Implication of prostaglandins in models of sleep-wake (conscious) disorders prepared in experimental animals (looking for a clue to a novel drug to treat sleep-wake disorders)

随着日本社会的老龄化，这些天越来越多的人患有失眠，苯二氮类药物被用来治疗这种症状。然而，这些药物以非特异性的方式抑制神经元活动，从而产生副作用。因此，需要专门作用于大脑中睡眠-觉醒调节机制的新型药物。因此，我们首先要弄清楚睡眠-觉醒现象背后的大脑机制。在我们最近试图这样做的研究中，前列腺素(PG)D_2促进睡眠的作用部位被定义在吻侧基底-前脑区域的腹面表层。这个基底前脑区域包括腹侧纹状体，即伏隔核和嗅结节。此外，脑中的PGD合成酶在覆盖在脑表面的软膜中有丰富的表达，并且大鼠脑脊液中的PGD_2浓度在动物的睡眠期间白天高于夜间。由此推测，前脑吻侧腹侧表面膜组织合成的PGD_2作用于脑区表层，启动睡眠。PGD_2产生的信号可能被传递到负责睡眠-觉醒调节的神经回路。在这个过程中，腹侧纹状体中大量表达的腺苷受体参与了这一过程，因为腺苷激动剂CGS21680在同一区域给药时显著促进睡眠，而A2-腺苷拮抗剂KF17837则抑制PGD_2产生的睡眠促进作用。这些结果表明，腺苷相关化合物和PGD_2相关化合物可能成为治疗睡眠觉醒障碍的新的候选药物。

Along with the aging of the society in Japan, an increasing number of people is suffering from insomnia in these days, and benzodiazepines are used to treat this symptom. However, these drugs suppress neuronal activities in a non-specific manner, which causes side effects. Therefore, novel drugs which specifically act on sleep-wake regulating mechanisms in the brain are required. Thus, we first have to clarify the brain mechanisms underlying sleep-wake phenomena. In our recent study attempting to do so, the site of action for the sleep-promoting effect of prostaglandin (PG) D_2 was defined in the ventral surface layr of a rostral basal-forebrain region. This basal-forebrain region includes ventral striatum, i.e., the accumbens nucleus and the olfactory tubercle. Further, the brain PGD synthase was shown to be abundantly expressed in the leptomeninges covering the surface of the brain, and the concentration of PGD_2 in the cerebrospinal fluid (CSF) of the rat was found to be higher during the daytime, the sleeping period of the animal, than during the night. Thus, it is inferred that PGD_2 synthesized in the membrane tissues surrounding the ventral surface of the rostral basal forebrain acts at the surface layr of the brain region to initiate sleep. The signals produced by PGD_2 may be transmitted to neural circuits responsible for the sleep-wake regulation. In the process, A_<2a>-adenosine receptors abundantly expressed in the ventral striatum are crucially involved, because CGS21680, an A_<2a>-adenosine agonist, markedly promoted sleep when administered to the same region, whereas KF17837, an A_2-adenosine antagonist, inhibited the sleep promotion produced by PGD_2. These results indicate that adenosine-related as well as PGD_2-related compounds may become novel candidates for the therapeutic drug effective in the treatment of sleep-wake disorders.