Immunolesioning of identified motoneuron pools by the intramuscular injection of the immunotoxins, 192-IgG-saporin and OX7-saporin, in rats
Peterson, William E.
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Many animal models have been developed to study motoneuron diseases, including amyotrophic lateral sclerosis (ALS), which involves the selective degeneration of upper and/or lower motoneurons (MNs). Unfortunately, the animal models developed, to date, have characteristics that limit their utility for assessing the therapeutic value of cell replacement strategies, including stem cells, for the treatment of MN diseases. Recently, immunotoxins have been developed which may allow for a more selective lesion of cells not previously obtained with other techniques. Immunotoxins combine the specificity of a monoclonal antibody with the cytotoxicity of a ribosome-inactivating protein. In this study, two immunotoxins, 192-IgG-saporin and OX7-saporin, have been used to lesion motoneurons in the neonatal and adult rat respectively. Moreover, this study demonstrates for the first time that MNs in the neonatal rat can interalize the monoclonal antibody, 192-IgG conjugated to Cy3 or saporin, by receptor-mediated endocytosis. Once internalized, 192-IgG-Cy3/-saporin are retrogradely transported to the soma of MNs within the spinal cord. The novel finding that the immunotoxin, 192-IgG-saporin, can be used to lesion MNs following an intramuscular (I.M.) injection in neonatal rats has not previously been demonstrated. In addition, this study provides strong evidence that the observed muscular atrophy following an I.M. injection of 192-IgG-saporin in neonatal rats is likely due to direct necrotic effects on the muscle. Finally, this study also demonstrates that the immunotoxin, OX7-saporin, can produce MN loss following I.M. injection in adult rats, but unlike 192-IgG-saporin, does not result in severe muscular atrophy. This may serve as a useful model for studying cell replacement strategies for motoneuron diseases like ALS.