Study Of Qilong Toutong Granule’s Efficacy Of Treating Migraine And Its Mechanism

Objective:To verify the analgesic, sedative effect of Qilong Toutong granule (QLTT), and to investigate the underlying antimigraine mechanism of QLTT, then providing pharmacological evidence for further research and exploitation of QLTT.Methods:Kunming mice were used in the hot-plate test and acetic acid-induced writhing test to assess the analgesic effect; Kunming mice were adopted in spontaneous locomotor test and sodium pentobarbital-induced hypnosis activity to estimate the sedative and hypnotic effect; The whole blood viscosity and bleeding time of acute blood stasis model rats were detected to evaluate the effect of QLTT on promoting blood circulation and removing blood stasis, and to investigate the potential mechanism of QLTT; Measuring the levels of plasma CGRP and (3-EP by radioimmunoassay, as well as the levels of Fos protein expression in trigeminal nucleus caudalis by immunohistochemical method in nitroglycerin-induced migraine model test to elucidate the possible mechanism of action of QLTT; Observing the blood clotting time of reserpine-induced low5-HT migraine model mice and detecting the monoamine neurotransmitters (NE, DA and5-HT) of brain tissue and plasma to further understand the mechanism of action of QLTT.Results:QLTT (5.2g/kg,2.6g/kg) raised the pain threshold significantly compared to the blank group at60min and remained high until180min post treatment (P<0.01, P<0.05), and QLTT (1.3g/kg) raised the pain threshold significantly at120min post treatment (P<0.01); Compared with blank group, QLTT (5.2g/kg,2.6g/kg) induced a significant reduction in spontaneous locomotor activity at the1hour and2hours after drug administration (P<0.05, P<0.01), and QLTT (1.3g/kg) remarkably decreased locomotor activity of mice at2hours after drug administration (P<0.01); Compared with blank group, the three doses of QLTT do not have the property of hypnosis. Compared with the model group, the three doses of QLTT could significantly prolong the bleeding time of acute blood stasis model rats (P<0.01) and improve the whole blood viscosity of blood stasis model rats (P<0.01). Compare with behavioral change of the model rats, QLTT (3.6g/kg,0.9g/kg) could decrease the frequency of scratching their heads or patting their faces at these three time quantums of30～60min,60～90min and120～150min (P<0.01), and QLTT (1.8g/kg) could decrease the frequency of scratching their heads or patting their faces at these four time quantums of30～60min,60～90min,120～150min, and150～180min (P<0.01, P<0.05). Compared with the model group, the three doses of QLTT all decreased the level of plasma CGRP reduced by nitroglycerin (P<0.01), and QLTT (3.6g/kg,1.8g/kg) could increase the plasma (3-EP level significantly (P<0.01). Compared with the model group, the three doses of QLTT groups significantly lowered the C-Fos immunoreactivity, among which the QLTT (1.8g/kg) group had the lowest number of Fos-positive neurons (P<0.01). Compared with the model group, QLTT at dosages of5.2g/kg and2.6g/kg could significantly prolong the clotting time of reserpine-induced low5-HT model mice (P<0.01). Compared with model group, QLTT (2.6g/kg) significantly enhanced the plasma5-HT levels (P<0.05), meanwhile, QLTT (5.2g/kg,2.6g/kg and1.3g/kg) could remarkably increase5-HT, NE and DA contents of brain tissue (P<0.01).Conclusions:QLTT has good effect on analgesia, sedation, activating blood and dissolving stasis, and anti-platelet aggregation. The potential mechanism of QLTT in migraine treatment are listed as follows:(1) Inhibiting platelet aggregation, reducing the release of5-HT, preventing the occurrence of extracranial vasospasm to prevent migraine;(2) Reducing blood viscosity, improving blood circulation to alleviate headache;(3) Affecting the release and metabolism of vascular active substances CGRP, regulating vasomotion, and playing a role of anti-inflammatory;(4) Affecting the endogenous opioid peptide system, increasing the release of the beta-EP, and then improving the pain threshold;(5) β-EP can adjust the release of sympathetic neurotransmitters, inhibiting the pain signal conduction of migraine;(6) Regulating vasomotor function of brain, reducing neuronal firing of trigeminocervical complex neurons and inhibiting nociceptive transmission from the trigeminocervical complex up to the thalamus by enhancing the plasma5-HT levels and5-HT, NE, DA contents of brain tissues.