Acrylamide-induced distal axon degeneration: a proposed mechanism of action.
Exposure to acrylamide (ACR) monomer produces distal swelling and subsequent degeneration in central and peripheral myelinated axons of humans and laboratory animals. The molecular and cellular events leading to this type of axonopathy are currently unknown. Herein we describe a new mechanism of ACR axonopathy that represents a synthesis of recent research findings and prior hypotheses. According to this model, ion regulation in distal paranodal axon regions is compromised by diminished axolemmal Na/K-ATPase activity. It is suggested that decreased NA/K-ATPase activity is a consequence of aberrant cell body processing and/or deficient axonal transport. Reduced Na pump activity promotes membrane depolarization in conjunction with axoplasmic accumulation of Na and loss of K. Thermodynamically, this favors reverse operation of the Na/Ca-exchanger which permits axonal Ca entry in exchange for Na. The influx of Ca eventually overwhelms buffering mechanisms and leads to distal axon degeneration. Distal axons are predisposed to regulatory failure of this type due to a dependency on cell body output and the unique differential distribution of enzymes, ion channels and exchangers among nodal and internodal regions. This heuristic model might account for axon degeneration occurring as a result of exposure to other chemical neurotoxicants and following axotomy and other forms of mechanical injury.
LoPachin
R M
RM
Department of Anesthesiology, S.U.N.Y. Stony Brook, New York 11794.
Lehning
E J
EJ
D020106:Acrylamide; D000178:Acrylamides / Q000633:toxicity*; D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004577:Electron Probe Microanalysis; D009410:Nerve Degeneration / Q000187:drug effects*; D010525:Peripheral Nerves / Q000187:drug effects; D000254:Sodium-Potassium-Exchanging ATPase / Q000502:physiology
D000178:Acrylamides; D020106:Acrylamide; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium