Dichloroacetate-induced peripheral neuropathy.

摘要: Dichloroacetate (DCA) has been the focus of research by both environmental toxicologists and biomedical scientists for over 50 years. As a product water chlorination metabolite certain industrial chemicals, DCA is ubiquitous in our biosphere at low μg/kg body weight daily exposure levels without obvious adverse effects humans. an investigational drug numerous congenital acquired diseases, administered orally or parenterally, usually doses 10-50mg/kg per day. therapeutic, its principal mechanism action to inhibit pyruvate dehydrogenase kinase (PDK). In turn, PDK inhibits key mitochondrial energy homeostat, complex (PDC), reversible phosphorylation. By blocking PDK, activates PDC and, consequently, respiratory chain ATP synthesis. A sensory/motor peripheral neuropathy clinically limiting effect chronic experimental data implicate Schwann cell as toxicological target. It postulated that stimulation activity normally glycolytic cells causes uncompensated oxidative stress from increased reactive oxygen species production. Additionally, metabolism interferes with catabolism amino acids phenylalanine tyrosine heme synthesis, resulting accumulation molecules capable forming adducts DNA proteins also stress. Preliminary evidence rodent models suggest DCA-induced neurotoxicity may be mitigated naturally occurring antioxidants specific class muscarinic receptor antagonists. These findings generate number testable hypotheses regarding etiology treatment neuropathy.