| ObjectiveVD (Vascular Dementia) is the dementia caused by brain damage from ischemic or hemorrhagic cerebral vessels, and accounts for approximately 20%of senile dementia only after AD (Alzheimer’s disease) and DLB (Dementia with Lewy body). The incidence of VD increases with age and influences the suffers’life significantly, causing great burden to their families and society. VD is the only preventive and curable dementia to date, and the prognosis of early treatment is promising. However, its etiology and pathogenesis are not clear, and there are considerable adverse reactions of western medicine; hence, the treatment of VD with Chinese medicine gets more and more concern. In recent years, Chinese scholars have performed some researches on the treatment of VD with Chinese medicine and found that the advantages lie in that Chinese medicine can greatly improve clinical symptoms and decrease adverse reactions.Professor DENG Tietao has proposed the idea of treating VD by tonifying Qi, eliminatinig phlegm and activating blood based on his abundant clinical experiences. He thinks that the pathogenesis of VD is rooted in Qi deficiency and marked by phlegm stasis, and it should be treated under the principle of "holistic concept" based on TCM syndrome differentiation. Although VD is located in the brain, the root cause lies in the spleen; therefore, the key to the treatment is to replenish Qi to invigorate the spleen. Professor DENG Tietao advocates that the treatment of phlegm stasis should be based on phlegm resolving and assisted by phlegm eliminating. He has made a recipe called Jiannao 1 Fang (a recipe for brain fitness) which proves to be quite effective in clinical practice and deserves deep researches and clinical promotion.Guided by TCM theories, this study evaluated the clinical efficacy and safety of Jiannao 1 Fang and provided data to prove them, thus enriching TCM theories. Through a vast literature review of domestic and international studies, this paper proposed the hypothesis that "the possible mechanism of Jiannao 1 Fang is to regulate some downstream proteins by interfering with NMDAR-CaMK II signal transduction pathways". Through the researches on the genetic expression of NR2B and CaMKIIin the hippocampi of VD rats, this study aimed to explain the molecular biological mechanism of Jiannao 1 Fang influencing the learning and memorizing abilities of VD rats, thus providing new targets and ideas to the treatment of VD with Chinese medicine.MethodsClinical study:in a parallel, randomized trial,60 patients with VD (syndrome of Qi deficiency and phlegm stasis) from Cardiology Department of the First Affiliated Hospital of GZUCM (Guangzhou University of Chinese Medicine) and Encephalopathy Department of Guangdong Second Traditional Chinese Medicine Hospital (Jan.2014-Dec.2014) were enrolled and divided into the treatment group and control group,30 in each group. While both groups were given routine antihypertensive and lipid-lowering treatment, the treatment group was given Jiannao 1 Fang and the control group was given nimodipine. During the 6-week treatment, other drugs related to the treatment of VD were stopped. Scores of MMSE, ADL, NPI and TCM syndrome were recorded respectively for each patient before the treatment and 6 weeks after the treatment, as well as security indicators of blood routine test, liver and kidney functions, and adverse events.Experimental study:the VD rat model was established by permanent bilateral occlusion of the common carotid arteries. Sixty male SD rats were randomly divided into 5 groups:sham-operated group, model group, high dosage group, low dosage group and nimodipine group; the first 2 groups were given normal saline by gavage, while the last 3 groups were given high dosage Jiannao 1 Fang, low dosage Jiannao 1 Fang, and nimodipine suspension respectively. After 30 days of medication, the learning and memorizing abilities of VD rats were evaluated by Morris water maze tests, the hippocampal histological change of VD rats were observed with HE staining, and the levels of NR2B mRNA and CaMKⅡmRNA in the hippocampi of VD rats were measured by RT-PCR technique.ResultsClinical study:there was no statistical significance (P>0.05) in sex, age, course and severity of disease, and education between the two groups, as well as scores of MMSE, ADL, NPI, and TCM syndrome before the treatment. Six weeks after the treatment, the scores of MMSE in both groups increased significantly (P<0.01); After the treatment, there was no significant difference of MMSE scores between the two groups (P>0.05), while there was statistical significiance of MMSE differences before and after the treatment between the two groups (P<0.01);the total effective rate of the treatment group was 80.0%, while that of the control group was 53.3%, which suggested that both groups could improve patients’cognitive abilities and the treatment group worked better (P<0.05). The scores of ADL after the treatment in both groups decreased significantly (P<0.01); There was no statistical significiance of ADL scores between the two groups after the treatment, as well as of ADL differences before and after the treatment between the two groups (P>0.05);the total effective rate of the treatment group was 23.3%, while that of the control group was 30.0%, which suggested that both groups could