinal bacteria
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Oral BBR behaves like vitamins
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Levodopa produced by intestinal bacteria enters the brain through the circulation and is converted into dopamine
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In order to verify that the effect of BBR activates the gut-brain axis, Enterococcus faecalis was transplanted into Parkinson's disease (PD) mice
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This bacterium significantly increased brain dopamine in mice and improved PD performance
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In addition, the combination of BBR and bacteria showed a better therapeutic effect than bacteria alone
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In addition, 2,4,6-trimethylpyrantetrafluoroborate (TMP-TFB)-derived MALDI-MS imaging of dopamine confirmed that the level of dopamine in the striatum of mice receiving oral enterococcus was elevated, while BBR was enhanced.
The imaging intensity of brain dopamine
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These results indicate that BBR is an agonist of TH in enterococci and may lead to the production of L-dopa in the intestine
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In addition, a study of 28 patients with hyperlipidemia confirmed that oral BBR can increase the blood/fecal levodopa of intestinal bacteria
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Therefore, BBR may up-regulate the biosynthesis of L-dopa in the intestinal flora through vitamin-like effects, thereby improving brain function
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Intestinal flora is a recognized factor affecting brain function, but its mechanism is still unclear
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Dopamine is a major neurotransmitter, and its level in the brain is closely related to brain function
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Dopamine is mainly synthesized in brain neurons
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In the human body, the main synthesis pathway of dopamine is "L-phenylalanine (Phe)→L-tyrosine (Tyr)→(s)-3,4-dihydroxyphenylalanine (levodopa, L -Dopa→dopamine (Phe-Tyr-dopa-dopamine)" metabolic pathway
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In this process, the first stage (Phe-Tyr step) is catalyzed by phenylalanine hydroxylase (PAH), and the conversion mainly occurs in Liver and kidneys
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The liver (or kidney) and/or blood-derived tyrosine (in the diet) can cross the blood-brain barrier and enter the brain
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Tyr-dopa-dopamine conversion is the second stage, which is completed in the brain by tyrosine hydroxylase (TH) and dopa decarboxylase (DDC)
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Disruption of this pathway can cause neurological diseases, such as phenylketonuria and Parkinson’s disease (PD)
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Tyrosine hydroxylase (TH) is the rate-limiting enzyme for catecholamine biosynthesis, which can hydroxylate L-Tyr to L-dopa
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Tyrosine hydroxylase (TH) is an iron-containing monooxygenase that requires tetrahydrobiopterin (BH4) as a cofactor
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When L-dopa is produced, BH4 is converted to 7,8-dihydrobiopterin (BH2), during which BH4 is continuously consumed
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BH4 can be synthesized in the cytoplasm in two ways
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Under normal conditions, BH4 can be synthesized by the GTP (guanosine triphosphate)-NH2P3 (D-erythro-7,8-dihydropterin triphosphate)-PPH4 (6-pyruvyltetrahydropterin)-BH4 pathway , Called "source synthesis"; on the other hand, BH4 can be supplemented by the repair pathway of Sepaapterin→BH2→BH4, and dihydrofolate reductase (DHFR) is the key enzyme responsible for converting BH2 into BH4
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Therefore, it was found that DHFR agonists may be an effective method to increase BH4 levels and enhance TH activity
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The article pattern (picture from Signal Transduction and Targeted Therapy) has confirmed the BH4 producing bacteria in the intestinal flora, and the Phe-Tyr-dopa-dopamine metabolic pathway is also present in the microorganisms
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This suggests that the bacteria may contain homologues of the gene for the enzyme that mammals use to produce dopamine
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In fact, some bacteria can be regarded as biotech factories that produce dopa/dopamine
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Recent studies have shown that the intestinal flora can regulate brain function through microbial-derived metabolites (such as serotonin)
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Therefore, the key question becomes how to regulate brain function in a practical way
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Berberine (BBR) is a natural compound (molecular weight 371.
8) extracted from herbs, such as berberine and berberine
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BBR has been used as an over-the-counter (OTC) drug in China to treat patients with diarrhea
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Since 2004, BBR has been identified as a safe and effective hyperlipidemia and type 2 diabetes drug with a novel mechanism
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In the past ten years, the clinical efficacy of BBR in reducing blood lipids and blood sugar has been widely confirmed
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In addition, independent research teams have repeatedly reported that BBR has a beneficial effect on brain function
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The study found that oral BBR can trigger the biosynthesis of BH4 in the intestinal flora, increase blood and brain dopa/dopamine concentration to enhance TH activity to produce L-dopa, and ultimately improve the animal's body function
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Detection of pathway intermediates in clinical subjects confirmed the effects of BBR on humans
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These results may provide new ideas for controlling the crosstalk between the intestine and the brain
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