| Background:With 65 million people affected worldwide, epilepsy is the most common, chronic, recurrent disease in neurology. Despite long-term treatment of antiepileptic drugs, up to one-third of patients with epilepsy (PWE) continue to have seizures. PWE usually experience comorbid illnesses, such as cognitive impairment, psychological diseases, sleep disorder, etc. How to find a suitable therapy for epilepsy has always been the focus and tough problem in medical research.The prophylactic treatment is very important in different phases of epilepsy. The past development of AEDs targeted in blocking seizure generation, providing best measures only in symptomatic treatment. Developing new antiepileptic drugs with antiepileptogenic activity, to prevent and delay the epilepsy progress, may be a clue to better treatment of epilepsy.Traditional Chinese medicine (TCM) has experienced a long history in treating epilepsy with exact clinical effect. The constitution is the nature of individual, which is closely related to the occurrence, development and prognosis of epilepsy. In latent, interical and stable periods of epilepsy, adjusting biased constitution with TCM is of great significance to prevent seizures.Objective:This study firstly analyzed constitution distribution of PWE in 322 cases, and then observed the effect of Chai bei zhi xian decoction on animal behavior and expression of N-cadherin/MAP2 in the progress of epilepsy. Provided the objective basis for the treatment based on constitution, in order to delay the occurrence and development of epilepsy, prevent seizures and improve the efficacy of AEDs.Methods:Clinical research:The general clinical information of PWE was collected by using a cross-sectional survey. The questionnaire included clinical observation form, classification and determination of TCM constitution scale and some other scales assessment for cognition, psychological condition, sleep and quality of life in PWE. Firstly, the physical distribution was observed in totally. Secondly, using chi-square test to analyze the distribution in different genders, ages, seizure severity degrees and efficacy of treatment and compare the incidence of cognitive impairment, sleep disorders and psychological problems in different constitutions. Finally, the correlation between the score of constitution and quality of life in epilepsy inventory-89 was analyzed by Spearman correlation analysis and multiple linear regression analysis.Experimental study:150 rats were randomly devided into sham operation group and model group. Eastablishing post-status epilepticus models of temporal lobe epilepsy by intracerebroventricular injection of kainic acid and then divided rats into 2-week group and 4-week group randomly. Each group was divided into model group, Chinese medicine group, Western medicine group, and Chinese-Western medicine group. Rats of sham operation group were also divided into 2-week group and 4-week group, which were injected by saline in lateral ventricle instead. Twenty four hours after operation, rats in Chinese medicine group, Western medicine group and Chinese-Western medicine group were received intragastric administration by chai bei zhi xian decoction, carbamazepine, chai bei zhi xian decoction and carbamazepine separately. The proportion of rats that developed epilepsy, latency for the first spontaneous seizure, seizure frequency and the duration of seizures were compared between different groups after 4 weeks drug administration. After treatment, all rats were sacrificed after chloral hydrate anesthesia. Western blot and real time fluorescence quantitative PCR were used to bserve the expression of N-cadherin, MAP2 and mRNA in hippocampus of rats in each group at different time points.Results:Clinical research:1.121 cases of total 322 patients were of gentleness type, others were of biased constitution, including wet-heat (21.43%), Qi-deficiency (21.12%), Qi-depression (17.08%), Yang-deficiency (15.53%), Yin-deficiency (14.29%), phlegm-wetness (10.25%), blood-stasis (4.97%), special diathesis (4.04%).2. The distribution characteristics among nine constitution types(1) Sex:the proportion of women in Qi-depression (P<0.05) and blood stasis (P<0.01) were higher than men.(2) Age:gentleness type was higher in patients below 18 years old than other ages (P<0.01). Over 40 years old patients in Qi-deficiency (P<0.05), Qi-depression (P<0.05), phlegm-wetness (P<0.01) and Yang-deficiency (P<0.01) got a higher proportion.(3) The severity:patients with gentleness constitution took the majority part in the PWE with no seizures or light degree (P<0.01).(4) Non-intractable epilepsy (NIE) and intractable epilepsy (IE):there’s a higher ratio in NIE than IE in gentleness type (P<0.05), the proportion of Qi-depression and Yang-deficiency was higher in IE than NIE (P<0.05).(5) Obesity:the proportion of the obese in the patients with wet-heat type was higher than that of patienst with BMI<28 (P<0.01).3. The occurrence of comorbid illnesses with epilepsy in different constitutional types(1) Cognitive impairment:ratio of Qi deficiency patients with cognitive impairment was higher than patients with normal cognition (P<0.05).(2) Anxiety:the proportion of patients with anxiety was lower than non-anxiety patients in gentleness type (P<0.01), Qi-deficiency (P<0.01), Qi-depression (P<0.01), phlegm-wetness (P<0.05), wet-heat (P<0.05) and Yin-deficiency (P<0.05) patients with anxiety are more than non-anxiety.(3) Depression:proportion of patients with depression was significantly lower than the non-depression in gentleness type (P<0.01), while the results of Qi-deficiency (P<0.01) and Qi-depression (P<0.01) were vice versa.(4) Insomnia:the proportion of insomnia in gentleness was significantly lower than that of patients without sleep disorders (P<0.01), while the proportion of insomnia in Qi-deficiency (P<0.01), Yang-deficiency (P<0.05), Yin-deficiency (P<0.05) was higher than that of non-insomnia (P<0.05 or P<0.01).