| Sleep disorders are main clinical symptoms in perimenopausal women, including the difficulty in falling asleep or maintaining sleep, waking early, and daytime drowsiness. These sleep problems had made serious impacts on the quality of women’s life during menopausal periods. Menopausal sleep disorders can be caused by changes of serum estrogen levels, hot flushes, mood disorders and so on. This paper investigated that the pharmacological effects of Jing Wu Jiao Nang on the sleep disorders of mice and rats induced by withdraw ovarium and PCPA plus withdraw ovarium, and analysized its machenisms through the measurement of the estrogen hormone level in serum, rectal temperature, mood disorders, and ERα expression in hypothalamus.The pharmacodynamics research of Jing Wu Jiao Nang on treatment for sleep disturbances in ovariectomized miceFemale KM mice (weight:18-22g) were used to research the effects of Jing Wu Jiao Nang on sleep disturbances in ovariectomized mice. All mice were divided into six groups randomly:sham-operated group, model group, Kun Bao Wan group, Jing Wu Jiao Nang high dose group, Jing Wu Jiao Nang middle dose group and Jing Wu Jiao Nang small dose group. All mice were ovariectomized except the sham-operated group mice. The sham-operated group only underwent the resection of a bit fet.4weeks after operations, Kun-Bao-Wan group mice were administrated intragastrically (1.667g/kg), mice in Jing Wu Jiao Nang high dose group, Jing Wu Jiao Nang middle dose group, Jing Wu Jiao Nang small dose group were administrated intragastrically2.70g/kg,1.35g/kg,0.675g/kg respectively, once a day, for28consecutive days; Mice in sham-operated group and model group were administrated intragastrically with distilled water only.Sleeping duration and sleep latency of mice induced by pentobarbital sodium, locomotor activity and Elevated Plus Maze test (EPM), levels of Progesterone (P), Luteinizing Hormone (LH), Follicle-Stimulating Hormone (FSH) and Gonadotropin-Releasing Hormone (GnRH) in serum, organ coefficients of uterus and kidneys, pathologic changes of uterus, the expression level of ER alpha in hypothalamus were tested by different methods.Compared with sham-operated group, sleep latency of ovariectomized mice in model group was prolonged significantly (P<0.05); Percentage of open arms entries (OE%) and percentage of time spent in open arms (OT%) of ovariectomized mice were no significant differences (P>0.05); Locomotor activity and rearing behavior increased obviously (P<0.05), and the grooming time decreased significantly (P<0.05) in model group mice; the levels of LH and GnRH in serum, the organ coefficients of uterus and the expression level of Estrogen Receptor alpha (ERa) in hypothalamus were decreased in ovariectomized mice.Compared with model group, sleep latency of ovariectomized mice shortened markedly in Kun Bao Wan1.670g/kg group, Jing Wu Jiao Nang2.70g/kg group, Jing Wu Jiao Nang1.35g/kg group and Jing Wu Jiao Nang0.675g/kg group; locomotor activity of ovariectomized mice in Jing Wu Jiao Nang1.35g/kg group and0.675g/kg group significantly reduced (P>0.05); Kun Bao Wan2.70g/kg group, Jing Wu Jiao Nang1.35g/kg group and0.675g/kg group could obviously increase the expression level of ERa in hypothalamus in ovariectomized mice; however, there are no significant effects on OE%and OT%in Elevated Plus Maze, the levels of GnRH, P, LH and FSH in serum and the the organ coefficients of uterus and kidneys in ovariectomized mice treated with Kun Bao Wan group and Jing Wu Jiao Nang groups.These results suggested that Jing Wu Jiao Nang has the obvious sedative hypnotic effects in ovariectomized mice, which maybe related with regulation the expression levels of ER alpha, instead of the estrogen hormone regulation.The pharmacodynamics research of Jing Wu Jiao Nang on treatment for sleep disturbances in ovariectomized plus PCPA rat model84female Sprague-Dawley rats (weight:180-220g) were used to research the effects of Jing Wu Jiao Nang on sleep disturbances in ovariectomized plus PCPA rat model. All rats were divided into six groups randomly:control group, model group, Kun Bao Wan group, Jing Wu Jiao Nang high dose group, Jing Wu Jiao Nang middle dose group and Jing Wu Jiao Nang small dose group. Except the control group, the mice in other groups were underwent bilateral oophorectomy.28days after operations, Kun Bao Wan (1.667g/kg), Jing Wu Jiao Nang (1.890g/kg,0.945g/kg,0.473g/kg) were administrated intragastrically, respectively, once each day, for28consecutive days; Rats in model