| Migraine is a familiar and multiple primary brain functional disease, the morbidity at home and abroad is 12.9%~17.6%, 0.985%, respectively. And male female ratio is 1:4. Due to recurrent attacks and protraction, patients suffered tremendously. Traditionally, it has been regarded as stubborn disease by physicians, and the study concerning the pathogenesis and drug treatment of migraine is one of the hottest spots for medical circle. The disease has not been made up the uniform recognition by modern medicine. The blood vessel theory was brought up by Wolff in 1863. The neurogenic theory was put forward by Lieving in 1873, furthermore, trigeminal nerve-vascular reflex theory was raised by Moskowitz in 1990 and Leac brought forth Cortical spreading depression theory in 1994. The above-mentioned rear three theories were put emphasis on explaining the clinical symptom. For the past few years, the researches relative to the biochemical mechanism and molecular genetics of migraine marked it had penetrated into cell and molecule levels. The well-documented humoral factors pertinent to the migraine mainly included 5-HT, NO, DA, NE, cGRP, intracellular Ca2+ overloading and so on. At the attack process of migraine, angiokinesis of intracalvarium and exterior was still present, and biochemistry factor causing the change of angiokinesis was also received reconstruction in recent year. However, migraine is a kind of multiple factor disease, at present, the pathogenesis of it has not been an accepted argument. Therefore, there has not yet an affirmative radical cure, and the effective way is only to adopt the measures in the prophylaxis and controlling episodes. Frequently used prophylactic treatment medicines included calcium antagonist, tricyclic antidepressant (TCA),β-receptor blocking pharmacon and antiepileptic drug (AED) and so on. Above-mentioned evidence showed that migraine was a disease involved problems in ion channel, and in which calcium channel plays an important role, for this reason, blocking calcium channel will become an important strategy for prophylactic treatment of migraine.Dipfluzine (Dip) synthesized by Hebei Medical University, with similar structure to flunarizine, is a novel Ca2+ channel blocker of diphenylpiperazines. The previous studies demonstrated that Dip could inhibit calcium influx and maintain intracellular calcium homeostasis. In this kind of drugs, flunarizine and lomerizine are effective in the prophylaxis and treatment of migraine. Nevertheless, Dip maybe has equivalent activity in treating migraine. For this reason, the present study mainly explored the preventive and therapeutic effect of Dip on migraine animal model to provide foundation for the clinical application of Dip.Objective: To investigate the preventive and curative effect of dipfluzine on experimental migraine and study its mechanism.Methods:⑴Study of effect on the scratching frequency of mice: Kunming mice were used in this experiment. The mice were divided randomly according to weight into 6 groups with 20 in each group: control group, model group (0.5% CMC), dipfluzine 1mg/kg, 3mg/kg, and 10 mg/kg groups, and flunarizine 3mg/kg group. Drugs were given by ig once daily for 3 days. After 30 minutes of the third administration, mice in control group were treated by subcutaneous injection with saline 20 ml/kg, while the mice in the other groups were treated by subcutaneous injection with NTG by the same volume. The frequency that the mice scratched their head was observed in 10 minutes after modeling.⑵Study of effect on pain threshold and clotting time of mice: Kunming mice were used in this experiment. The mice were divided randomly according to weight into 6 groups with 10 in each group: control group, model group (0.5% CMC), dipfluzine 1mg/kg, 3mg/kg, and 10mg/kg groups, and flunarizine 3mg/kg group. Drugs were given by sc once daily for 4 days. Mice in control group were treated by subcutaneous injection with saline 20 ml/kg, while the mice in the other groups were treated by sc with reserpine by the same volume. And just a day after beginning making model, drugs were given by ig once daily for 5 days. The mice in control group and model group were treated by ig with distilled water and solvent 20 ml/kg accordingly, while the mice in the other groups were treated by sc with designated drugs by the same volume. Determination of pain threshold using hot plate method and clotting time after picking eyeballs did not start until one hour after the last administration.