Doxorubicin (Adriamycin) is an autofluorescent anthracycline antineoplastic antibiotic that acts at the cell nucleus by intercalating between base pairs of DNA thus inhibiting DNA- directed messenger RNA synthesis. Intraneural microinjection of 0.19-0.38 mug of doxorubicin causes a delayed selective Schwann cell degeneration and accompanying demyelination without significantly affecting axons. However when greater than or equal to 0.5 mug of doxorubicin is injected, it is also retrogradely transported to anterior horn cells causing a delayed progressive degeneration of these lower motor neurons. We plan to study these two experimentally separable processes in greater detail. Using both electrophysiological and neuropathological methods we plan to further study doxorubicin- induced motor neuron degeneration as as possible model of amyotrophic lateral sclerosis (ALS). We will determine if such characteristics as axonal length, axonal diameter, and neuronal function correlate with neuron vulnerability. Using immuno- histochemical methods we plan to identify the satellite cells which are labeled following intercellular transfer of doxorubicin from anterior horn cells. In addition, there may be transcellular transport of this toxin to interneurons and upper motor neurons projecting to the anterior horn. This new animal model of a toxin-induced motor degeneration may provide new insights into the etiology of human motor neuron degenerations, especially ALS. additionally the intercellular of neurotoxicity could be an important clue to the pathogenesis of other nervous system diseases. In a separate set of observations we plan to further describe some of the pathophysiological consequences of doxorubicin-induced Schwann cell degeneration/demyelination in peripheral nerve. Using antibodies generated against component parts of the Na+ channel, we will determine the Na+ channel distribution along demyelinated and remyelinating axons. Correlating these immunocytochemical findings with electrophysiological data should provide information concerning the mechanism by which demyelinated axons re-establish conduction. These studies are of obvious importance for understanding the pathophysiological changes that occur in human demyelinating diseases.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
Project #
Application #
Study Section
Neurological Disorders Program Project Review B Committee (NSPB)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Colorado Denver
Schools of Medicine
United States
Zip Code
England, J D; Levinson, S R; Shrager, P (1996) Immunocytochemical investigations of sodium channels along nodal and internodal portions of demyelinated axons. Microsc Res Tech 34:445-51
England, J D; Ferguson, M A; Hiatt, W R et al. (1995) Progression of neuropathy in peripheral arterial disease. Muscle Nerve 18:380-7
England, J D; Gamboni, F; Ferguson, M A et al. (1994) Sodium channels accumulate at the tips of injured axons. Muscle Nerve 17:593-8
England, J D; Regensteiner, J G; Ringel, S P et al. (1992) Muscle denervation in peripheral arterial disease. Neurology 42:994-9
London, S F; England, J D (1991) Dynamic F waves in neurogenic claudication. Muscle Nerve 14:457-61
England, J D; Gamboni, F; Levinson, S R (1991) Increased numbers of sodium channels form along demyelinated axons. Brain Res 548:334-7
England, J D; Gamboni, F; Levinson, S R et al. (1990) Changed distribution of sodium channels along demyelinated axons. Proc Natl Acad Sci U S A 87:6777-80
Rhee, E K; England, J D; Sumner, A J (1990) A computer simulation of conduction block: effects produced by actual block versus interphase cancellation. Ann Neurol 28:146-56