Dichloroacetate causes reversible demyelination in vitro: potential mechanism fo

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J Neurochem. 2007 Jan;100(2):429-36.

Dichloroacetate causes reversible demyelination in vitro: potential

mechanism for its neuropathic effect.

Felitsyn N, Stacpoole PW, Notterpek L.

Department of Neuroscience, College of Medicine, McKnight Brain

Institute, University of Florida, Gainesville, Florida, USA.

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.