Hong Kong’s compacted urban form brings about potential problems including mental illness. Meanwhile stressful life mainly originates from working pressure brought a lot of physical and mental problems for the people themselves and generating serious family and social problems. As more and more people start to aware mental health issue, the current mental health services system is no longer sustainable due to increasing number of patients. This thesis aims to excavate the potential for landscape to become element in healthcare delivery in the context of community as following: refine the definition of therapeutic landscape, define the scope of work, and identify components essential for therapeutic environment. Last but not least, dig out possible interpretation/physical form through set an example of a particular design introduce for a typical site. Therapeutic landscape which introduce to community recreation system will become a new approach to backup mental health service system as well provide people more convenient and broad healthcare service to cultivate healthy personality. Thus promote community organic development to become a thoughtful and institutional environment. / published_or_final_version / Architecture / Master / Master of Landscape Architecture

The overall objective of this thesis was to test the hypothesis that through developmental programming maternal overnutrition-induced metabolic derangements in the offspring could be offset by supplementing the maternal diet with green tea epigallocatechin gallate (GTEG). The obesogenic diet was a high-fat (HF, 30%) diet. Female Sprague-Dawley rats were fed the HF, low-fat (LF, 7%) or HF diet containing 0.75% or 1.0% GTEG (GT1, GT2) from before conception and throughout gestation and lactation. Both doses of GTEG significantly improved metabolic control of the HF-fed lactating dams. The weaned male pups received the HF, GT1 or GT2 diet forming 6 dam/pup groups: LF/HF, HF/HF, HF/GT1, HF/GT2, GT1/HF and GT2/HF. At wk 13 they had similar weight but insulin resistance index (IRI), serum non-esterified fatty acid (NEFA) and liver triglyceride of rats born to GTEG dams was 57, 23 and 26% lower and accompanied by improved gene/protein expressions related to lipid and glucose metabolism compared to HF/HF rats (P < 0.05). Although the HF/GT1 and HF/GT2 rats had lower serum NEFA, their serum insulin and IRI remained comparable with the HF/HF rats. To determine if there is a critical time period for the actions of GTEG, in the second experiment female rats were fed the LF, HF, or GT1 diet prior to conception and throughout gestation. During lactation, half of the dams had their diet switched from HF to GT1 and vice versa. Pups were weaned to the HF or LF diet, forming the LF/LF/LF, LF/LF/HF, HF/HF/LF, HF/HF/HF, HF/GT1/LF, HF/GT1/HF, GT1/GT1/LF, GT1/GT1/HF, GT1/HF/LF and GT1/HF/HF groups. Metabolic controls of dams given GT1 during gestation or lactation were improved compared with the HF/HF dams (P < 0.05). Three-way ANOVA revealed that 22 wk old offspring born to dams fed the HF diet during gestation had higher serum and muscle triglyceride (TG) concentration and lower ferric reducing ability of plasma (FRAP) (P < 0.05), all of which were reversed by supplementing GT1 to the gestational diet. Oral glucose tolerance at wk 15 was improved in those offspring born to dams given GT1 supplementation during lactation (P < 0.05). The increased serum NEFA concentration and IRI in offspring of dams fed the HF diet during gestation or lactation were reversible upon GT1 supplementation during either time period (P < 0.05). These rats (HF/GT1/HF, GT1/GT1/HF and GT1/HF/HF) had similar level of hepatic insulin receptor gene expression as well as protein abundance for muscle glucose transporter 4 and hepatic sterol regulatory element binding protein-1c but lower protein mass for hepatic glucose-6-phosphatase (P < 0.05) compared with the LF/LF/HF rats. Hence, maternal overnutrition-induced metabolic derangements in male offspring are reversible through supplementing GTEG to the maternal diet during gestation or lactation and this approach is more effective than giving GTEG to offspring born to overnourished mothers. Offspring metabolism could be programmed via manipulations of the maternal diet. / published_or_final_version / Biological Sciences / Doctoral / Doctor of Philosophy