group and control group were administrated intragastrically with distilled water only. After26days of drug administration,4-Chloro-DL-phenylalanine (PCPA) was injected into abdominal cavity of the ovariectomized rats250mg/kg once a day, for two consecutive days to establish sleep deprivation rat model. Real-time gait analysis, locomotor activity, behaviors of rats in Open Field Test (OFT) Elevated Plus Maze test (EPM), sleeping duration and sleep latency of rats induced by pentobarbital sodium, rectal temperature, levels of Estradiol (E2), Progesterone (P), Luteinizing Hormone (LH), Follicle-Stimulating Hormone (FSH), Gonadotropin-releasing hormone (GnRH) and Prolactin (PRL) in serum, organ coefficients of uterus and kidneys, content of5-HT,5-HIAA, NE, DA in hypothalamus and cortex and the expression level of ER alpha in hypothalamus were tested to observe the pharmacological effects of Jing Wu Jiao Nang in ovariectomized plus PCPA rats.Compared with control group, sleep duration of ovariectomized plus PCPA rats in model group shortened significantly (P<0.05); ovariectomized plus PCPA had no effect on the locomotor activity and behaviors of rats in the Open Field Test (crossing score, rearing score and the defecation) and in the Elevated Plus Maze (OE%and OT%)(P>0.05); however, there were significant changes in ovariectomized plus PCPA rats by the Gait analysis, including the increase of the track width and stride time, the decrease of the print position, stride length, Rf-Rh homolateral coupling, Rf-Lf homologous coupling, and swing speed of four limbs; ovariectomized plus PCPA also could significantly decrease uterus coefficients, rectal temperature and levels of FSH and PRL in serum (P<0.05), significantly increase the content of NE in hypothalamus (P<0.05), deceased the the content of5-HT,5-HIAA in hypothalamus (P<0.05), the content of NE, DA,5-HT,5-HIAA in cortex (P<0.05) and the expression of Estrogen Receptor alpha (ERa) in hypothalamus.Compared with ovariectiomized plus PCPA model group, Kun Bao Wan1.160g/kg group could prolong sleep duration of model rats significantly (P<0.05), and Jing Wu Jiao Nang0.945g/kg group could shorten the sleep latency; Kun Bao Wan1.160g/kg group, Jing Wu Jiao Nang0.945g/kg,0.473g/kg group could significantly increase print position; Jing Wu Jiao Nang0.945g/kg group could improve stride length, and Jing Wu Jiao Nang0.473g/kg group could increase the Rf-Lf homologous coupling in ovariectomized plus PCPA rats markedly (P<0.05), Kun Bao Wan1.160g/kg group could significantly increase print position and the Rf-Lf homologous coupling (P<0.05); The content of5-HT,5-HIAA, ratio of5-HT/DA in hypothalamus and content ofNE, ratio of5-HT/NE,5-HT/DA in cortex increased significantly in Kun Bao Wan1.160g/kg group rats (P<0.05), Jing Wu Jiao Nang0.945g/kg group could increase the content of NE,5-HT and ratio of5-HT/DA in hypothalamus (P<0.05), Jing Wu Jiao Nang0.473g/kg group could significantly increase the content of NE, DA,5-HT,5-HIAA in hypothalamus (P<0.05); Jing Wu Jiao Nang1.890g/kg,0.945g/kg,0.473g/kg group could significantly increase the content of NE,5-HT and ratio of5-HT/NE in cotex in ovariectomized plus PCPA rats (P<0.05); Jing Wu Jiao Nang0.945g/kg,0.473g/kg group could increase the levels of GnRH in serum of ovariectomized plus PCPA rats (P<0.05). And there were obviously increases of ERa expression in hypothamalus of rats treated with Jing Wu Jiao Nang1.890g/kg,0.473g/kg group. Howerer, treatment with Jing Wu Jiao Nang had no improvement on the locomotor activity, behaviors in Elevated Plus Maze and Open Field Test, and the uterus and kidney organ coefficients in ovariectomized plus PCPArats.The above results suggested that Jing Wu Jiao Nang could promote sleep and improve the gait behavior due to sleep disturbance in rats induced by ovariectomized plus PCPA, which maybe by regulating the monoamine neurotransmitter in the hypothamalus and cortex, and the expression of ERa in hypothamalus.In conclusion, Jing Wu Jiao Nang showed therapeutical effects on sleep disturbance and the consequent gait abnormality in ovariectomized mice and ovariectomized plus PCPA rats. But it has no effect on the estrogen level in ovariectomized mice and ovariectomized plus PCPA rats. So we presumed that the improvement of Jing Wu Jiao Nang on the sleep disorders in perimenoparusal maybe related with regulation of the neurotransmitter level in the hypothamalus and cortex, and the expression of ERa in hypothamalus. |
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