Acrylamide axonopathy revisited.
Distal swelling and eventual degeneration of axons in the CNS and PNS have been considered to be the characteristic neuropathological features of acrylamide (ACR) neuropathy. These axonopathic changes have been the basis for classifying ACR neuropathy as a central-peripheral distal axonopathy and, accordingly, research over the past 30 years has focused on the primacy of axon damage and on deciphering underlying mechanisms. However, based on accumulating evidence, we have hypothesized that nerve terminals, and not axons, are the primary site of ACR action and that compromise of corresponding function is responsible for the autonomic, sensory, and motor defects that accompany ACR intoxication (NeuroToxicology 23 (2002) 43). In this paper, we provide a review of data from a recently completed comprehensive, longitudinal silver stain study of brain and spinal cord from rats intoxicated with ACR at two different daily dosing rates, i.e., 50 mg/kg/day, ip or 21 mg/kg/day, po. Results show that, regardless of dose-rate, ACR intoxication was associated with early, progressive nerve terminal degeneration in all CNS regions and with Purkinje cell injury in cerebellum. At the lower dose-rate, initial nerve terminal argyrophilia was followed by abundant retrograde axon degeneration in white matter tracts of spinal cord, brain stem, and cerebellum. The results support and extend our nerve terminal hypothesis and suggest that Purkinje cell damage also plays a role in ACR neurotoxicity. Substantial evidence now indicates that axon degeneration is a secondary effect and is, therefore, not pathophysiologically significant. These findings have important implications for future mechanistic research, classification schemes, and assessment of neurotoxicity risk.
Department of Anesthesiology, Albert Einstein College of Medicine, Montefiore Medical Center, 111 E. 210th St., Bronx, NY 10467, USA. lopachin@aecom.yu.edu
R M
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LoPachin
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Balaban
J F
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Ross
D020106:Acrylamide / Q000633:toxicity*; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology*; D001933:Brain Stem / Q000187:drug effects / Q000473:pathology; D008860:Microscopy, Ultraviolet; D009410:Nerve Degeneration; D011689:Purkinje Cells / Q000187:drug effects / Q000473:pathology; D051381:Rats; D016622:Silver Staining; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology
D020106:Acrylamide