The relationship between fructose consumption and metabolic diseases has drawn substantial attention in recent years. Dietary fructose consumption has climbed dramatically in the past 40 years, and this trend coincides with the prevalence of obesity and diabetes worldwide. In rodents, maternal obesogenic diets are associated with higher risks of metabolic derangement later in life whereas bitter melon (BM) supplementation has been shown to improve blood glucose and lipid profiles. The overall objective of this thesis was to test the hypothesis that through developmental programming metabolic derangement in offspring born to rat dams fed a high-fructose (F) diet could be offset by the addition of BM to the maternal diet. Virgin female rats received a control (C), F (60%) or BM-supplemented F (FBM,1%) diet 8 weeks before conception and throughout gestation and lactation. Weaned male offspring consumed C diet (C/C,F/C,FBM/C) for 11 weeks. The concentrations of serum insulin, triglyceride, free fatty acid (FFA), and hepatic lipids in FBM/C offspring matched that in C/C offspring and were significantly lower than F/C offspring. These phenotypic changes were accompanied with suppressed hepatic lipogenic gene expression but enhanced expression of lipid oxidation-related genes. In the second experiment, we extended the earlier findings by examining whether adding BM to F-fed dams would still benefit offspring if they continued to consume the F diet postweaning. This simulates the scenario in affluent societies where fructose overconsumption may occur in two consecutive generations. The dose-response effect of BM at doses of 0.85% (FBM1) and 1% (FBM2) was also examined. Male offspring born to dams fed the C, F, FBM1 or FBM2 diet were weaned to C or F diet (C/C,C/F,F/F,FBM1/F,FBM2/F) for 20 weeks. BM normalized the serum FFA elevation observed in F/F offspring, although hyperinsulinemia remained in FBM1/F and FBM2/F offspring. The altered liver lipid profile and its molecular changes observed in F/F offspring were ameliorated by maternal BM supplementation. Lower adipose expression of mesoderm-specific transcript, hormone sensitive lipase, sterol regulatory element-binding transcription factor 1, and peroxisome proliferator-activated receptor-gamma (PPARγ) and PPARγ-target genes in FBM1/F and FBM2/F offspring indicated that BM could reduce adipocyte size as well as lower lipolysis and lipogenesis. Since FFA stimulates reactive oxygen species generation that enhances cellular stress, oxidative stress and inflammation in offspring of two-generation F exposure with or without maternal BM supplementation were examined. FBM1/F and FBM2/F offspring showed reduced lipid peroxidation but enhanced antioxidant capacity in the liver. BM suppressed the expression of proinflammatory genes and phosphorylation of c-Jun amino terminal kinase1, as well as promoted insulin receptor substrate 1 protein expression. These BM-mediated antioxidant and anti-inflammatory effects may be associated with a reduction of circulating FFA. Taken together, the data support the concept of developmental programming as maternal fructose clearly induced dyslipidemia, adipocyte dysfunction, oxidative stress and inflammation in offspring. That these abnormalities were largely reversed by adding BM to the maternal diet suggests that perinatal BFC supplementation could alter the course of maternal malnutrition-induced metabolic defects later in life. / published_or_final_version / Biological Sciences / Doctoral / Doctor of Philosophy

Low back pain (LBP) is a common complaint and health problem in Hong Kong, particularly among middle-aged individuals. LBP is the main cause of chronic disability which significantly affects the daily life activities of patients. Pain might result in repeated hospital admissions and subsequently increase the burden on health care providers in Hong Kong. LBP has an enormous effect on quality of life and therefore deserves research attention. Growing evidence shows that yoga may help reduce the level of chronic LBP in adult patients. However, no systematic review has been conducted to support the translation of this theory into practice. Therefore, this thesis aims to evaluate the current evidence on the efficacy of yoga in reducing chronic LBP among adult patients to achieve the following objectives: formulate an evidence-based protocol on yoga practice, assess the implementation potential of the formulated protocol, and develop implementation strategies and evaluation plan for the use of this protocol in a local public hospital in Hong Kong. Five databases were used for the systemic review of relevant studies. These databases were those of Cochrane Library, CINAHL Plus, PudMed, British Nursing Index and Medline (Ovid). A total of eight papers (randomized controlled trials) fulfilled the inclusion criteria of this study. The Scottish Intercollegiate Guidelines Network (SIGN) was used to extract the data and evaluate the paper quality. The findings of the selected papers indicated that yoga practice has a significant effect on reducing pain among adult patients with chronic LBP. The innovation is proposed to be conducted in an adult orthopedic and traumatoloy (O&T) ward. Evidence-based yoga guideline is developed to guide nurses in the effective implementation of the protocol. The SIGN grading system is chosen to grade the recommendations in the guideline. Adult patients with persistent LBP longer than three months are the target