Curcumin

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Information on nutritional supplements people with ALS have been taking

Curcumin is a bright yellow colored component of the Indian spice turmeric, a key ingredient in curry. Curcumin has poor bioavailability. It can be significantly improved by:

  • concomitant administration of piperine [6]. Caution: Piperine can alter pharmacological dynamics such as half-life time of many prescription medicines and other substances.
  • Another method to increase bioavailability is to dissolve it in fat or oil before consumption. Cooking food with turmeric as spice, using fat or oil and pepper supposedly increase curcumin utilization.
  • Life Extension Foundation claims that 0.4 g of their optimized curcumin product called BCM-95 (said to contain some other components from turmeric in addition to curcumin) produces the same amount of bioavailable curcumin as 2.5 g of plain curcumin.
  • Thorne Research has curcumin complexed with phosphatidylcholine (PC) for what they claim optimal absorption, sustained-release version is known with name Meriva-SR.

Habitual usage of turmeric in oily food with pepper, together with highly-absorbable curcumin supplements may maximize amount of curcumin.

Effect of curcumin on ALS[edit]

Curcumin is an antioxidant and a strong inducer of heat shock response.[1] It attenuates glutamate-induced HT22 cell death by suppressing MAP kinase signaling.[2] and inhibits neuroglial cell proliferation, migration and growth.[3][4] In a study made on lipopolysaccharide affected rats, valproic acid was found to potentiate the neuroprotective effect of curcumin.[5] Another study[6] suggested that the neuroprotective effect of curcumin against glutamate-induced neurotoxicity might be mediated via BDNF/TrkB mediated pathway.

Curcumin is a biologically active iron chelator.[7]

Cautions and risks[edit]

Curcumin inhibits proteasome[8], which may have a negative effect on the cell cleanup function.

Discussion threads on the ALSTDI forum[edit]

Pubmed link collection at Studies on ALS[edit]

Regulated pathways[edit]

Inactivates JNK and p38.[2] Upregulates p21cip1.[2] Downregulates cyclin D1.[2]

Where to get it[edit]

References[edit]

