Berberine

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Information on nutritional supplements people with ALS have been taking

Wikipedia page

examine.com summarizes:

Berberine is an alkaloid extracted from various plants used in Traditional Chinese Medicine.

Berberine is supplemented for its anti-inflammatory and anti-diabetic effects. It can also improve intestinal health and lower cholesterol. Berberine is able to reduce glucose production in the liver. Human and animal research demonstrates that 1500mg of berberine, taken in three doses of 500mg each, is equally effective as taking 1500mg of metformin or 4mg glibenclamide, two pharmaceuticals for treating type II diabetes. Effectiveness was measured by how well the drugs reduced biomarkers of type II diabetes.

Berberine may also synergize with anti-depressant medication and help with body fat loss. Both of these benefits need additional evidence behind them before berberine can be recommended specifically for these reasons.

Berberine’s main mechanism is partly responsible for its anti-diabetic and anti-inflammatory effects. Berberine is able to activate an enzyme called Adenosine Monophosphate-Activated Protein Kinase (AMPK) while inhibiting Protein-Tyrosine Phosphatase 1B (PTP1B).

According to Wikipedia, the half-life of berberine in vivo seems to be three to four hours, thus suggesting administration three times a day if steady levels are to be achieved.

Effect of berberine on ALS

In rat cerebral cortex, berberine inhibits synaptosomal glutamate release. [1] By downregulating several proinflammatory pathways [2] it presumably reduces the neuroinflammatory component of ALS.

In a study [3] on rat astrocyte primary cultures, berberine and the alkaloid extract of B. aetnensis roots were able to restore the oxidative status modified by glutamate and the levels of TG2 to control values. Consequently berberine or the alkaloid extract of B. aetnensis roots are able to ameliorate the excessive production of glutamate, protein misfolding and aggregation, mitochondrial fragmentation, and neurodegeneration.

On the negative side, berberine has been found to impair muscle metabolism by two mechanisms. It impairs mitochondrial function stimulating the expression of atrogin-1 without affecting phosphorylation of forkhead transcription factors. The increase in atrogin-1 not only stimulates protein degradation but also suppresses protein synthesis, causing muscle atrophy. [4]

Berberine has been found [5] to restore SOD1 activity inhibited by lipopolysaccharides.

Discussion threads on the ALSTDI forum

Berberine

Berberine Suppresses Pro-Inflammatory Responses:

In adipose tissue of obese db/db mice, BBR treatment significantly down-regulated the expression of pro-inflammatory genes such as TNFalpha, IL-1beta, IL-6, MCP-1, iNOS and COX2. Consistently, BBR inhibited LPS-induced expression of pro-inflammatory genes including IL-1beta, IL-6, iNOS, MCP-1, COX 2, and MMP9 in peritoneal macrophages and RAW 264.7 cells. Upon various pro-inflammatory signals including LPS, free fatty acids, and hydrogen peroxide, BBR suppressed the phosphorylation of MAPKs such as p38, ERK, and JNK, and the level of reactive oxygen species in macrophages. [2]

References

[1] <bibtex> @article{Lin2013, abstract = {Berberine, an isoquinoline plant alkaloid, protects neurons against neurotoxicity. An excessive release of glutamate is considered to be one of the molecular mechanisms of neuronal damage in several neurological diseases. In this study, we investigated whether berberine could affect endogenous glutamate release in nerve terminals of rat cerebral cortex (synaptosomes) and explored the possible mechanism. Berberine inhibited the release of glutamate evoked by the K(+) channel blocker 4-aminopyridine (4-AP), and this phenomenon was prevented by the chelating extracellular Ca(2+) ions and the vesicular transporter inhibitor bafilomycin A1, but was insensitive to the glutamate transporter inhibitor DL-threo-beta-benzyl-oxyaspartate. Inhibition of glutamate release by berberine was not due to it decreasing synaptosomal excitability, because berberine did not alter 4-AP-mediated depolarization. The inhibitory effect of berberine on glutamate release was associated with a reduction in the depolarization-induced increase in cytosolic free Ca(2+) concentration. Involvement of the Cav2.1 (P/Q-type) channels in the berberine action was confirmed by blockade of the berberine-mediated inhibition of glutamate release by the Cav2.1 (P/Q-type) channel blocker $\omega$-agatoxin IVA. In addition, the inhibitory effect of berberine on evoked glutamate release was prevented by the mitogen-activated/extracellular signal-regulated kinase kinase (MEK) inhibitors. Berberine decreased the 4-AP-induced phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and synapsin I, the main presynaptic target of ERK; this decrease was also blocked by the MEK inhibition. Moreover, the inhibitory effect of berberine on evoked glutamate release was prevented in nerve terminals from mice lacking synapsin I. Together, these results indicated that berberine inhibits glutamate release from rats cortical synaptosomes, through the suppression of presynaptic Cav2.1 channels and ERK/synapsin I signaling cascade. This finding may provide further understanding of the mode of berberine action in the brain and highlights the therapeutic potential of this compound in the treatment of a wide range of neurological disorders.}, author = {Lin, Tzu-Yu and Lin, Yu-Wan and Lu, Cheng-Wei and Huang, Shu-Kuei and Wang, Su-Jane}, doi = {10.1371/journal.pone.0067215}, editor = {Woodhall, Gavin}, file = {:C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Lin et al. - 2013 - Berberine Inhibits the Release of Glutamate in Nerve Terminals from Rat Cerebral Cortex(2).pdf:pdf}, issn = {1932-6203}, journal = {PLoS ONE}, mendeley-groups = {berberine}, month = jun, number = {6}, pages = {e67215}, pmid = {23840629}, title = Template:Berberine Inhibits the Release of Glutamate in Nerve Terminals from Rat Cerebral Cortex, url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3686739\&tool=pmcentrez\&rendertype=abstract}, volume = {8}, year = {2013} }

