Editing Dichloroacetate (DCA)

[[Information on nutritional supplements people with ALS have been taking]]

* [https://en.wikipedia.org/wiki/Dichloroacetic_acid Wikipedia page]

== Effects on ALS == 

''Applied to astrocyte cultures isolated from rats expressing the SOD1(G93A) mutation, DCA reduced phosphorylation of PDH and improved mitochondrial coupling as expressed by the respiratory control ratio (RCR). Notably, DCA completely prevented the toxicity of SOD1(G93A) astrocytes to motor neurons in coculture conditions. Chronic administration of DCA (500 mg/L) in the drinking water of mice expressing the SOD1(G93A) mutation increased survival by 2 weeks compared to untreated mice. Systemic DCA also normalized the reduced RCR value measured in lumbar spinal cord tissue of diseased SOD1(G93A) mice. A remarkable effect of DCA was the improvement of grip strength performance at the end stage of the disease, which correlated with a recovery of the neuromuscular junction area in extensor digitorum longus muscles. Systemic DCA also decreased astrocyte reactivity and prevented motor neuron loss in SOD1(G93A) mice.'' [1]

''DCA, or TCA in a concentration of 10 mM did not compromise cell viability nor affect cellular glutathione content or GAPDH activity. However, the presence of DCA and TCA significantly lowered the rate of cellular lactate production in viable astrocytes.'' [2]

== References ==

[1]
<bibtex>
@article{Miquel2012,
abstract = {Mitochondrial dysfunction is one of the pathogenic mechanisms that lead to neurodegeneration in Amyotrophic Lateral Sclerosis (ALS). Astrocytes expressing the ALS-linked SOD1(G93A) mutation display a decreased mitochondrial respiratory capacity associated to phenotypic changes that cause them to induce motor neuron death. Astrocyte-mediated toxicity can be prevented by mitochondria-targeted antioxidants, indicating a critical role of mitochondria in the neurotoxic phenotype. However, it is presently unknown whether drugs currently used to stimulate mitochondrial metabolism can also modulate ALS progression. Here, we tested the disease-modifying effect of dichloroacetate (DCA), an orphan drug that improves the functional status of mitochondria through the stimulation of the pyruvate dehydrogenase complex activity (PDH). Applied to astrocyte cultures isolated from rats expressing the SOD1(G93A) mutation, DCA reduced phosphorylation of PDH and improved mitochondrial coupling as expressed by the respiratory control ratio (RCR). Notably, DCA completely prevented the toxicity of SOD1(G93A) astrocytes to motor neurons in coculture conditions. Chronic administration of DCA (500 mg/L) in the drinking water of mice expressing the SOD1(G93A) mutation increased survival by 2 weeks compared to untreated mice. Systemic DCA also normalized the reduced RCR value measured in lumbar spinal cord tissue of diseased SOD1(G93A) mice. A remarkable effect of DCA was the improvement of grip strength performance at the end stage of the disease, which correlated with a recovery of the neuromuscular junction area in extensor digitorum longus muscles. Systemic DCA also decreased astrocyte reactivity and prevented motor neuron loss in SOD1(G93A) mice. Taken together, our results indicate that improvement of the mitochondrial redox status by DCA leads to a disease-modifying effect, further supporting the therapeutic potential of mitochondria-targeted drugs in ALS.},
author = {Miquel, Ernesto and Cassina, Adriana and Mart??nez-Palma, Laura and Bolatto, Carmen and Tr??as, Emiliano and Gandelman, Mandi and Radi, Rafael and Barbeito, Luis and Cassina, Patricia},
doi = {10.1371/journal.pone.0034776},
file = {:C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Miquel et al. - 2012 - Modulation of astrocytic mitochondrial function by dichloroacetate improves survival and motor performance in inh.pdf:pdf},
issn = {1932-6203},
journal = {PLoS ONE},
keywords = {Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: drug therapy,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: metabolism,Animals,Astrocytes,Astrocytes: drug effects,Astrocytes: metabolism,Cell Death,Cell Death: drug effects,Cell Survival,Cell Survival: drug effects,Cells, Cultured,Dichloroacetic Acid,Dichloroacetic Acid: pharmacology,Disease Models, Animal,Female,Humans,Male,Mice,Mice, Transgenic,Mitochondria,Mitochondria: drug effects,Mitochondria: physiology,Motor Neurons,Motor Neurons: drug effects,Oxidation-Reduction,Oxidation-Reduction: drug effects,Phosphorylation,Phosphorylation: drug effects,Pyruvate Dehydrogenase Complex,Pyruvate Dehydrogenase Complex: metabolism,Rats,Superoxide Dismutase,Superoxide Dismutase: genetics,Superoxide Dismutase: metabolism},
mendeley-groups = {dca},
month = jan,
number = {4},
pages = {e34776},
pmid = {22509356},
title = {{Modulation of astrocytic mitochondrial function by dichloroacetate improves survival and motor performance in inherited amyotrophic lateral sclerosis}},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3318006\&tool=pmcentrez\&rendertype=abstract},
volume = {7},
year = {2012}
}
</bibtex>