  1. Calabrese et al.: Redox regulation of cellular stress response in aging and neurodegenerative disorders: role of vitagenes. Neurochem. Res. 2007;32:757-73. PMID: 17191135. DOI. Reduced expression and/or activity of antioxidant proteins lead to oxidative stress, accelerated aging and neurodegeneration. However, while excess reactive oxygen species (ROS) are toxic, regulated ROS play an important role in cell signaling. Perturbation of redox status, mutations favoring protein misfolding, altered glyc(osyl)ation, overloading of the product of polyunsaturated fatty acid peroxidation (hydroxynonenals, HNE) or cholesterol oxidation, can disrupt redox homeostasis. Collectively or individually these effects may impose stress and lead to accumulation of unfolded or misfolded proteins in brain cells. Alzheimer's (AD), Parkinson's and Huntington's disease, amyotrophic lateral sclerosis and Friedreich's ataxia are major neurological disorders associated with production of abnormally aggregated proteins and, as such, belong to the so-called "protein conformational diseases". The pathogenic aggregation of proteins in non-native conformation is generally associated with metabolic derangements and excessive production of ROS. The "unfolded protein response" has evolved to prevent accumulation of unfolded or misfolded proteins. Recent discoveries of the mechanisms of cellular stress signaling have led to new insights into the diverse processes that are regulated by cellular stress responses. The brain detects and overcomes oxidative stress by a complex network of "longevity assurance processes" integrated to the expression of genes termed vitagenes. Heat-shock proteins are highly conserved and facilitate correct protein folding. Heme oxygenase-1, an inducible and redox-regulated enzyme, has having an important role in cellular antioxidant defense. An emerging concept is neuroprotection afforded by heme oxygenase by its heme degrading activity and tissue-specific antioxidant effects, due to its products carbon monoxide and biliverdin, which is then reduced by biliverdin reductase in bilirubin. There is increasing interest in dietary compounds that can inhibit, retard or reverse the steps leading to neurodegeneration in AD. Specifically any dietary components that inhibit inappropriate inflammation, AbetaP oligomerization and consequent increased apoptosis are of particular interest, with respect to a chronic inflammatory response, brain injury and beta-amyloid associated pathology. Curcumin and ferulic acid, the first from the curry spice turmeric and the second a major constituent of fruit and vegetables, are candidates in this regard. Not only do these compounds serve as antioxidants but, in addition, they are strong inducers of the heat-shock response. Food supplementation with curcumin and ferulic acid are therefore being considered as a novel nutritional approach to reduce oxidative damage and amyloid pathology in AD. We review here some of the emerging concepts of pathways to neurodegeneration and how these may be overcome by a nutritional approach.
  2. 2.0 2.1 2.2 2.3 Suh et al.: Curcumin attenuates glutamate-induced HT22 cell death by suppressing MAP kinase signaling. Mol. Cell. Biochem. 2007;298:187-94. PMID: 17131042. DOI. Glutamate induces cell death by upsetting the cellular redox homeostasis, termed oxidative glutamate toxicity, in a mouse hippocampal cell line, HT22. Extracellular signal-regulated kinases (ERK) 1/2 are known key players in this process. Here we characterized the roles of both MAP kinases and cell cycle regulators in mediating oxidative glutamate toxicity and the neuroprotective mechanisms of curcumin in HT22 cells. c-Jun N-terminal kinase (JNK) and p38 kinase were activated during the glutamate-induced HT22 cell death, but at a later stage than ERK activation. Treatment with a JNK inhibitor, SP600125, or a p38 kinase inhibitor, SB203580, partly attenuated this cell death. Curcumin, a natural inhibitor of JNK signaling, protected the HT22 cells from glutamate-induced death at nanomolar concentrations more efficiently than SP600125. These doses of curcumin affected neither the level of intracellular glutathione nor the level of reactive oxygen species, but inactivated JNK and p38 significantly. Moreover, curcumin markedly upregulated a cell-cycle inhibitory protein, p21cip1, and downregulated cyclin D1 levels, which might help the cell death prevention. Our results suggest that curcumin has a neuroprotective effect against oxidative glutamate toxicity by inhibiting MAP kinase signaling and influencing cell-cycle regulation.
