title: High concentrations of dichloroacetate have minor effects on the vitality of the mammalian nerve fibers: an ex-vivo electrophysiological study.
abstract: Dichloroacetate has been used extensively in the treatment of cancer and genetic mitochondrial diseases, but there have been reports of dichloroacetate-induced peripheral neuropathy. In this study, the acute effects of sodium dichloroacetate on the peripheral nerve fibers were investigated, using an ex-vivo preparation, in the isolated sciatic nerve of the rat. The amplitude of the evoked nerve compound action potential (CAP) was measured to confirm the proper functioning of the nerve fibers. The half-vitality time [the time required to decrease the CAP to 50% of its initial value, here called inhibitory time 50% (IT50)], of the nerve fibers, which had been incubated in normal saline, was 30.4 ± 0.26 h (n=12). When the nerve fibers were incubated in 10 mmol/l of dichloroacetate, the IT50 was 29.7 ± 0.34 h (n=8), with no significant difference from the control (P>0.05). The fact that such a high concentration of dichloroacetate as 10 mmol/l had no effect on the parameters of the evoked CAP is an indication of the high tolerance of peripheral nerve fibers to this compound. When a concentration of 20 mmol/l of dichloroacetate was tested, a 15.2 ± 1.25% (n=12) inhibition in the CAP amplitude occurred, but although a relatively small population of nerve fibers was inactive, the vitality of the remaining active axons was not affected, with a final IT50 of 28.1 ± 0.64 h (n=12), with no significant difference from the IT50 of the control, which for this group of experiments was 28.1 ± 0.17 h (P>0.05). This moderate effect, with a 15.2 ± 1.25% decrease in the CAP amplitude, suggests that within the exposure limitation of the sciatic nerve preparation of 28-30 h, there could be a gradual development of certain biochemical changes leading to the early stages of dichloroacetate-induced neurotoxicity.
authors.affiliation: Laboratory of Animal Physiology, Department of Zoology, School of Biology, Aristotle University, Thessaloniki, Greece.
authors.forename: Alexia
authors.initials: A
authors.lastname: Kagiava
authors.forename: George
authors.initials: G
authors.lastname: Theophilidis
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000633:toxicity*; D001369:Axons / Q000187:drug effects*; D003999:Dichloroacetic Acid / Q000494:pharmacology / Q000633:toxicity*; D005071:Evoked Potentials / Q000187:drug effects*; D008297:Male; D009412:Nerve Fibers / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D012584:Sciatic Nerve / Q000187:drug effects* / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D003999:Dichloroacetic Acid