population. All study participants practice specific yoga postures under the supervision of yoga instructors and trained nurses in the outpatient clinic. These patients continue home practice for 30 minutes daily or at least twice a week. Based on the findings of the reviewed literatures and the adaptation of these findings into the proposed innovation, the feasibility of implementing evidence-based yoga guideline in the local clinical setting in Hong Kong is demonstrated. An effective communication plan is developed to gain support from stakeholders and efficiently implement the innovation. A two-month pilot study is designed to test the feasibility of the guideline. Pain level, which is the primary outcome of the study, is measured by using Pain Numerical Pain Scale (NRS). Evaluation will be completed after the pilot test and at the end of the whole programme and refinement of the protocol will be accomplished according if necessary. Protocol effectiveness will be determined by a decrease in back pain level after practicing yoga. Other outcomes include the knowledge and satisfactory level of the staff with regards to the protocol, as well as and the costs and benefits of program implementation. / published_or_final_version / Nursing Studies / Master / Master of Nursing

Liver is one of the most important organs in the body that maintains the homeostasis of metabolism, immunity, detoxification and hematopoiesis. A large number of acute and chronic intoxications and diseases can influence the normal functions of the liver, leading to irreversible liver damage and even cancer. Currently, applying herbs or herbal derivatives in the prevention and therapy of acute and chronic liver injury receive numerous attentions since they hold great potentials as food supplements in the treatment strategy of liver injuries. There were two major hypotheses of this current work namely: a)In CCl4-inducedacute liver injury animal model, whether pre-treatment with garlic derived S-allylmercaptocysteine (SAMC)or Wolfberry derived Lycium barbarum polysaccharides (LBP)could reduce liver injury, oxidative stress and inflammation partly through a NF-κB-dependent pathway. SAMC or LBP could also promote liver regeneration after acute damage. b)In non-alcoholic steatohepatitis (NASH)-induced chronic liver injury animal model, whether administration of SAMC or LBP along with high-fat diet induction could attenuate liver injury, lipid metabolism dysfunction, fibrosis, oxidative stress, inflammation, apoptosis and transcription factors activities in the liver. In this study, SAMC and LBP were applied in a carbon tetrachloride (CCl4) induced mice acute liver injury model and a high-fat diet induced non-alcoholic steatohepatitis model. In the acute model, an eight-hour CCl4treatment induced severe acute liver injury. Pre-treatment with SAMC or LBP (1) attenuated hepatic histological injury; (2) reduced serum ALT level; (3) ameliorated oxidative stress; (4) reduced expression of inflammatory mediators and chemokines; (5) promoted liver regeneration; and (6) decreased NF-κB activity. Vehicle-treated SAMC or LBP did not exhibit obvious adverse effects on healthy mice. In the chronic NASH model, when compared with control rats, NASH rats showed typical clinical features of human NASH patients, including increased liver injury, lipid content, oxidative stress, inflammation, and apoptosis. In comparison, SAMC or LBP co-treated NASH rats showed (1) reduced fat accumulation, cellular necrosis, collagen formation, as well as reduced serum ALT and free fatty acids levels; (2) restored insulin resistance related kinase phosphorylation status which had been altered during NASH; (3) reduced pro-fibrogenic factors; (4) restored antioxidant enzymes, as well as attenuated end-products of lipid peroxidation and NO production through a cytochrome P450 2E1-dependent pathway; (5) reduced hepatic pro-inflammatory mediators and chemokines production; (6) diminished activities of nuclear transcription factors (NF-κB and AP-1); and (7) ameliorated hepatic cellular apoptosis through a p53-dependentpathwaywhich was under the regulation of LKB1/AMPK axis and PI3K/Akt axis. In conclusion, our data demonstrated that SAMC or LBP consumption protects the liver from acute injury caused by CCl4and chronic damages caused by a high-fat diet. These effects were mainly mediated by the amelioration of hepatic oxidative stress, inflammation, and cell death. In the NASH model, SAMC or LBP also improved hepatic lipid metabolism, fibrosis, and apoptosis. Therefore, the present study proposed that both garlic and Wolfberry, which are novel hepatoprotective herbal products, can be taken as part of the daily dietary supplements in the prevention of acute and chronic liver injury. / published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