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[2]<bibtex> @article{Jeong2009, abstract = {Berberine (BBR) has been shown to improve several metabolic disorders, such as obesity, type 2 diabetes, and dyslipidemia, by stimulating AMP-activated protein kinase (AMPK). However, the effects of BBR on proinflammatory responses in macrophages are poorly understood. Here we show that BBR represses proinflammatory responses through AMPK activation in macrophages. In adipose tissue of obese db/db mice, BBR treatment significantly downregulated the expression of proinflammatory genes such as TNF-alpha, IL-1beta, IL-6, monocyte chemoattractant protein-1 (MCP-1), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Consistently, BBR inhibited LPS-induced expression of proinflammatory genes including IL-1beta, IL-6, iNOS, MCP-1, COX-2, and matrix metalloprotease-9 in peritoneal macrophages and RAW 264.7 cells. Upon various proinflammatory signals including LPS, free fatty acids, and hydrogen peroxide, BBR suppressed the phosphorylation of MAPKs, such as p38, ERK, and JNK, and the level of reactive oxygen species in macrophages. Moreover, these inhibitory effects of BBR on proinflammatory responses were abolished by AMPK inhibition via either compound C, an AMPK inhibitor, or dominant-negative AMPK, implying that BBR would downregulate proinflammatory responses in macrophages via AMPK stimulation.}, author = {Jeong, Hyun Woo and Hsu, Kuan Chi and Lee, Joo-Won and Ham, Mira and Huh, Jin Young and Shin, Hyun Jung and Kim, Woo Sik and Kim, Jae Bum}, doi = {10.1152/ajpendo.90599.2008}, issn = {0193-1849}, journal = {American journal of physiology. Endocrinology and metabolism}, keywords = {3T3-L1 Cells,Adenylate Kinase,Adenylate Kinase: metabolism,Adenylate Kinase: physiology,Adipose Tissue, White,Adipose Tissue, White: drug effects,Adipose Tissue, White: pathology,Animals,Anti-Inflammatory Agents,Anti-Inflammatory Agents: pharmacology,Anti-Inflammatory Agents: therapeutic use,Berberine,Berberine: pharmacology,Berberine: therapeutic use,Cells, Cultured,Drug Evaluation, Preclinical,Gene Expression Regulation,Gene Expression Regulation: drug effects,Inflammation,Inflammation Mediators,Inflammation Mediators: antagonists \& inhibitors,Inflammation: drug therapy,Inflammation: genetics,Inflammation: pathology,Macrophages,Macrophages: drug effects,Macrophages: enzymology,Macrophages: metabolism,Male,Mice,Mice, Inbred C57BL,Mice, Obese,Mice, Transgenic,Receptors, Leptin,Receptors, Leptin: genetics}, mendeley-groups = {berberine}, month = apr, number = {4}, pages = {E955--64}, pmid = {19208854}, title = Template:Berberine suppresses proinflammatory responses through AMPK activation in macrophages., url = {http://www.ncbi.nlm.nih.gov/pubmed/19208854}, volume = {296}, year = {2009} } </bibtex>

