Acrylamide intoxication modifies in vitro responses of peripheral nerve axons to anoxia

Decreased axolemmal Na+/K(+)-ATPase activity has been considered as a possible mechanism for peripheral nerve axon damage induced by acrylamide (ACR) or 2,5-hexanedione (HD). Reduced activity of this enzyme is also presumed to be the basis of peripheral nerve resistance to ischemia or hypoxia associated with other neuropathies (e.g., diabetes). In the present study, we tested the hypothesis that peripheral nerve of ACR (50 mg/kg/d x 10 d) or HD (400 mg/kg/d x 20 d) exposed rats are resistant to oxygen-limiting conditions as a result of reduced axonal Na+/K(+)-ATPase activity. As an index of resistance, effects of in vitro anoxia on subaxonal concentrations of Na, K and Ca were assessed in isolated segments of tibial nerve from control and neurotoxicant-treated animals. Results show axons from HD rats were not resistant to anoxic challenge; i.e., axons exhibited disrupted elemental composition comparable to anoxic control changes. In contrast, ACR-exposed axons displayed anoxic resistance. Ouabain-exposed tibial axons subjected to anoxic conditions were also resistant, but the corresponding elemental pattern did not resemble that associated with ACR axons. Moreover, ACR axons were capable of maintaining elemental gradients during normoxic exposure which should not be possible if Na+ pump activity is depressed. Considered together, these data are not consistent with a role for diminished Na+/K(+)-ATPase activity in neurotoxicant-induced peripheral axonopathy. We also assessed the ability of ACR- and HD-exposed tibial nerve axons to recover from anoxia. Unlike control fibers which can fully restore normal elemental composition, neurotoxicant-exposed axons were incapable of such restoration. These data suggest the axonal machinery responsible for post-anoxia recovery (e.g., energy metabolism, ion translocation, Ca2+ and free radical buffering) is compromised by ACR or HD intoxication.