Introduction: Early childhood caries (ECC) is common among Hong Kong preschool children. It is a disease caused by dental plaque bacteria and may be controlled by good toothbrushing habits. However, preschool children are often too young to perform effective tothbrushing, and therefore parental toothbrushing is recommended for them. The oral hygiene status of Hong Kong preschool children is usually not good and parental toothbrushing is not common. Fluoride varnish is effective in preventing dental caries in school children and adolescents but its effectiveness in preventing dental caries in preschool children is still inconclusive. Objective: To investigate the effectiveness of hands-on training in parental toothbrushing, with or without semi-annual applications of a 5% sodium fluoride varnish in preventing ECC. Methods: Children aged 8-23 months were recruited and randomly allocated to one of three groups: Group 1 - positive control, a brief oral health education to parents; Group 2 - oral health education to parents, hands-on training in parental toothbrushing, and home visits every six months to reinforce parental toothbrushing; Group 3 - application of a 5% sodium fluoride varnish onto the child’s teeth during home visits in addition to the intervention provided to Group 2. Clinical examination of the children and a questionnaire survey of the parents were conducted at baseline. Interventions for the children and parents were delivered according to their group assignment. Evaluation of the main outcome, development of new dental caries, was conducted after 24 months through clinical examination. Information on children’s oral health-related behaviors and parents’ knowledge of and attitude towards their child’s oral health was collected using a questionnaire at the 24-month follow-up. Results: Out of the 450 children recruited at baseline, 415 (92%) children were examined after 24 months and all examined children’s parents completed the questionnaire. Including both noncavitated and cavitated carious lesions, the incidences of ECC in Gp1 to Gp3 were 11.9%, 11.8%, and 17.5%, respectively (p > 0.05) and; the mean dmfs scores in Gp1 to Gp3 were 0.3, 0.2, and 0.4, respectively (p > 0.05). Proportions of parents who practiced parental toothbrushing twice a day were 62.7%, 60.4%, and 65.7% in Gp1, Gp2, and Gp3, respectively (p > 0.05). Results from a logistic regression analysis showed that children who were older, who had poorer oral hygiene, who had high frequency of sugary snack intake, who had visited a dentist during the study, and whose parents had lower education level would have a higher chance to develop new dental caries during the 24-month study period. Conclusion: Hands-on training in parental toothbrushing, reinforced by face-to-face interview every 6 months, with or without a semi-annual application of 5% sodium fluoride varnish, may not have any additional effect on preventing development of dental caries in young children compared to the standard oral health education provided to parents in Hong Kong. The child’s socio-demographic background, oral hygiene status, and frequency of sugary snack intake are related to ECC. / published_or_final_version / Dentistry / Doctoral / Doctor of Philosophy

Motivation Impairments of attention and memory are detectable in early psychosis, and often result in severe, longstanding functional impairments. Pharmacological interventions for cognitive impairments have been largely unsuccessful. The current study aims to explore the effects of aerobic exercise and mind-body exercise (yoga) on cognitive functioning and clinical symptoms in female patients with early psychosis. The potential neuromechanism underlying the clinical consequences was also investigated. Methods Female patients (n=120) diagnosed with schizophrenia spectrum disorders, brief psychosis, psychosis NOS, or delusional disorder (according to SCID) were recruited from three hospital/clinic sites. They were randomized into integrated yoga therapy group, aerobic exercise programme group, and waiting list as the control group. Both interventions were held three times weekly. At baseline and at 12 weeks, clinical symptoms, cognitive functions, quality of life and fitness levels were assessed in all participants, and completed structural MRI data were collected in 58 patients. Repeated measures ANOVA and ANCOVA analyses of the clinical, cognitive, quality of life and fitness data were compared between baseline and at 12 weeks among the three groups. Post-hoc Bonferroni test was used for comparing between two groups. Structural MRI data was analyzed by FreeSurfer V5.1 and Qdec V1.4 to calculate the brain volume and cortical thickness. Results Completed clinical and cognitive data were collected in 85 patients, and completed MRI imaging data of good quality were collected in 39 patients. No significant differences in age, education years, and duration of the illness at baseline were observed among the three groups. Both yoga and aerobic exercise groups demonstrated