TY - JOUR

T1 - Acute energy restriction triggers Wallerian degeneration in mouse

AU - Alvarez, Susana

AU - Moldovan, Mihai

AU - Krarup, Christian

N1 - Keywords: 2,4-Dinitrophenol; Animals; Axons; Cell Respiration; Energy Metabolism; Female; Mice; Mice, Inbred C57BL; Mice, Neurologic Mutants; Mitochondria; Mitochondrial Diseases; Neural Conduction; Neurons, Afferent; Nitric Oxide; Peripheral Nerves; Sciatic Nerve; Uncoupling Agents; Wallerian Degeneration

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

U2 - 10.1016/j.expneurol.2008.03.022

DO - 10.1016/j.expneurol.2008.03.022

M3 - Journal article

C2 - 18486130

VL - 212

SP - 166

EP - 178

JO - Experimental Neurology

JF - Experimental Neurology

SN - 0014-4886

IS - 1

ER -