Nagai Y, Narumi S, Miyamoto M, Saji Y, Nagawa Y
Jpn J Pharmacol. 1983 Jun;33(3):635-45. doi: 10.1254/jjp.33.635.
Effects of a TRH (thyrotropin-releasing hormone) analog, DN-1417 (gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate), with regard to the rate of local cerebral glucose utilization (LCGU) were assessed using the autoradiographic 2-deoxy-D-[14C]glucose method to clarify the possible sites of action in conscious and pentobarbitalized rats. DN-1417 (0.5-5 mg/kg, i.v.) significantly shortened the pentobarbital-induced sleeping time in a dose dependent manner, and this effect of DN-1417 was reduced by intracerebroventricular (i.c.v.) pretreatment with atropine methylbromide (20 micrograms). DN-1417 (5 mg/kg, i.v.) by itself slightly increased the LCGU in the thalamus dorsomedial nucleus and mammillary body and significantly increased it in the septal nucleus. Pentobarbital (30 mg/kg, i.v.) alone produced a marked and diffuse reduction in LCGU throughout the brain at a rate of about 46% of the control. DN-1417 (5 mg/kg, i.v.) markedly reversed the reduction of LCGU induced by pentobarbital. The antagonistic effect of DN-1417 in LCGU was about twice as potent as that of TRH. Locally, significant reversal effects by DN-1417 were observed in the hypothalamus, septal nucleus, hippocampus, mammillary body, thalamus dorsomedial nucleus, caudate-putamen, nucleus accumbens, pontine gray matter and so on. These actions of DN-1417 were almost completely abolished in all areas except for the visual cortex under the condition of pretreatment with atropine methylbromide (20 micrograms, i.c.v.). On the other hand, pimozide (1 mg/kg, i.p.) augmented the actions of DN-1417. Thus, DN-1417 seems to act on the level of consciousness via a reticulo-thalamo-cortical system, and reverses the LCGU reduction induced by pentobarbital via a cholinergic mechanism. The hypothalamus appears to be a crucial site in mediation of the antagonistic action of DN-1417 on pentobarbital.
使用放射自显影2-脱氧-D-[14C]葡萄糖法评估促甲状腺激素释放激素（TRH）类似物DN-1417（γ-丁内酯-γ-羰基-L-组氨酰-L-脯氨酰胺柠檬酸盐）对局部脑葡萄糖利用率（LCGU）的影响，以明确其在清醒和戊巴比妥麻醉大鼠体内可能的作用位点。DN-1417（0.5 - 5毫克/千克，静脉注射）以剂量依赖的方式显著缩短戊巴比妥诱导的睡眠时间，且用甲基溴化阿托品（20微克）脑室内预处理可减弱DN-1417的这种作用。DN-1417（5毫克/千克，静脉注射）本身可使丘脑背内侧核和乳头体的LCGU略有增加，并使隔核的LCGU显著增加。单独使用戊巴比妥（30毫克/千克，静脉注射）会使全脑的LCGU显著且广泛降低，降低幅度约为对照的46%。DN-1417（5毫克/千克，静脉注射）可显著逆转戊巴比妥诱导的LCGU降低。DN-1417对LCGU的拮抗作用约为TRH的两倍。局部而言，在丘脑下部、隔核、海马体、乳头体、丘脑背内侧核、尾状核 - 壳核、伏隔核、脑桥灰质等部位观察到DN-1417有显著的逆转作用。在甲基溴化阿托品（20微克，脑室内注射）预处理的情况下，除视皮质外，DN-1417在所有区域的这些作用几乎完全被消除。另一方面，匹莫齐特（1毫克/千克，腹腔注射）增强了DN-1417的作用。因此，DN-1417似乎通过网状 - 丘脑 - 皮质系统作用于意识水平，并通过胆碱能机制逆转戊巴比妥诱导的LCGU降低。下丘脑似乎是介导DN-1417对戊巴比妥拮抗作用的关键位点。