significant improvements in verbal encoding (p<0.01), short-term memory (p<0.05), long-term memory (p<0.01), and working memory (p<0.01) with moderate to large effect sizes compared to control groups. The yoga group showed significantly enhanced attention and concentration (p<0.05). Both yoga and aerobic exercise significantly improved overall clinical symptoms (p<0.05) and depressive symptoms (p<0.05) after 12 weeks. Significant increases were observed in the thickness of the left superior frontal gyrus and the right inferior frontal gyrus (pars triangularis) in the aerobic exercise group. Significant increases were observed in the volume of the postcentral gyrus and the posterior corpus callosum in the yoga group. There was a statistically significant correlation between improvements in working memory and changes in the postcentral gyrus (r=0.54, p<0.01) after controlling for the multiple comparisons with a Bonferroni adjusted alpha level. Discussion Both types of exercise improved memory in early psychosis patients, with yoga having a superior effect on attention than aerobic exercise. Observed increments in the cortical thicknesses and volume may indicate improved neurogenesis. Significance There have been few systematic clinical trial studying exercise and psychosis, and none of them has explored the effects of exercise in female patients with early stage psychosis. The present study indicates possible interventions for cognitive impairments in the patients with early psychosis, which are non-invasive and mostly safe. The application of yoga and aerobic exercise as adjunct treatments to treat psychosis in the clinical setting should be advocated. / published_or_final_version / Psychiatry / Doctoral / Doctor of Philosophy

Cancer is one of the leading causes of death worldwide. Monoclonal antibodies (mAbs) have been proved effective for cancer therapy. MAbs possess advantages over chemical drugs and small molecular drugs in cancer treatment, such as high specificity, low toxicity, effector function, long half-life in circulation system and less side effects. There are eight FDA-approved anti-cancer antibody drugs now, and many more are under development. Antibodies have two functional domains, the Fab region that is responsible for antigen recognition, and the Fc region that couples the antibody to immune effector pathways. Fab-mediated interference with cancer cell signalling may lead to growth inhibition and direct cell death, while Fc-mediated effector function through interactions with Fc-gamma receptors (FcrRs) expressed in immune cells or through complement cascades may lead to target cell cytotoxicity. Antibody engineering to increase the binding affinity and effector function may improve antibody in vivo efficacy. Anti-Her2 mAb herceptin (trastuzumab) is effective in treatment of Her2-overexpressing breast cancer patients. However, only 25–30% of patients with Her2-overexpressing tumors respond to single agent trastuzumab, and drug resistance develops even in responding patients. Accumulating evidence showed that cross-talk between Her2 and the insulin-like growth factor receptor type I (IGF-IR), including receptor heterodimerization and transactivation, and elevated IGF-IR signalling have been associated with trastuzumab resistance. Therefore, we hypothesized that dual specific antibodies co-targeting both IGF-IR and Her2 may prevent or delay the emergence of resistance to mono-specific antibodies. Mouse monoclonal antibody, M590 showed very good binding activity to IGF-IR. By engineering the CH3 domain of human Fc in pDR12 plasmid, we developed a “knobs-into-holes” hybrid IgG expression system, and successfully produced M590-Herceptin bi-specific IgG, which showed high binding avidity for both antigens and preserved antibody-dependent cell-mediated cytotoxicity (ADCC), a main route of immune protections conferred by therapeutic antibodies in vivo. M590-Herceptin dual specific antibody inhibited breast cancer and ovarian cancer cell proliferation in vitro, and inhibited cancer growth in a SKOV-3 Her2- and IGF-IR-overexpressing ovarian cancer xenograft mouse model. M590-Herceptin hybrid showed better anti-cancer activity compared with M590 and Herceptin alone, or in combination. Meantime, I also constructed a phage display antibody Fab library using the mRNA of rabbits immunized by membrane proteins of SKOV-3 cells, and isolated a novel anti-Her2 mAb, designated as 1C6. Results from in vitro assays showed that 1C6 had anti-cancer activity which was comparable to that of herceptin. M590-1C6 hybrid IgG was also constructed, and the results from in vitro assays and mouse study showed that M590-1C6 hybrid IgG also possess better inhibitory activity of Her2 positive tumours compared with m590 or 1C6 alone. In summary, this study indicates that bi-specific antibodies co-targeting two elevated cancer receptors are more effective than mono-specific antibodies for cancer therapy. / published_or_final_version / Microbiology / Doctoral / Doctor of Philosophy

