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ToxSci Advance Access published online on February 24, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfj143
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received November 3, 2005
Accepted January 10, 2006

Safety Evaluation

Safety evaluation of Intrathecal Substance P-Saporin, a targeted neurotoxin, in dogs

Jeffrey W. Allen Ph.D. 1, Patrick W. Mantyh Ph.D. 2, Kjersti Horais B.S. 3, Nicole Tozier 3, Scott D. Rogers 2, Joseph R. Ghilardi 2, Dasa Cizkova D.V.M. 3, Marjorie R Grafe D.V.M. 4, Phillip Richter D.V.M 5, Douglas A. Lappi Ph.D. 6, and Tony L. Yaksh Ph.D. 3 *

1 Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093; Present address: Medtronic Neurological 800 53rd Avenue, NE (MS N335) Columbia Heights, MN 55421
2 Neurosystems Center, Department of Preventive Sciences, University of Minnesota, 18-208 Moos Tower, 515 Delaware Street SE, Minneapolis, MN 55455, and VA Medical Center, Minneapolis, MN 55417 USA
3 Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093
4 Department of Pathology, Oregon Health Science Center, Portland OR
5 Campus Veterinary Medicine, University of California, San Diego, La Jolla, CA 92093
6 Advanced Targeting Systems Inc., 11175A Flintkote Avenue, San Diego, CA 92121

* To whom correspondence should be addressed.
Tony L. Yaksh, E-mail: tyaksh{at}ucsd.edu


  Abstract

Intrathecal Substance P-Saporin (SP-SAP), a 33 kDa targeted neurotoxin, produces selective destruction of superficial neurokinin 1 receptor (NK1r) bearing cells in the spinal dorsal horn. In rats, SP-SAP prevents formation of hyperalgesia and can reverse established neuropathic pain behavior in rodents. To determine the safety of this therapeutic modality in a large animal model, beagles received bolus intrathecal lumbar injections of vehicle, SP-SAP (1.5, 15, 45 or 150 µg) or a non-targeted preparation of Saporin (SAP, 150 µg) for immunohistological analysis of spinal cords. Doses of 15 µg SP-SAP and above produced a significant and equivalent loss of NK1r - bearing cells and dendrites in lumbar Laminae II and I compared to vehicle or SAP-treated animals. Cervical regions in all animals displayed no loss of NK1r immunoreactivity as compared to controls. Total numbers of neurons in the lumbar dorsal horn or alpha-motor neurons in the ventral horn demonstrated no significant changes. No increases in the astrocytic marker glial fibrillary acidic protein (GFAP) were noted following treatment with SP-SAP suggesting a lack of generalized neurotoxicity. Additional dogs received doses of 1.5 to 150 µg SP-SAP or SAP and were sacrificed after 28 or 90 days to assess behavioral and physiological parameters. Although some acute motor signswer observed with both sP-SAP and SAP, no long-lasting significant events were noted in any of these animals. These data indicate no adverse toxicity at doses up to 10 times those necessary for producing loss of superficial NK1r-bearing neurons in a large animal model.

Keywords: spinal; neurotoxin; neurokinin 1 receptor; substance P; saporin.
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