Effect Of Anshen Dingzhi Ling On Dopamine And CAMP/PKA Signaling Pathway For Animal Model Of Attention Deficit Hyperactivity Disorder

Part one Methodological standardization of Animal Studies on Chinese Herbal MedicineObjective:The current study is to assess the quality and methodologies of the available animal studies of CHM treatments on ADHD.Methods:We searched studies in Pubmed and three Chinese databases (China National Knowledge Infrastructure, VIP information, Wanfang data) up to June,2013, and used the following terms:ADHD or hyperactivity or attention deficit or minimal brain dysfunction, rats ormouse or experiment, CHM. The ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines and GSPC (Gold Standard Publication Checklist) were used to extract the data, evaluate the reporting characteristics and standardize the methodologies.Results:Thirty-four studies were retained for the review. All the studies were carried out from1991to2013in China (n=31) and Korea (n=3), majority (27/34) were conducted in the last five years.Among them,30studies were published in Chinese Journals with no impact factor scores. Most of the studies reported "positive" evidence to support the CHM treatment for ADHD based on animal behavior and/or biochemical markers (such as dopamine system). However, there were substantial quality issues in the study design, research methodology andand reporting methods.Conclusions:Despite promising clinical outcome with CHM treatment of ADHD, poor methodological and reporting quality in the current animal studies CHM therapies for ADHD warrants cautious interpretation of the results and future studies with improved research design and more creditable reporting standards. Part two Effect of Anshen Dingzhi Ling on Animal model of Attention Deficit Hyperactivity DisorderObject:To explore the sustained efficacy and potential action of mechanism of Anshen Dingzhi Ling (ADL) in the treatment of SHR ratsMethods:Forty-five SHR rats were randomly divided into five groups:ADHD model group, MPH (2mg/kg) groups, Baicalein(200mg/kg) group, ADL-medium-dose groups(ADM,4.78g/kg/day), ADL-high-dose groups(ADH,9.56g/kg/day). All the rats were dosed for five weeks in a row, and for the groups of normal and model group, rats were given vehicle (CMC-Na,3ml/kg/day). and other groups were dosed under the definite dose. We weighted the body weight and food intake every day, employed the open field, elevated plus maze(EPM), Barnse maze and novel object habitation and recognitation(NOHR) to observe the change in the animal behavior, and then used competive enzyme linked immune-sorbent assay (ELISA) to detect the DA and cAMP expression in the prefrontal cortex and striatum.Results:(1) Food intake and body weights of SHR rats were not influenced by ADL, Baicalein and MPH have the same efficacy.(2) ADL decreased the spontaneous hyperactivity at the end of treatment and two weeks after stopping the medication, the ADM has the better efficacy.(3) ADL can improve the anxiety of SHR rats, but the high viscosity of ADL and oral administration can confound the results. MPH can improve the anxiety of SHR rats obviously.(4) ADM and MPH can improve the recognition learning of SHR rats.(5) ADM, ADL and Baicalein can improve the space learning and memory, but there is no obvious effect. MPH can improve the short memory of rats, ADH can improve the long-term memory of SHR rats.(6) ADM and ADH can increased the DA content in the PFC, which following the decrease of DAT expression in Striatum.(7) ADL can increased the expression of cAMP/PKA two weeks after stopping the medication, which may mediate the sustained effect of stopping the ADL.Conclusions:ADL didn’t influence the physical development of SHR, reduced the spontaneous hyperactivity, improve the space learning and memory and recognition memory, reduced the DAT content in the striatum, increased the DA content in the Striatum and PFC, further to modulate the cAMP/PKA signaling pathway. Part three Study of clinical literature of Chinese herbal medicineObjective:The current study is to systematically review evidence on the efficacy and safety of oral CHM, either alone or with methylphenidate (MPH), in treating Children with ADHD.Methods:A systematic search of articles (until July2013) was carried out using Pubmed and three Chinese databases (China National Knowledge Infrastructure, VIP information, Wanfang data) for clinical trials comparing CHM or CHM plus MPH versus MPH alone in Children with ADHD, with main outcome measures as hyperactivity index. We assessed the quality of included studies, extracted valid data and undertook a meta-analysis.Results:1. Study selection:54studies were included, which involved2077participants in CHM group,584in CHM plus MPH group,2123in MPH group. Duration of treatment ranged from1.4to26weeks, with12or13weeks in the majority of studies.39CHM formula including90single herbs were used in the studies.2. Methodological quality:All the included studies has the poor methodological quality.3. Assessment of Outcomes1) Conners Index of Hyperactivity (CIH):There was no statistically significant difference between between the CHM and MPH at the end of treatment[overall SMD=-0.00,95%CI (-0.08,-0.08), P=0.870], and CHM combined with MPH were superior to MPH [overall SMD=-1.24,95%CI (-1.42,-1.06), P=0.00].2) Total effective rate:We sorted out the different subgroup according to the different levels of CIH scores reduced rate and conducted the pooled analysis for the total effect rate at the end of treatment. CHM and CHM combined with MPH were superior to MPH at the end-point of treatment[overall OR=1.24,95%CI (1.05,1.47); overall OR=3.00,95%CI (2.22,4.05)].3) Neurological Soft Signs (NSS):There were no significant difference between the CHM and MPH in the test of pronation and supination of the hand [overall OR=0.97,95%CI(0.62,1.52), P=0.906]. CHM combined with MPH were superior to MPH alone [overall OR=4.92,95%CI (2.12,8.65), P=0.000]. There were no significant difference between the CHM and MPH in the finger-to-finger tests [overall OR=0.95,95%CI (0.56,1.63), P=0.858]; CHM combined with MPH were superior to MPH alone [overall OR=4.80,95%CI (2.31,9.99), P=0.000]. There were no significant difference between the CHM and MPH in finger-to-nose tests [overall OR=0.87,95%CI (0.39,1.95), P=0.739].4) Chinese medicine symptom curative efficacy:CHM was superior to MPH for Chinese medicine symptom curative efficacy [overall OR=4.72,95%CI(2.64,8.45), P=0.00].5) The other outcome measures:There were no significant difference between the CHM and MPH for number cancellation tests, electroencephalographic, blood zinc. CHM and CHM combined with MPH can improved the other outcome measure of Children with ADHD, such as SNAP-W rating scale, the IQ and C factor in the Chinese Wechsler Intelligence Scale for Children, Integrated Visual and Auditory Continuous Performance Test, and the included studies were scattered, we can just employ the descriptive analysis.6) Safety evaluation:CHM and CHM combined with MPH were superior to MPH, or there were no significant differences between the CHM and MPH. Conclusions: The current evidences showed that the CHM and CHM combined with MPH were superior to MPH in the efficacy and safety, and considering the methodology heterogeneity and de-normalization between the studies, large sample size, multi-center, double-blind and double-dummy randomized controlled trials were needed to verify it, and we had to make a clinic diagnostic and treatment mode which were recognized by international adadema and emboding the features of CHM.