TY - JOUR
T1 - Acute energy restriction triggers Wallerian degeneration in mouse
AU - Alvarez, Susana
AU - Moldovan, Mihai
AU - Krarup, Christian
PY - 2008/7
Y1 - 2008/7
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.
KW - 2,4-Dinitrophenol/toxicity
KW - Animals
KW - Axons/drug effects
KW - Cell Respiration/drug effects
KW - Energy Metabolism/drug effects
KW - Female
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Neurologic Mutants
KW - Mitochondria/drug effects
KW - Mitochondrial Diseases/chemically induced
KW - Neural Conduction/drug effects
KW - Neurons, Afferent/drug effects
KW - Nitric Oxide/toxicity
KW - Peripheral Nerves/drug effects
KW - Sciatic Nerve/drug effects
KW - Uncoupling Agents/toxicity
KW - Wallerian Degeneration/chemically induced
U2 - 10.1016/j.expneurol.2008.03.022
DO - 10.1016/j.expneurol.2008.03.022
M3 - Journal article
C2 - 18486130
SN - 0014-4886
VL - 212
SP - 166
EP - 178
JO - Experimental Neurology
JF - Experimental Neurology
IS - 1
ER -