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 Citations (Scopus)

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 2006
Externally publishedYes

Fingerprint

Neurotoxins
Neurokinin-1 Receptors
Dogs
Bearings (structural)
Safety
Animals
Neurons
Animal Models
Substantia Gelatinosa
Spinal Injections
Glial Fibrillary Acidic Protein
Hyperalgesia
Neuralgia
Motor Neurons
Horns
Dendrites
substance P-saporin
Toxicity
Rats
Rodentia

Keywords

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

ASJC Scopus subject areas

  • Toxicology

Cite this

Allen, J. W., Mantyh, P. W., Horais, K., Tozier, N., Rogers, S. D., Ghilardi, J. R., ... 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

Safety evaluation of intrathecal substance P-Saporin, a targeted neurotoxin, in dogs. / Allen, Jeffrey W.; Mantyh, Patrick W; Horais, Kjersti; Tozier, Nicole; Rogers, Scott D.; Ghilardi, Joseph R.; Cizkova, Dasa; Grafe, Marjorie R.; Richter, Phillip; Lappi, Douglas A.; Yaksh, Tony L.

In: Toxicological Sciences, Vol. 91, No. 1, 05.2006, p. 286-298.

Research output: Contribution to journalArticle

Allen, JW, Mantyh, PW, Horais, K, Tozier, N, Rogers, SD, Ghilardi, JR, Cizkova, D, Grafe, MR, Richter, P, Lappi, DA & Yaksh, TL 2006, 'Safety evaluation of intrathecal substance P-Saporin, a targeted neurotoxin, in dogs', Toxicological Sciences, vol. 91, no. 1, pp. 286-298. https://doi.org/10.1093/toxsci/kfj143
Allen, Jeffrey W. ; Mantyh, Patrick W ; Horais, Kjersti ; Tozier, Nicole ; Rogers, Scott D. ; Ghilardi, Joseph R. ; Cizkova, Dasa ; Grafe, Marjorie R. ; Richter, Phillip ; Lappi, Douglas A. ; Yaksh, Tony L. / Safety evaluation of intrathecal substance P-Saporin, a targeted neurotoxin, in dogs. In: Toxicological Sciences. 2006 ; Vol. 91, No. 1. pp. 286-298.
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