Toide K, Okamiya K, Iwamoto Y, Kato T
Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka.
J Neurochem. 1995 Jul;65(1):234-40. doi: 10.1046/j.1471-4159.1995.65010234.x.
The effects of a novel prolyl endopeptidase (PEP) inhibitor, (S)-2-[[(S)-2-(hydroxyacetyl)-1-pyrrolidinyl]carbonyl]-N-(phenylmethyl) - 1-pyrrolidinecarboxamide (JTP-4819), on the PEP activity in the brain and on the contents of substance P (SP)- and arginine-vasopressin (AVP)-like immunoreactivity (LI) in the cerebral cortex and hippocampus of young and aged rats were investigated using enzyme immunoassay. JTP-4819 exhibited a concentration-dependent in vitro inhibitory action on PEP activity in the brains of both young and aged rats, with IC50 values of approximately 0.7 and 0.8 nM, respectively. A single dose of JTP-4819 (3 mg/kg, p.o.) increased the SPLI content in the cerebral cortex but not the hippocampus of aged rats (23-24 months old). In addition, repeated administration of JTP-4819 (1 mg/kg, p.o., for 21 days) increased the SPLI content in the cerebral cortex and restored the SPLI content in the hippocampus, which had decreased with aging. In contrast, single (1 mg/kg, p.o.) and repeated (1 mg/kg, p.o., for 21 days) administration of JTP-4819 only tended to increase the AVPLI content of the hippocampus and cerebral cortex in aged rats, respectively. These results indicate that JTP-4819 increases the cerebral and hippocampal SPLI content in aged rats by inhibiting the action of PEP.
使用酶免疫测定法，研究了一种新型脯氨酰内肽酶（PEP）抑制剂（S）-2-[[（S）-2-（羟基乙酰基）-1-吡咯烷基]羰基]-N-（苯甲基）-1-吡咯烷甲酰胺（JTP-4819）对年轻和老年大鼠大脑中PEP活性以及大脑皮质和海马中P物质（SP）和精氨酸加压素（AVP）样免疫反应性（LI）含量的影响。JTP-4819对年轻和老年大鼠大脑中的PEP活性均表现出浓度依赖性的体外抑制作用，IC50值分别约为0.7和0.8 nM。单剂量的JTP-4819（3 mg/kg，口服）可增加老年大鼠（23 - 24月龄）大脑皮质中的SP-LI含量，但对海马中的含量无影响。此外，重复给予JTP-4819（1 mg/kg，口服，共21天）可增加大脑皮质中的SP-LI含量，并恢复海马中随衰老而降低的SP-LI含量。相比之下，单剂量（1 mg/kg，口服）和重复剂量（1 mg/kg，口服，共21天）的JTP-4819仅分别倾向于增加老年大鼠海马和大脑皮质中的AVP-LI含量。这些结果表明，JTP-4819通过抑制PEP的作用增加老年大鼠大脑和海马中的SP-LI含量。
