NERVE TERMINAL AS A SITE OF ACRYLAMIDE ACTION

Montefiore Medical Center (Bronx, Ny), New York NY

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Abstract

Exposure to acrylamide (ACR) causes nerve damage characterized by distal axon swelling and degeneration. We investigated (years 08-11) the possibility that degeneration is caused by reverse Na+/Ca2+ exchanger- mediated Ca/2+ entry secondary to reduced Na+/K+ ATPase activity. Subchronic oral ACR intoxication of rats produced distal tibial nerve axon degeneration and decreased Na/+ pump activity whereas neither enzymatic nor structural perturbation of PNS axons was associated with subacute i.p. treatment despite development of classic neurotoxicity. To determine whether route-specific differences in biotransformation might be involved in differential expression of axonopathy, Specific Aim #1 studies of this competitive renewal application will characterize ACR disposition and kinetics following i.p. and oral exposure. To provide conclusive evidence that axon degenerations does not occur during subacute i.p. intoxication, Specific Aim #2 studies will assess axon morphology in nervous tissue (CNS, intramuscular nerves) not examined during years 08-11. Overall, our results (years 08-11) suggest other non-axonal sites might mediate the neurotoxic actions of ACR. Nerve terminals are rationale sites for mediation of ACR-induce dysfunction (skeletal muscle weakness, sensory ataxia) and have been found to be damaged as an early consequence of exposure. We hypothesize ACR acts at presynaptic sites in CNS and PNS to reduce quantal release of neurotransmitter. Therefore, research proposed in Specific Aims #3-#5 will evaluate the role of nerve terminal injury in ACR-induced neurotoxicity and identify corresponding molecular mechanisms. Specific Aim #3 studies will define the onset and magnitude of synaptic damage in ACR-treated rats. In Specific Aim #4 experiments, the rat hindlimb neuromuscular junction will be used a model system to investigate potential pre- and post-junctional sites of ACR action. Specific Aim #5 studies are proposed to quantitate ACR-induced changes in binding of synaptic vesicles with presynaptic plasma membrane. In addition, ACR adduction of cysteine string protein and SNAP-25 will be determined in brain synaptosomes from intoxicated rats. Exploring compromised nerve terminal function during ACR intoxication and identifying corresponding molecular mechanism of action represents a new area of investigation in toxic axonopathies. Results could lead to a better understanding of acquired and inherited human neuropathies and the development of efficacious pharmacotherapies.