[3] <bibtex> @article{Campisi2011, abstract = {Berberis aetnensis C. Presl. is a bushy-spiny shrub common on Mount Etna (Sicily, Italy), containing various alkaloids with several pharmacological properties. This study assessed the effect of berberine and of the alkaloid extract of B. aetnensis roots on the glutamate-evoked tissue transglutaminase (TG2) up-regulation in rat astrocyte primary cultures, used as an in vitro model of excitotoxicity. The findings show that the alkaloid extract of B. aetnensis roots consists mainly of berberine. Furthermore, berberine and the alkaloid extract of B. aetnensis roots were able to restore the oxidative status modified by glutamate and the levels of TG2 to control values. It was found that berberine or the alkaloid extract of B. aetnensis roots are able to ameliorate the excessive production of glutamate, protein misfolding and aggregation, mitochondrial fragmentation, and neurodegeneration. Thus, it is suggested that berberine and the alkaloid extract of B. aetnensis roots, may represent a natural therapeutic strategy in the neuropathological conditions associated with excitotoxicity.}, author = {Campisi, Agata and Acquaviva, Rosaria and Mastrojeni, Silvana and Raciti, Giuseppina and Vanella, Angelo and {De Pasquale}, Rita and Puglisi, Salvatore and Iauk, Liliana}, doi = {10.1002/ptr.3340}, issn = {1099-1573}, journal = {Phytotherapy research : PTR}, keywords = {Alkaloids,Alkaloids: pharmacology,Animals,Astrocytes,Astrocytes: drug effects,Astrocytes: enzymology,Astrocytes: metabolism,Berberine,Berberine: pharmacology,Berberis,Berberis: chemistry,Cells, Cultured,Glutamic Acid,Glutamic Acid: pharmacology,Plant Extracts,Plant Extracts: pharmacology,Plant Roots,Plant Roots: chemistry,Rats,Sicily,Transglutaminases,Transglutaminases: metabolism,Up-Regulation,Up-Regulation: drug effects}, mendeley-groups = {berberine}, month = jun, number = {6}, pages = {816--20}, pmid = {21086546}, title = Template:Effect of berberine and Berberis aetnensis C. Presl. alkaloid extract on glutamate-evoked tissue transglutaminase up-regulation in astroglial cell cultures., url = {http://www.ncbi.nlm.nih.gov/pubmed/21086546}, volume = {25}, year = {2011} } </bibtex>

[4] <bibtex> @article{Wang2010, abstract = {OBJECTIVE: Defects in insulin/IGF-1 signaling stimulate muscle protein loss by suppressing protein synthesis and increasing protein degradation. Since an herbal compound, berberine, lowers blood levels of glucose and lipids, we proposed that it would improve insulin/IGF-1 signaling, blocking muscle protein losses.

RESEARCH DESIGN AND METHODS: We evaluated whether berberine ameliorates muscle atrophy in db/db mice, a model of type 2 diabetes, by measuring protein synthesis and degradation in muscles of normal and db/db mice treated with or without berberine. We also examined mechanisms for berberine-induced changes in muscle protein metabolism.

RESULTS: Berberine administration decreased protein synthesis and increased degradation in muscles of normal and db/db mice. The protein catabolic mechanism depended on berberine-stimulated expression of the E3 ubiquitin ligase, atrogin-1. Atrogin-1 not only increased proteolysis but also reduced protein synthesis by mechanisms that were independent of decreased phosphorylation of Akt or forkhead transcription factors. Impaired protein synthesis was dependent on a reduction in eIF3-f, an essential regulator of protein synthesis. Berberine impaired energy metabolism, activating AMP-activated protein kinase and providing an alternative mechanism for the stimulation of atrogin-1 expression. When we increased mitochondrial biogenesis by expressing peroxisome proliferator-activated receptor gamma coactivator-1alpha, berberine-induced changes in muscle protein metabolism were prevented.