(5) EDS:ratio of PWE with EDS in gentleness was significantly lower than that of non-sleepiness (P<0.01), while opposite results occured in Qi deficiency (P<0.01), wet-heat (P<0.01), wet-heat (P<0.01) and Yang-deficiency constitution (P<0.01).4. The correlation between constitution and quality of life(1) Spearman correlation analysis between QOLIE-89 score and 9 types of constitution score showed that there was a positive correlation between the total score and 17 items of QOLIE-89 and gentleness constitution score (P<0.05),while a negative correlation with other eight biased constitution score, mostly of significant difference (P<0.05).(2) Linear regression analysis showed that the gentleness type was a promoting factor in each facet of QOLIE-89 (P<0.05), Qi-depression is a major factor to reduce the most parts in quality of life (P<0.05), Qi deficiency mainly affected the energy/fatigue and pain (P<0.05).Experimental study:1. Behavioral Assessment of Seizure:(1) There was no significant difference of the SRSs incidence among each epileptic group in 4 weeks (P>0.05).(2) When compared with model group, the latency for the first spontaneous seizure was prolonged in all treatment groups (P<0.01), but the difference was not statistically significant between themselves (P>0.05).(3) Only combined Chinese and Western medicine could effectively reduce the seizure frequency (P<0.01).(4) Comparing to model group, Chinese medicine group (P<0.01), Western medicine group (P<0.01) and Chinese-Western medicine group (P<0.01) got shorter seizure duration, while Chinese-We stern medicine group got shorter seizure duration than that of Chinese medicine group (P<0.01) and Western medicine group (P<0.05).2. The expression of N-cadherin and MAP2 by western blot(1) N-cadherin expressed higher in 2-week model group (P<0.01). Comparing to model group, the expression in Chinese medicine group (P<0.05) and Chinese-Western medicine group (P<0.01) both decreased.(2) N-cadherin expressed higher in 4-week model group (P<0.01). Comparing to model group, the expression in Western medicine group (P<0.05) and Chinese-Western medicine group (P<0.01), meanwhile the protein level was lower in Chinese-Western medicine group than that in Western medicine group (P<0.05).(3) The expression of MAP2 was increased in 2-week model group (P<0.01); the protein expression was only decreased in Chinese-Western medicine group than that in model group (P<0.05).(4) There was no difference of the MAP2 expression among 4-week groups (P>0.05).3. The expression of N-cadherin mRNA and MAP2 mRNA by real-time PCR(1) The expression of N-cadherin mRNA in hippocampus of the 2-week model group was higher than that in the sham operation group (P<0.01); comparing to the model group, the expression in Chinese medicine group (P<0.05) and Chinese-Western medicine group (P<0.01) were decreased.(2) The level of N-cadherin mRNA in the 4 week model group was higher than that in the sham operation group (P<0.01); Comparing to the model group, the expression of Chinese medicine group (P<0.05) and Western medicine group (P<0.01) were decreased.(3) MAP2 mRNA tended to get higher expression in 2-week model group than that in the sham operation group; the level of mRNA was lower in Western medicine group (P<0.01) and Chinese western medicine (P<0.01) than that in the model group.(4) The level of MAP2 mRNA in the 4 week model group was lower than that in the sham operation group (P<0.01); comparing to the model group, the expression of the Chinese medicine group (P<0.05), Western medicine group (P<0.05) and Chinese-Western medicine group (P<0.01) were increased.Conclusion:1. Biased constitution is the common constitution type of PWE, orderly by wet-heat, Qi-deficiency and Qi-depression.2. Distribution of constitution in different sexes, ages, severity and the difficulty of treatment are different:women are much more common than men in Qi-depression and blood stasis; gentleness type is higher in adolescents, Qi-deficiency, Qi-depression, phlegm-wetness and Yang-deficiency is much more common in middle-aged; gentleness type in the PWE with no seizure or light degree is very common; IE in gentleness type takes minority and in Qi-depression and Yang-deficiency is majority.3. The conditions of comorbid illnesses with PWE are various in different types: gentleness type is a protective constitution to prevent PWE from comorbidity; PWE with Qi-deficiency constitution are vulnerable to cognitive impairment; anxiety is common in PWE with Qi-deficiency, Qi-depression, phlegm-wetness, wet-heat and Yin-deficiency constitution; depression usually occures in PWE with Qi-depression and Qi-deficiency constitution; PWE with Qi-deficiency, Yang-deficiency and Yin-deficiency constitution are vulnerable to insomnia; EDS is common in PWE with Qi deficiency, wet-heat and Yang-deficiency constitution.4. There is correlation between the QOLIE-89 and Chinese constitution score:gentleness type was a promoting factor and Qi-depression is a major factor to reduce the quality of life.5. The expression of N-cadherin, MAP2 and mRNA are increased at second week after SE induced by KA, N-cadherin N-cadherin mRNA and MAP2 mRNA are also increased in 4 weeks. The results indicated that the two factors may be involved in the epileptogenesis.6. Chai bei zhi xian decoction can prolong the latency for the first spontaneous seizure, shorten the seizure duration and decrease the seizure frequency when combined with carbamazepine.7. In the latent period, Chai bei zhi xian decoction can regulate the expression of N-cadherin, MAP2 and mRNA in hippocampus, which may be one of the mechanisms on antiepileptogenesis.
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