  3. Ambegaokar et al.: Curcumin inhibits dose-dependently and time-dependently neuroglial cell proliferation and growth. Neuro Endocrinol. Lett. 2003;24:469-73. PMID: 15073579. OBJECTIVES: Curcumin (CUR), the active chemical of the Asian spice turmeric, has strong anti-oxidant and anti-inflammatory properties. CUR inhibits proliferation and growth of several cell types, e.g. cancer cells. While CUR inhibitory effects on microglial cells are demonstrated, little is known of its effects on neuroglia, astrocytes (AST) and oligodendrocytes (OLG). Our work focuses on CUR's effects on neuroglial proliferation and growth in vitro, utilizing C-6 rat glioma 2B-clone cells, a mixed colony of both neuroglial cells, in 6 day trials. METHODS: The doses studied included 4, 5, 10, 15, and 20 microM - concentrations slightly smaller than those shown to stimulate protein expression in ASTs. Automated particle counter was used to determine proliferation, and marker enzyme assays were used to determine AST and OLG activity. RESULTS: CUR inhibited neuroglial proliferation, with the degree of inhibition correlated directly with the CUR concentration. Proliferative inhibition was observed after a concentration as low as 5 microM by day 6, while inhibition of 20 microM doses occurred by day 2 of culture. Proliferative inhibition is associated with morphological changes, e.g. cell elongation and neurite prolongation, and increased activity of a marker enzyme corresponding to differentiation of OLG and with a reduced activity of the marker enzyme for AST. CONCLUSIONS: Our data suggests CUR acts continuously over a period of time, with low doses being as effective as higher doses given a longer period of treatment. It has been suggested that CUR's anti-inflammatory and anti-oxidant actions may be useful in the prevention-treatment of neurodegenerative diseases, e.g. Alzheimer's and Parkinson's Diseases. Given neuroglial involvement in these diseases, and CUR's observed actions on neuroglia, the data presented here may provide further explanations of CUR's preventative-therapeutic role in these diseases.
  4. Karlstetter et al.: Curcumin is a potent modulator of microglial gene expression and migration. J Neuroinflammation 2011;8:125. PMID: 21958395. DOI. BACKGROUND: Microglial cells are important effectors of the neuronal innate immune system with a major role in chronic neurodegenerative diseases. Curcumin, a major component of tumeric, alleviates pro-inflammatory activities of these cells by inhibiting nuclear factor kappa B (NFkB) signaling. To study the immuno-modulatory effects of curcumin on a transcriptomic level, DNA-microarray analyses were performed with resting and LPS-challenged microglial cells after short-term treatment with curcumin. METHODS: Resting and LPS-activated BV-2 cells were stimulated with curcumin and genome-wide mRNA expression patterns were determined using DNA-microarrays. Selected qRT-PCR analyses were performed to confirm newly identified curcumin-regulated genes. The migration potential of microglial cells was determined with wound healing assays and transwell migration assays. Microglial neurotoxicity was estimated by morphological analyses and quantification of caspase 3/7 levels in 661W photoreceptors cultured in the presence of microglia-conditioned medium. RESULTS: Curcumin treatment markedly changed the microglial transcriptome with 49 differentially expressed transcripts in a combined analysis of resting and activated microglial cells. Curcumin effectively triggered anti-inflammatory signals as shown by induced expression of Interleukin 4 and Peroxisome proliferator activated receptor α. Several novel curcumin-induced genes including Netrin G1, Delta-like 1, Platelet endothelial cell adhesion molecule 1, and Plasma cell endoplasmic reticulum protein 1, have been previously associated with adhesion and cell migration. Consequently, curcumin treatment significantly inhibited basal and activation-induced migration of BV-2 microglia. Curcumin also potently blocked gene expression related to pro-inflammatory activation of resting cells including Toll-like receptor 2 and Prostaglandin-endoperoxide synthase 2. Moreover, transcription of NO synthase 2 and Signal transducer and activator of transcription 1 was reduced in LPS-triggered microglia. These transcriptional changes in curcumin-treated LPS-primed microglia also lead to decreased neurotoxicity with reduced apoptosis of 661W photoreceptor cultures. CONCLUSIONS: Collectively, our results suggest that curcumin is a potent modulator of the microglial transcriptome. Curcumin attenuates microglial migration and triggers a phenotype with anti-inflammatory and neuroprotective properties. Thus, curcumin could be a nutraceutical compound to develop immuno-modulatory and neuroprotective therapies for the treatment of various neurodegenerative disorders.
  5. Zaky et al.: Valproic acid potentiates curcumin-mediated neuroprotection in lipopolysaccharide induced rats. Front Cell Neurosci 2014;8:337. PMID: 25374508. DOI. The etiology of neuroinflammation is complex and comprises multifactorial, involving both genetic and environmental factors during which diverse genetic and epigenetic modulations are implicated. Curcumin (Cur) and valproic acid (VPA), histone deacetylase 1 inhibitor, have neuroprotective effects. The present study was designed with an aim to investigate the ability of co-treatment of both compounds (Cur or VPA, 200 mg/kg) for 4 weeks to augment neuroprotection and enhance brain recovery from intra-peritoneal injection of (250 μg/kg) lipopolysaccharide-stimulated neuroinflammatory condition on rat brain cortex. Cortex activation and the effects of combined treatment and production of proinflammatory mediators, cyclooxygenase-2 (COX-2), APE1, and nitric oxide/inducible nitric oxide synthase (iNOS) were investigated. Neuroinflammation development was assessed by histological analyses and by investigating associated indices [β-secretase (BACE1), amyloid protein precursor (APP), presenilin (PSEN-1), and PSEN-2)]. Furthermore we measured the expression profile of lethal-7 (let-7) miRNAs members a, b, c, e, and f