improve patients’daily living abilities, and their clinical effects were similar (P>0.05). There was no significant difference (P>0.05) between the scores of NPI after the treatment in both groups; There was no statistical significiance of NPI scores between the two groups after the treatment, as well as of NPI differences before and after the treatment between the two groups (P>0.05);the total effective rates of both groups were 6.67%, which suggested that both groups could not improve patients’mental capacities significantly (P>0.05) or decrease the caregivers’degree of distress (P>0.05). The score of TCM syndrome after the treatment in the treatment group decreased significantly (P<0.01), while that of the control group did not decrease significantly (P>0.05);There was statistical significiance of TCM syndrome scores between the two groups after the treatment, as well as of TCM syndrome differences before and after the treatment between the two groups (P<0.01); the total effective rate of the treatment group was 56.67%, while that of the control group was 10.0%, which suggested that the treatment group could improve patients’TCM syndrome significantly, but there was little improvement in the control group(P<0.01). All the patients in this study did not show any abnormalities in blood routine test, liver or kidney functions; both groups showed few adverse reactions and proved to be safe.Experimental study:the results of water maze tests:as the training days increased, the escape latency of the rats decreased gradually in each group, which suggested that the rats learned to look for platforms during the training However, there were significant differences in the learning and memorizing abilities:during the 4 training days, compared with the sham-operated group, the escape latency of the rats in the modal group increased significantly each day (P<0.05 or P<0.01), which indicated that the rats in the model group had difficulty in space learning and memorizing; compared to the model group, on the third day the escape latency of the rats in the high dosage group decreased significantly (P<0.05), and on the fourth day the escape latency of the rats_in both the high dosage group and the nimodipine group decreased signif icantly-(P<0.01 or P<0.05). The results of spatial probe tests:within 120 seconds, compared with the model group, the spatial probe numbers were significantly higher in the sham-operated group and high.dosage group (P<0.01). Compared to the model group, there was no statistical significance in the time during which each other group stayed at the quadrant of the platform (P>0.05), which suggested that the learning and memorizing abilities of the rats in the high dosage group was significantly increased.The hippocampal histological change of VD rats:in the model group, the loss of hippocampus neural cells was observed, nerve nuclei splintered, nuclear membrane was not clear, nucleolus disappeared, nerve cells shrinked, cytoplasmic acidophily increased, astrocytes proliferated, and the lesions concentrated in CA1, CA2 and CA3 regions. In the nimodipine group, the lesions concentrated in CA1 region, and some neurons were damaged. In the high and low dosage groups, the lesions concentrated in CA1 and CA3 regions, the damage of neurons could be observed, but the extent of lesions was slighter than that of the model group, which suggested that Jiannao 1 Fang and nimodipine could decrease the scope and extent of neuron damage in hippocampal tissues.The expressions of NR2B mRNA and CaMKIImRNA:The results of the experiment suggested that the expression of NR2B mRNA in the model group decreased significantly compared to the sham-operated group(P<0.01). Compared with the model group, the expression level of NR2B mRNA was significantly increased in the nimodipine group and high dosage group(P<0.05), and there was a tendency of increasing the expression of NR2B mRNA in the low dosage group. Compared with the sham-operated group, the expression of CaMKⅡmRNA in the model group decreased somewhat, but there was no statistical significance (P>0.05); there was little increase in the expresson of CaMKIImRNA in the high dosage group and nimodipine group with no statistical significance (P>0.05).ConclusionsThe results of the clinical study show that the treatment of VD with Jiannao 1 Fang is effective in improving patients’cognitive abilities, daily living abilities, and TCM clinical symptoms, but show little effect in improving patients’mental capacities. There are few adverse reactions and it proves to be safe. This study indicates a direction for the treatment of VD with Chinese medicine, proves the correctness and scientificalness of Professor DENG Tietao’s idea of treating VD by "tonifying Qi, eliminatinig phlegm and activating blood", and provides data to prove the efficacy and safety of Jiannao 1 Fang.The results of the experimental study show that Jiannao 1 Fang improves the learning and memorizing abilities in VD rats significantly, and the therapeutic mechanism is probably associated with reducing the scope and extent of neuronal damage in hippocampus and increasing the expression of NR2B mRNA. The study does not show similar improvement to CaMKIImRNA, which suggests that CaMKIIis not an important target for Jiannao 1 Fang. |
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