A tachykinin NK1 receptor antagonist, CP-122,721-1, attenuates kainic acid-induced seizure activity.
Substance P (SP) can play an important role in neuronal survival. To analyze the role of SP in excitotoxicity, kainic acid (KA) was administered to rats and in situ hybridization was used to analyze the levels of the SP encoding preprotachykinin-A (PPT-A) mRNA in striatal and hippocampal subregions 1, 4, and 24 h and 7 days after KA. In striatum and piriform cortex, PPT-A mRNA peaked 4 h after KA while in hippocampus, levels peaked after 24 h. KA caused seizures and neuronal toxicity as indicated by a reduction of the number of neurons in the hippocampal CA1 subregion after 7 days. KA was later administered alone or following pretreatment with the tachykinin NK1 receptor antagonist CP-122,721-1 (0.3 mg/kg). The pretreatment decreased seizure activity and a negative correlation was found between seizure activity and survival of CA1 neurons. Conclusively, treatment with CP-122,721-1 has a seizure inhibiting property and may possibly counteract KA-induced nerve cell death in CA1.
Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Karolinska Hospital, S-171 76, Stockholm, Sweden.
O
O
Zachrisson
N
N
Lindefors
S
S
Brené
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007608:Kainic Acid / Q000037:antagonists & inhibitors / Q000633:toxicity*; D007700:Kinetics; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000494:pharmacology*; D011498:Protein Precursors / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D013373:Substance P / Q000235:genetics / Q000502:physiology*; D015320:Tachykinins / Q000096:biosynthesis / Q000235:genetics*; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*
D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D011498:Protein Precursors; D012333:RNA, Messenger; D015320:Tachykinins; C044206:preprotachykinin; D013373:Substance P; C099414:(2S,3S)-2-phenyl-3-((5-trifluoromethoxy-2-methoxy)benzylamino)piperidine; D007608:Kainic Acid