Safety evaluation of intrathecal substance P-saporin, a targeted neurotoxin, in dogs.
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 microg), or a nontargeted preparation of saporin (SAP, 150 microg) for immunohistological analysis of spinal cords. Doses of 15 microg 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 microg 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.
Allen
Jeffrey W
JW
Department of Anesthesiology, University of California, San Diego, La Jolla, California 92093-0818, USA.
Mantyh
Patrick W
PW
Horais
Kjersti
K
Tozier
Nicole
N
Rogers
Scott D
SD
Ghilardi
Joseph R
JR
Cizkova
Dasa
D
Grafe
Marjorie R
MR
Richter
Phillip
P
Lappi
Douglas A
DA
Yaksh
Tony L
TL
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004285:Dogs; D007278:Injections, Spinal; D009498:Neurotoxins / Q000008:administration & dosage / Q000009:adverse effects* / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D013116:Spinal Cord / Q000473:pathology; D013373:Substance P / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics
D009498:Neurotoxins; D054789:Ribosome Inactivating Proteins, Type 1; C468274:substance P-saporin; D013373:Substance P; D000076985:Saporins