Safety evaluation of intrathecal substance P-Saporin, a targeted neurotoxin, in dogs

Jeffrey W. Allen, Patrick W. Mantyh, Kjersti Horais, Nicole Tozier, Scott D. Rogers, Joseph R. Ghilardi, Dasa Cizkova, Marjorie R. Grafe, Phillip Richter, Douglas A. Lappi, Tony L. Yaksh

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Intrathecal (IT) 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 the 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 IT lumbar injections of vehicle, SP-SAP (1.5, 15, 45, or 150 μg), or a nontargeted 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 were noted following treatment with SP-SAP, suggesting a lack of generalized neurotoxicity. Additional dogs received doses of 1.5-150 μg SP-SAP or SAP and were sacrificed after 28 or 90 days to assess behavioral and physiological parameters. Although some acute motor signs were 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.

Original languageEnglish (US)
Pages (from-to)286-298
Number of pages13
JournalToxicological Sciences
Volume91
Issue number1
DOIs
StatePublished - May 1 2006

Keywords

  • Neurokinin 1 receptor
  • Neurotoxin
  • Saporin
  • Spinal
  • Substance P

ASJC Scopus subject areas

  • Toxicology

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    Allen, J. W., Mantyh, P. W., Horais, K., Tozier, N., Rogers, S. D., Ghilardi, J. R., Cizkova, D., Grafe, M. R., Richter, P., Lappi, D. A., & Yaksh, T. L. (2006). Safety evaluation of intrathecal substance P-Saporin, a targeted neurotoxin, in dogs. Toxicological Sciences, 91(1), 286-298. https://doi.org/10.1093/toxsci/kfj143