Dichloroacetate (DCA)
Information on nutritional supplements people with ALS have been taking
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]
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 = Template: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>
