Possible role of the N-terminus of substance P in kainic acid-induced toxicity in rats.
Subcutaneously administered kainic acid (KA) in the rat results in brain damage accompanied by a behavioral response characterized by wet dog shakes (WDS), seizures and brain damage, an effect that is potentiated by opioids. Based on the potentiative effect of the N-terminus of substance P (SP) on the ability of KA to induce behavioral responses in mice, we tested the hypothesis that the N-terminus of SP also plays a role in KA-induced neurotoxicity in rats. Pretreatment i.p. with 1 or 10 nmol of SP(1-7), a major N-terminal metabolite of the undecapeptide SP, 15 min before administration of 12 mg/kg of KA potentiated the incidence of WDS. In contrast, after administration of 1 nmol of [D-Pro2, D-Phe7]SP(1-7) (D-SP(1-7)), the D-isomer of SP(1-7) and a substance P N-terminal antagonist, the intensity of KA-induced WDS was no different from those in either the KA- or saline-injected rats. However, pretreatment with D-SP(1-7) completely blocked the potentiative effect of SP(1-7) on the KA-induced WDS. While the severity of KA-induced lesions was not significantly altered by pretreatment with 1 nmol of SP(1-7), the effect of KA was not significantly different from that in control rats when administered with 1 nmol of D-SP(1-7). These results suggest a possible involvement of endogenous SP N-terminal activity in the effects following subcutaneous (s.c.) administration of KA.(ABSTRACT TRUNCATED AT 250 WORDS)
Velázquez
R A
RA
Department of Veterinary Pathobiology, University of Minnesota, St. Paul 55108.
Sun
X
X
Kurtz
H J
HJ
Larson
A A
AA
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology; D001925:Brain Damage, Chronic / Q000139:chemically induced* / Q000473:pathology / Q000523:psychology; D007608:Kainic Acid / Q000633:toxicity*; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013373:Substance P / Q000494:pharmacology
D010446:Peptide Fragments; D013373:Substance P; C036877:substance P (1-7); D007608:Kainic Acid