CONCLUSIONS: Berberine impairs muscle metabolism by two novel mechanisms. It impairs mitochonidrial function stimulating the expression of atrogin-1 without affecting phosphorylation of forkhead transcription factors. The increase in atrogin-1 not only stimulated protein degradation but also suppressed protein synthesis, causing muscle atrophy.}, author = {Wang, H. and Liu, D. and Cao, P. and Lecker, S. and Hu, Z.}, doi = {10.2337/db10-0207}, file = {:C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Wang et al. - 2010 - Atrogin-1 Affects Muscle Protein Synthesis and Degradation When Energy Metabolism Is Impaired by the Antidiabetes D.pdf:pdf}, issn = {0012-1797}, journal = {Diabetes}, keywords = {Animals,Berberine,Berberine: pharmacology,DNA Primers,Energy Metabolism,Energy Metabolism: drug effects,Gene Expression Regulation,Gene Expression Regulation: drug effects,Hypoglycemic Agents,Hypoglycemic Agents: pharmacology,Mice,Mice, Inbred Strains,Muscle Fibers, Skeletal,Muscle Fibers, Skeletal: drug effects,Muscle Fibers, Skeletal: metabolism,Muscle Proteins,Muscle Proteins: biosynthesis,Muscle Proteins: drug effects,Muscle Proteins: genetics,Muscle Proteins: metabolism,Muscle, Skeletal,Muscle, Skeletal: drug effects,Muscle, Skeletal: metabolism,Muscular Atrophy,Muscular Atrophy: chemically induced,Myoblasts,Myoblasts: drug effects,Myoblasts: metabolism,Polymerase Chain Reaction,RNA,RNA: genetics,SKP Cullin F-Box Protein Ligases,SKP Cullin F-Box Protein Ligases: genetics,SKP Cullin F-Box Protein Ligases: metabolism,Transcription Factors,Transcription Factors: drug effects,Transcription Factors: metabolism}, mendeley-groups = {berberine}, month = jun, number = {8}, pages = {1879--1889}, pmid = {20522589}, title = Template:Atrogin-1 Affects Muscle Protein Synthesis and Degradation When Energy Metabolism Is Impaired by the Antidiabetes Drug Berberine, url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2911075\&tool=pmcentrez\&rendertype=abstract}, volume = {59}, year = {2010} } </bibtex>

[5] <bibtex> @article{Sarna2010, abstract = {Oxidative stress and amplified redox signaling contribute to the pathogenesis of many human diseases including atherosclerosis. The superoxide-generating phagocytic NADPH oxidase is a key source of oxidative stress in the developing atheroma. The aim of the present study was to examine the effect of berberine, a plant-derived alkaloid, on NADPH oxidase-mediated superoxide anion production in macrophages. Lipopolysaccharide (LPS) treatment activated NADPH oxidase in THP-1 monocyte-derived macrophages and increased the intracellular level of superoxide anions. Preincubation of cells with berberine demonstrated a concentration-dependent (10-50 micromol/L) and time-dependent (6-24 h) inhibition of superoxide anion generation in LPS-stimulated macrophages. Cell viability tests confirmed that berberine, at concentrations sufficient for inhibiting NADPH oxidase-mediated superoxide anion generation in macrophages, did not affect cell viability. Real-time PCR analysis revealed that addition of berberine to the culture medium was able to reduce gp91phox mRNA expression in LPS-treated cells. Berberine also restored superoxide dismutase (SOD) activity, which was found to be inhibited by LPS treatment. In conclusion, results from the present study demonstrate that berberine can effectively reduce intracellular superoxide levels in LPS- stimulated macrophages. Such a restoration of cellular redox by berberine is mediated by its selective inhibition of gp91phox expression and enhancement of SOD activity. The therapeutic relevance of berberine in the prevention and management of atherosclerosis remains to be further investigated.}, author = {Sarna, Lindsei K. and Wu, Nan and Hwang, Sun-Young and Siow, Yaw L. and O, Karmin}, doi = {10.1139/Y09-136}, issn = {0008-4212}, journal = {Canadian Journal of Physiology and Pharmacology}, keywords = {Berberine,Berberine: pharmacology,Cell Line, Tumor,Cell Survival,Cell Survival: drug effects,Cell Survival: physiology,Humans,Macrophages,Macrophages: drug effects,Macrophages: enzymology,Macrophages: metabolism,Membrane Glycoproteins,Membrane Glycoproteins: biosynthesis,Membrane Glycoproteins: genetics,Monocytes,Monocytes: drug effects,Monocytes: enzymology,Monocytes: metabolism,NADPH Oxidase,NADPH Oxidase: antagonists \& inhibitors,NADPH Oxidase: biosynthesis,NADPH Oxidase: genetics,NADPH Oxidase: physiology,Oxidative Stress,Oxidative Stress: drug effects,Oxidative Stress: physiology,Superoxide Dismutase,Superoxide Dismutase: metabolism,Superoxides,Superoxides: antagonists \& inhibitors,Superoxides: metabolism}, mendeley-groups = {berberine}, month = mar, number = {3}, pages = {369--378}, pmid = {20393601}, title = Template:Berberine inhibits NADPH oxidase mediated superoxide anion production in macrophagesThis article is one of a selection of papers published in a Special Issue on Oxidative Stress in Health and Disease., url = {http://www.ncbi.nlm.nih.gov/pubmed/20393601}, volume = {88}, year = {2010} } </bibtex>