ToxSci Advance Access originally published online on February 24, 2006
Toxicological Sciences 2006 91(1):286-298; doi:10.1093/toxsci/kfj143
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Safety Evaluation of Intrathecal Substance P-Saporin, a Targeted Neurotoxin, in Dogs
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* Department of Anesthesiology, University of California, San Diego, La Jolla, California 92093; Neurosystems Center, Department of Preventive Sciences, University of Minnesota, Minneapolis, Minnesota 55455; VA Medical Center, Minneapolis, Minnesota 55417; Department of Pathology, Oregon Health Science Center, Portland, Oregon 97239; ¶ Campus Veterinary Medicine, University of California, San Diego, La Jolla, California 92093; and || Advanced Targeting Systems Inc., San Diego, California 92121
Received November 3, 2005; accepted January 10, 2006
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.
Key Words: spinal; neurotoxin; neurokinin 1 receptor; substance P; saporin.
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