Preliminary Study Of Total Flavonoids Of Murraya Paniculata Leaves On Sedative And Hypnotic Mechanism And Its Dependency

Objective: To observe the protective effects of total flavonoids of murraya paniculata leaves(TFMP) on insomnia rats, and to explore the sedative-hypnotic mechanism of TFMP and through natural withdrawal and induced experiments to explore whether PCPA has physical dependence.1. Study of TFMP sedative-hypnotic mechanismMethods: 120 male Wistar rats were randomly divided into six groups of 20. Intraperitoneal injection PCPA 450 mg/kg, 1 time a day for consecutive two days to establish the model of insomnia. Sham group and model group was given 0.5% sodium carboxymethyl cellulose, drug groups were given TFMP 40, 80, 160 mg/kg, positive drug group was given diazepam 1 mg/kg, each group of rats were given administration for 7 days after intragastric.Indicators: Rat hypothalamic monoamine neurotransmitters 5-HT, 5-HIAA, NE, DA and cytokines IL-1β, TNF-α, IL-6 levels.Results:(1) Compared with the sham group, the model group decreased hypothalamic 5-HT significantly(P<0.01). Compared with the model group, TFMP 40, 80, 160 mg/kg group could significantly improve hypothalamic 5-HT content(P<0.05 or P<0.01).(2) compared with sham group, model group decreased hypothalamic 5-HIAA content significantly(P<0.01). Compared with the model group, TFMP 80, 160 mg/kg group could significantly improve hypothalamic 5-HIAA content(P<0.05). TFMP 40 mg/kg group hypothalamic 5-HIAA content was on the rise, but not statistically significant. Diazepam group hypothalamus 5-HIAA content was not statistical significant.(3)compared with sham group, model group hypothalamic NE, DA content had upward trend but not statistically significant. Compared with the model group, TFMP 40, 80, 160 mg/kg group hypothalamic NE, DA content had downward trend but not statistically significant.(4)Compared with sham group, the model group hypothalamic IL-1β content decreased significantly(P<0.01). Compared with the model group, TFMP 80, 160 mg/kg dose group could significantly increase the content of hypothalamic IL-1β(P<0.01). TFMP 40 mg/kg dose group hypothalamus IL-1β content was on the rise, but not statistically significant. Diazepam group hypothalamus IL-1β content was not statistical significant.(5) Compared with the sham group, model group hypothalamus TNF-α content decreased significantly(P<0.01). Compared with the model group, TFMP 40, 80, 160 mg/kg dose group could significantly increase the content of TNF-α in hypothalamus(P<0.05 or P<0.01). Diazepam group hypothalamus TNF-α content increased significantly(P<0.01).(6)Compared with the sham group, model group hypothalamus IL-6 content decreased significantly(P<0.05). Compared with the model group, TFMP 160 mg/kg dose group significantly increased hypothalamic IL-6 content(P<0.05). TFMP 40, 80 mg/kg dose group hypothalamus IL-6 content was on the rise, but not statistically significant. Diazepam group hypothalamus IL-6 content was not statistical significant.Conclusion:(1)TFMP can significantly increase hypothalamic 5-HT, 5-HIAA, IL-1β, TNF-α, IL-6 content of PCPA rat.(2)TFMP tended to decrease hypothalamic NE, DA content of PCPA rat, but not statistically significant.(3)TFMP may play sedative and hypnotic effects by improving the hypothalamus monoamine neurotransmitter 5-HT, 5-HIAA content and hypothalamic cytokines IL-1β, TNF-α, IL-6 content.(4)Whether TFMP sedative-hypnotic mechanism is related to GABAA receptor and excitatory amino acid needs further study.2. Study of dependence of TFMP: Investigate whether TFMP has dependency by natural withdrawal and induced experiments.Natural withdrawal method: Rats and mice were intragastrically administered test drug for 60 days, administered twice daily, morning and afternoon. One day before withdrawal and 2 weeks after withdrawal, the animals were observed daily for signs of appearance, behavior, and the incidence of spontaneous seizures, namely: stress, diet, sleep, spontaneous activity, aggressive, alert level, nerve reflection, vertical tail, tremors, convulsions, respiration, body temperature and weight.Induced experimental method: Rats and mice were intragastrically administered test drug for 30 days, administered twice daily, morning and afternoon. At 16 h after the last administration intraperitoneally(ip) 55 mg/kg pentylenetetrazol azole to induce seizure responses and incidence of seizures within 15 min was observed.Conclusion: The results of natural withdrawal showed that, withdrawal symptoms do not appear in each TFMP group after withdrawal. At the same time, induced experiment results showed that after injection of the threshold dose of pentylenetetrazole, animal seizure incidence is much lower than phenobarbital sodium group. To sum up, TFMP plays sedative and hypnotic effects, while not produce physical dependence.