Liu H, Mazarati A M, Katsumori H, Sankar R, Wasterlain C G
Epilepsy Research Laboratory, Veteran Administration Medical Center, Sepulveda, CA 91343, USA.
Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):5286-91. doi: 10.1073/pnas.96.9.5286.
Substance P (SP), a member of the tachykinin family, is widely distributed in the central nervous system and is involved in a variety of physiological processes including cardiovascular function, inflammatory responses, and nociception. We show here that intrahippocampal administration of SP triggers self-sustaining status epilepticus (SSSE) in response to stimulation of the perforant path for periods too brief to have any effect in control rats, and this SSSE generates a pattern of acute hippocampal damage resembling that known to occur in human epilepsy. The SP receptor (SPR) antagonists, spantide II and RP-67,580, block both the initiation of SSSE and SSSE-induced hippocampal damage and terminate established anticonvulsant-resistant SSSE. SSSE results in a rapid and dramatic increase in the expression of preprotachykinin A (a precursor of SP) mRNA and SP in principal neurons in CA3, CA1, and the dentate gyrus as well as in hippocampal mossy fibers. SP also increases glutamate release from hippocampal slices. Enhanced expression of SP during SSSE may modulate hippocampal excitability and contribute to the maintenance of SSSE. Thus, SPR antagonists may constitute a novel category of drugs in antiepileptic therapy.
P物质（SP）是速激肽家族的一员，广泛分布于中枢神经系统，参与多种生理过程，包括心血管功能、炎症反应和痛觉感受。我们在此表明，海马内注射SP会引发自维持性癫痫持续状态（SSSE），这是对穿通通路刺激的反应，刺激时间过短，对对照大鼠无任何影响，且这种SSSE会产生一种急性海马损伤模式，类似于已知在人类癫痫中发生的情况。SP受体（SPR）拮抗剂，即spantide II和RP - 67,580，可阻断SSSE的起始以及SSSE诱导的海马损伤，并终止已确立的抗惊厥药物耐药性SSSE。SSSE导致CA3、CA1和齿状回的主要神经元以及海马苔藓纤维中前速激肽原A（SP的前体）mRNA和SP的表达迅速且显著增加。SP还会增加海马切片中谷氨酸的释放。SSSE期间SP表达的增强可能会调节海马兴奋性，并有助于维持SSSE。因此，SPR拮抗剂可能构成抗癫痫治疗中的一类新型药物。
