title: Acute energy restriction triggers Wallerian degeneration in mouse.
abstract: Acute exposure of peripheral axons to the free radical Nitric Oxide (NO) may trigger conduction block and, if prolonged, Wallerian degeneration. It was hypothesized that this neurotoxic effect of NO may be due primarily to energy restriction by inhibition of mitochondrial respiration. We compared the neurotoxic effect of NO with the effect of the mitochondrial uncoupler 2,4-dinitrophenol (DNP) on electrically active axons of mouse sciatic nerve. The right tibial nerve was stimulated at the ankle. Muscle responses were recorded from plantar muscles and ascending nerve action potentials were recorded form the exposed sciatic nerve by means of a hook electrode. The sciatic nerve was focally immersed over a length of 1 cm in either phosphate buffered saline (PBS), a solution of approximately 4 microM NO obtained from 10 mM of the NO-donor DETA NONOate, or a solution of up to 1 mM DNP. Following 3 hours of 200 Hz stimulation, the nerves were washed in PBS for 1 hour, the surgical wounds were closed and the mice were left to recover. Following repetitive stimulation in PBS, the nerve responses recovered within 1 hour and the muscle responses within 1 day. The effects of focal acute exposure to NO or DNP were similar: (i) a transient conduction failure that rapidly normalized within one hour of washout and (ii) subsequent Wallerian degeneration of some axons confirmed at morphological studies. Taken together, these data support the hypothesis that neurotoxicity may be caused by energy restriction. Since the pharmacologic effect of NO and DNP was only transient, our data suggest that even a brief period of focal energy restriction can trigger Wallerian degeneration.
authors.affiliation: Division of Neuroscience and Pharmacology, Panum Institute, Faculty of Health Sciences, University of Copenhagen, Denmark.
authors.forename: Susana
authors.initials: S
authors.lastname: Alvarez
authors.forename: Mihai
authors.initials: M
authors.lastname: Moldovan
authors.forename: Christian
authors.initials: C
authors.lastname: Krarup
mesh_terms: D019297:2,4-Dinitrophenol / Q000633:toxicity; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology*; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D009431:Neural Conduction / Q000187:drug effects / Q000502:physiology*; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000633:toxicity; D010525:Peripheral Nerves / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D014475:Uncoupling Agents / Q000633:toxicity; D014855:Wallerian Degeneration / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D014475:Uncoupling Agents; D009569:Nitric Oxide; D019297:2,4-Dinitrophenol