[2]
<bibtex>
@article{Schmidt2011,
abstract = {The chlorinated acetates monochloroacetate (MCA), dichloroacetate (DCA), and trichloroacetate (TCA) are generated in water disinfection processes and are formed during metabolic detoxification of industrial solvents such as trichloroethylene. In order to test for consequences of an exposure of brain cells to the different chlorinated acetates, glutathione levels and lactate production of primary astrocyte cultures were investigated as indicators for the potential of chlorinated acetates to disturb cellular detoxification processes and glucose metabolism, respectively. Application of MCA to cultured astrocytes caused a time and concentration dependent deprivation of cellular glutathione, inactivation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity, and loss in cell viability with halfmaximal effects observed for MCA concentrations between 0.3 and 3 mM. In contrast, the presence of acetate, DCA, or TCA in a concentration of 10 mM did not compromise cell viability nor affect cellular glutathione content or GAPDH activity. However, the presence of DCA and TCA significantly lowered the rate of cellular lactate production in viable astrocytes. These data demonstrate that the extent of chlorination strongly determines the potential of chlorinated acetates to disturb glutathione and/or glucose metabolism of astrocytes.},
author = {Schmidt, Maike M and Rohwedder, Astrid and Dringen, Ralf},
doi = {10.1007/s12640-010-9209-8},
issn = {1476-3524},
journal = {Neurotoxicity research},
keywords = {Acetates,Acetates: toxicity,Animals,Animals, Newborn,Astrocytes,Astrocytes: drug effects,Astrocytes: metabolism,Cells, Cultured,Dichloroacetic Acid,Dichloroacetic Acid: toxicity,Glutathione,Glutathione: metabolism,Glycolysis,Glycolysis: drug effects,Glycolysis: physiology,Rats,Rats, Wistar,Trichloroacetic Acid,Trichloroacetic Acid: toxicity},
mendeley-groups = {dca},
month = may,
number = {4},
pages = {628--37},
pmid = {20628842},
title = {{Effects of chlorinated acetates on the glutathione metabolism and on glycolysis of cultured astrocytes.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/20628842},
volume = {19},
year = {2011}
}
</bibtex>


[3]
<bibtex>
@article{Itoh2003,
abstract = {Neuronal cultures in vitro readily oxidized both D-[(14)C]glucose and l-[(14)C]lactate to (14)CO(2), whereas astroglial cultures oxidized both substrates sparingly and metabolized glucose predominantly to lactate and released it into the medium. [(14)C]Glucose oxidation to (14)CO(2) varied inversely with unlabeled lactate concentration in the medium, particularly in neurons, and increased progressively with decreasing lactate concentration. Adding unlabeled glucose to the medium inhibited [(14)C]lactate oxidation to (14)CO(2) only in astroglia but not in neurons, indicating a kinetic preference in neurons for oxidation of extracellular lactate over intracellular pyruvatelactate produced by glycolysis. Protein kinase-catalyzed phosphorylation inactivates pyruvate dehydrogenase (PDH), which regulates pyruvate entry into the tricarboxylic acid cycle. Dichloroacetate inhibits this kinase, thus enhancing PDH activity. In vitro dichloroacetate stimulated glucose and lactate oxidation to CO(2) and reduced lactate release mainly in astroglia, indicating that limitations in glucose and lactate oxidation by astroglia may be due to a greater balance of PDH toward the inactive form. To assess the significance of astroglial export of lactate to neurons in vivo, we attempted to diminish this traffic in rats by administering dichloroacetate (50 mgkg) intravenously to stimulate astroglial lactate oxidation and then examined the effects on baseline and functionally activated local cerebral glucose utilization (lCMR(glc)). Dichloroacetate raised baseline lCMR(glc) throughout the brain and decreased the percent increases in lCMR(glc) evoked by functional activation. These studies provide evidence in support of the compartmentalization of glucose metabolism between astroglia and neurons but indicate that the compartmentalization may be neither complete nor entirely obligatory.},
author = {Itoh, Yoshiaki and Esaki, Takanori and Shimoji, Kazuaki and Cook, Michelle and Law, Mona J and Kaufman, Elaine and Sokoloff, Louis},
doi = {10.1073/pnas.0831078100},
file = {:C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Itoh et al. - 2003 - Dichloroacetate effects on glucose and lactate oxidation by neurons and astroglia in vitro and on glucose utilizati.pdf:pdf},
issn = {0027-8424},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
keywords = {Animals,Astrocytes,Astrocytes: drug effects,Astrocytes: metabolism,Brain,Brain: drug effects,Brain: metabolism,Cells, Cultured,Citric Acid Cycle,Dichloroacetic Acid,Dichloroacetic Acid: pharmacology,Glucose,Glucose: metabolism,In Vitro Techniques,Kinetics,Lactic Acid,Lactic Acid: metabolism,Male,Neurons,Neurons: drug effects,Neurons: metabolism,Oxidation-Reduction,Rats,Rats, Sprague-Dawley},
mendeley-groups = {dca},
month = apr,
number = {8},
pages = {4879--84},
pmid = {12668764},
title = {{Dichloroacetate effects on glucose and lactate oxidation by neurons and astroglia in vitro and on glucose utilization by brain in vivo.}},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=153649\&tool=pmcentrez\&rendertype=abstract},
volume = {100},
year = {2003}
}
</bibtex>

[[Category:Supplement data pages]]
@@ Line 8: / Line 8: @@
 ''DCA, or TCA in a concentration of 10 mM did not compromise cell viability nor affect cellular glutathione content or GAPDH activity. However, the presence of DCA and TCA significantly lowered the rate of cellular lactate production in viable astrocytes.'' [2]
-== Cautions, risks and side effects ==
-Severe, including peripheral neuropathy if taken too much or for too long. In tumor cells, shifting metabolism towards oxidative phosphorylation increases apoptosis - what happens in ALS affected cells is unknown.
 == References ==