⑶Study of effect on NO content: The healthy SD rats were used in this experiment. They were divided randomly into 6 groups with 10 in each group: control group, model group (0.5% CMC), dipfluzine 0.5mg/kg, 1.5mg/kg, and 5mg/kg groups, and flunarizine 1.5mg/kg group. Drugs were given by ig once daily for 3 days. After 30 minutes of the third administration, rats in control group were treated by subcutaneous injection with saline 2.5 ml/kg, while the rats in the other groups were treated by subcutaneous injection with NTG by the same volume. Then, biochemistry method was utilized to determine the content of NO in blood plasma and brain tissue after modeling.Results:⑴The scratching frequency of mice: Dipfluzine was able to decrease the scratching frequency of migraine mice. The scratching frequency was 2.2±1.9, 19.9±11.8, 5.1±3.1, 12.4±8.4, 6.3±3.6 and 4.1±3.1 in control group, model group, dipfluzine 1mg/kg, 3mg/kg, and 10mg/kg groups and flunarizine 3mg/kg group, respectively, which was lower (P<0.05) in control group, dipfluzine 3mg/kg and 10mg/kg groups and flunarizine 3mg/kg group than that in model group.⑵Pain threshold and clotting time: Dip could prolong clotting time of the model mice and elevate pain threshold of them. Pain threshold was 17.2±4.7s, 23.5±5.6s, 34.5±4.9s, 31.1±5.0s, 33.9±8.2s and 35.6±5.1s in control group, model group, dipfluzine 1mg/kg, 3mg/kg, and 10mg/kg groups, and flunarizine 3mg/kg group, respectively. Compared with model group, pain threshold in dipfluzine 1mg/kg, 3mg/kg and 10mg/kg groups, and flunarizine 3mg/kg group had significant difference (P<0.01). Clotting time of migraine model mice was 43.7±0.7s, 36.3±8.7s, 42.7±0.8s, 40.4±2.9s, 42.3±2.2s and 43.0±1.3s in above six groups, respectively, which in model group was shorter than that in control group (P<0.05). While clotting time in three groups of Dip and flunarizine 3mg/kg group was longer than that in model group (P<0.05).⑶The content of NO in blood plasma: Dip could apparently decrease the content of NO in blood plasma of migraine model rats induced by nitroglycerin. The content of blood plasma NO in migraine model rats was 128±24μmol/L, 200±21μmol/L, 155±29μmol/L, 170±19μmol/L, 158±12μmol/L and 147±16μmol/L in control group, model group, dipfluzine 0.5mg/kg, 1.5mg/kg, and 5mg/kg groups, and flunarizine 1.5mg/kg group, respectively. The content of NO in control group, flunarizine 1.5mg/kg group and dipfluzine 0.5mg/kg, 1.5mg/kg, and 5 mg/kg groups was all lower than that in model group (P<0.01).⑷The content of NO in brain tissue: Dip could apparently decrease the content of NO in brain tissue of migraine model rats induced by nitroglycerin. The content of NO in brain tissue of migraine model rats was 3.3±0.9μmol/g pro, 4.7±0.9μmol/g pro, 3.4±0.6μmol/g pro, 3.4±0.8μmol/g pro, 3.3±0.8μmol/g pro and 3.3±0.6μmol/g pro in control group, model group, dipfluzine 0.5mg/kg, 1.5mg/kg, and 5mg/kg groups, and flunarizine 1.5mg/kg group. The content of NO in control group, flunarizine 1.5mg/kg group and dipfluzine 0.5mg/kg, 1.5mg/kg, and 5mg/kg groups was all lower than that in model group (P<0.01).Conclusion:⑴Dip could significantly decrease the scratching frequency, prolong clotting time and elevate pain threshold of migraine mice. To a certain extent, this explained the analgesic treating effect of Dip in migraine aspect.⑵Dip could significantly decrease the content of NO in blood plasma and brain tissue of migraine model rats, for that reason, theoretically which hinted not only the paroxysm of migraine was possibly relevant to NO, but also reducing the content of NO could curb some cascade reaction in vicious cycle in migraine occurrence so as to decrease harmful substance production, maintain organism a equilibrium level all the time, thereby playing relieving pain role.
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