in all groups, a highly abundant regulator of gene expression in the CNS. Protein and mRNA levels of neuroinflammation markers COX-2, BACE1, APP, and iNOS were also attenuated by combined therapy. On the other hand, assessment of the indicated five let-7 members, showed distinct expression profile pattern in the different groups. Let-7 a, b, and c disappeared in the induced group, an effect that was partially suppressed by co-addition of either Cur or VPA. These data suggest that the combined treatment induced significantly the expression of the five members when compared to rats treated with Cur or VPA only as well as to self-recovery group, which indicates a possible benefit from the synergistic effect of Cur-VPA combination as therapeutic agents for neuroinflammation and its associated disorders. The mechanism elucidated here highlights the particular drug-induced expression profile of let-7 family as new targets for future pharmacological development.
  6. Wang et al.: Curcumin protects against glutamate excitotoxicity in rat cerebral cortical neurons by increasing brain-derived neurotrophic factor level and activating TrkB. Brain Res. 2008;1210:84-91. PMID: 18420184. DOI. Curcumin is a major active component isolated from Curcuma longa. Previously, we have reported its significant antidepressant effect. However, the mechanisms underlying the antidepressant effects are still obscure. In the present study, we explored the effect of curcumin against glutamate excitotoxicity, mainly focusing on the neuroprotective effects of curcumin on the expression of Brain-Derived Neurotrophic Factor (BDNF), which is deeply involved in the etiology and treatment of depression. Exposure of rat cortical neurons to 10 microM glutamate for 24 h caused a significant decrease in BDNF level, accompanied with reduced cell viability and enhanced cell apoptosis. Pretreatment of neurons with curcumin reversed the BDNF expression and cell viability in a dose- and time-dependent manner. However, K252a, a Trk receptor inhibitor which is known to inhibit the activity of BDNF, could block the survival-promoting effect of curcumin. In addition, the up-regulation of BDNF levels by curcumin was also suppressed by K252a. Taken together, these results suggest that the neuroprotective effect of curcumin might be mediated via BDNF/TrkB signaling pathway.
  7. Jiao et al.: Curcumin, a cancer chemopreventive and chemotherapeutic agent, is a biologically active iron chelator. Blood 2009;113:462-9. PMID: 18815282. DOI. Curcumin is a natural product currently in human clinical trials for a variety of neoplastic, preneoplastic, and inflammatory conditions. We previously observed that, in cultured cells, curcumin exhibits properties of an iron chelator. To test whether the chelator activity of curcumin is sufficient to induce iron deficiency in vivo, mice were placed on diets containing graded concentrations of both iron and curcumin for 26 weeks. Mice receiving the lowest level of dietary iron exhibited borderline iron deficiency, with reductions in spleen and liver iron, but little effect on hemoglobin, hematocrit, transferrin saturation, or plasma iron. Against this backdrop of subclinical iron deficiency, curcumin exerted profound 2 effects on systemic iron, inducing a dose-dependent decline in hematocrit, hemoglobin, serum iron, and transferrin saturation, the appearance of microcytic anisocytotic red blood cells, and decreases in spleen and liver iron content. Curcumin repressed synthesis of hepcidin, a peptide that plays a central role in regulation of systemic iron balance. These results demonstrate that curcumin has the potential to affect systemic iron metabolism, particularly in a setting of subclinical iron deficiency. This may affect the use of curcumin in patients with marginal iron stores or those exhibiting the anemia of cancer and chronic disease.
  8. Weisberg et al.: Proteasome inhibitors, including curcumin, improve pancreatic β-cell function and insulin sensitivity in diabetic mice. Nutr Diabetes 2016;6:e205. PMID: 27110686. DOI. BACKGROUND: Type 2 diabetes stems from obesity-associated insulin resistance, and in the genetically susceptible, concomitant pancreatic β-cell failure can occur, which further exacerbates hyperglycemia. Recent work by our group and others has shown that the natural polyphenol curcumin attenuates the development of insulin resistance and hyperglycemia in mouse models of hyperinsulinemic or compensated type 2 diabetes. Although several potential downstream molecular targets of curcumin exist, it is now recognized to be a direct inhibitor of proteasome activity. We now show that curcumin also prevents β-cell failure in a mouse model of uncompensated obesity-related insulin resistance (Lepr(db/db) on the Kaliss background). RESULTS: In this instance, dietary supplementation with curcumin prevented hyperglycemia, increased insulin production and lean body mass, and prolonged lifespan. In addition, we show that short-term in vivo treatment with low dosages of two molecularly distinct proteasome inhibitors celastrol and epoxomicin reverse hyperglycemia in mice with β-cell failure by increasing insulin production and insulin sensitivity. CONCLUSIONS: These studies suggest that proteasome inhibitors may prove useful for patients with diabetes by improving both β-cell function and relieving insulin resistance.