Dichloroacetate causes reversible demyelination in vitro: potential mechanism for its neuropathic effect.
Dichloroacetate (DCA) is an investigational drug for genetic mitochondrial diseases whose use has been mitigated by reversible peripheral neuropathy. We investigated the mechanism of DCA neurotoxicity using cultured rat Schwann cells (SCs) and dorsal root ganglia (DRG) neurons. Myelinating SC-DRG neuron co-cultures, isolated SCs and DRG neurons were exposed to 1-20 mm DCA for up to 12 days. In myelinating co-cultures, DCA caused a dose- and exposure-dependent decrease of myelination, as determined by immunolabeling and immunoblotting for myelin basic protein (MBP), protein zero (P0), myelin-associated glycoprotein (MAG) and peripheral myelin protein 22 (PMP22). Partial recovery of myelination occurred following a 10-day washout of DCA. DCA did not affect the steady-state levels of intermediate filament proteins, but promoted the formation of anti-neurofilament antibody reactive whirls. In isolated SC cultures, DCA decreased the expression of P0 and PMP22, while it increased the levels of p75(NTR) (neurotrophin receptor), as compared with non-DCA-treated samples. DCA had modest adverse effects on neuronal and glial cell vitality, as determined by the release of lactate dehydrogenase. These results demonstrate that DCA induces a reversible inhibition of myelin-related proteins that may account, at least in part, for its clinical peripheral neuropathic effects.
Felitsyn
Natalia
N
Department of Neuroscience, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, Florida 32610-024, USA.
Stacpoole
Peter W
PW
Notterpek
Lucia
L
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques / Q000379:methods; D003711:Demyelinating Diseases / Q000139:chemically induced*; D003999:Dichloroacetic Acid / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D007150:Immunohistochemistry / Q000379:methods; D004676:Myelin Basic Protein / Q000378:metabolism; D018993:Myelin P0 Protein / Q000378:metabolism; D009185:Myelin Proteins / Q000378:metabolism; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D051381:Rats; D012583:Schwann Cells / Q000187:drug effects*; D012584:Sciatic Nerve / Q000166:cytology
D004676:Myelin Basic Protein; D018993:Myelin P0 Protein; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; C489546:Pmp22 protein, rat; D003999:Dichloroacetic Acid