Peripheral neuropathy in rats exposed to dichloroacetate.
The use of dichloroacetate (DCA) for treating patients with mitochondrial diseases is limited by the induction of peripheral neuropathy. The mechanisms of DCA-induced neuropathy are not known. Oral DCA treatment (50-500 mg/kg per day for up to 16 weeks) induced tactile allodynia in both juvenile and adult rats; concurrent thermal hypoalgesia developed at higher doses. Both juvenile and adult rats treated with DCA developed nerve conduction slowing that was more pronounced in adult rats. No overt axonal or glial cell abnormalities were identified in peripheral nerves or spinal cord of any DCA-treated rat, but morphometric analysis identified a reduction of mean axonal caliber of peripheral nerve myelinated fibers. Dichloroacetate treatment also caused accumulation of oxidative stress markers in the nerves. These data indicate that behavioral, functional, and structural indices of peripheral neuropathy may be induced in both juvenile and adult rats treated with DCA at doses similar to those in clinical use. Dichloroacetate-induced peripheral neuropathy primarily afflicts axons and involves both metabolic and structural disorders. The DCA-treated rat may provide insight into the pathogenesis of this peripheral neuropathy and facilitate development of adjuvant therapeutics to prevent this disorder that currently restricts the clinical use of DCA.
Calcutt
Nigel A
NA
Department of Pathology, University of California San Diego, La Jolla, California, USA. ncalcutt@ucsd.edu
Lopez
Veronica L
VL
Bautista
Arjel D
AD
Mizisin
Leah M
LM
Torres
Brenda R
BR
Shroads
Albert L
AL
Mizisin
Andrew P
AP
Stacpoole
Peter W
PW
D000367:Age Factors; D000818:Animals; D003999:Dichloroacetic Acid / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004576:Electromyography; D005260:Female; D005528:Foot / Q000294:innervation; D006987:Hypesthesia / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D009431:Neural Conduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000473:pathology* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000294:innervation
D003999:Dichloroacetic Acid
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