Glaucoma is a neurodegenerative disease and one of the major causes of blindness in the world. Secondary degeneration is involved in glaucoma. The retinal ganglion cells (RGCs) which are vulnerable to secondary degeneration in glaucoma are the promising target population for therapeutic intervention. Partial optic nerve transection (PONT) model has been established in the last decade. Primary and secondary degeneration can be separated in different regions of retinas in this model. Therefore, PONT is a good model for the study of mechanisms of secondary degeneration and the drug screening for secondary degeneration. Lycium barbarum (L. barbarum) has been shown to be neuroprotective for cortical neurons in vitro. It has also been shown that L. barbarum could delay RGCs death in a rat ocular hypertension model. In order to further investigate the effects of L. barbarum for RGCs, two models, complete optic nerve transaction (CONT) model and PONT model, were employed in my study. My results showed that the polysaccharide extract from L. barbarum (LBP) could partly prevent RGCs from death in the inferior retinas 4 weeks after PONT whereas it could not reduce the loss of RGCs after CONT. The1,1'-dioctadecyl-3, 3, 3’, 3’-tetramethylindocarbocyanine perchlorate(DiI) labeling of RGCs whose axons were transected showed that the majority of labeled cell bodies existed in the superior retinas. The result meant that more cell bodies in the superior retinas would die from primary degeneration than in the inferior retina after PONT. Therefore my results indicated that LBP protected RGCs which would die from secondary degeneration rather than primary degeneration. The results of Terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) staining showed that RGCs underwent apoptosis 1 week after PONT. Western-blot analysis demonstrated that oxidative stress was involved in the degeneration of RGCs after PONT. Furthermore, c-Jun N-terminal kinases (JNKs) pathway was activated which was indicated by an increase ofphospho-JNK2/3(p-JNK2/3)and phospho-c-jun(p-c-jun). Our results also revealed that orally feeding of LBP could increase the expression of manganese superoxide dismutase (MnSOD) and insulin growth factor-1 (IGF-1)and decrease the expression of p-JNK2/3 and p-c-jun. The results from optic nerve (ON) study showed that glial cells, including astrocytes and microglias/macrophages, were activated after PONT. Oxidative stress and inflammation were involved in the process. Secondary degeneration of ON was not obvious and LBP exerted no protective effects on the survival of axons in the ON. The multifocal electroretinography (mfERG) study showed that both the functions of inner retinas and outer retinas were damaged after PONT. The results indicated that other cell types or the synapses between different cell types were damaged in addition to RGCs. LBP could improve the function of the whole retinas, including both inner retinas and outer retinas after PONT. In conclusion, our results indicated that LBP protected RGCs from secondary degeneration via inhibiting oxidative stress and the activation of JNK pathway.LBP could also improve the function of both inner retinas and outer retinas after PONT. / published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

Ischemic stroke is a leading cause of disability and death around the world. Higher concentration of glutamate following ischemic stroke is a factor leading to cell death, including neural stem cell death. Up to now no effective treatments of ischemic stroke are available. Notoginsenoside R1 (Noto R1) is the main component of Panax notoginseng, which is a traditional Chinese medicine for the treatment of cardiovascular disease. Its protective effects on the neural cell were noted recently. The main purpose of this experimental study was to investigate the mechanism of Noto R1 against glutamate neurotoxicity on primary cultured mouse cortical neural stem cells in vitro, and its effects on ischemic stroke on mice brain in vivo. In the in vitro part, primary culture of neural stem cells was prepared from 12.5-day-old C57BL/6N mice embryos cortex. Neural stem cells were confirmed by nestin-staining and differentiation study afterwards. Then neural stem cells were incubated with Noto R1 and glutamate for 24 hours. Cells were fixed for TUNEL staining and caspase-3 staining. Protein was collected for western blot for Bax, Bcl-2, phos-AKT, JNK/SAPK, and phospho-p38 MAPK. Results showed that glutamate has cytotoxicity in a dose-dependent manner on neural stem cells. Noto R1 showed remarkable neuro-protective effects on neural stem cells exposed to excessive glutamate by higher viability. Noto R1 significantly reduced caspase-3 expression and TUNEL-positive cells. Furthermore, Noto R1 increased the protein expression of Bcl-2 and phospho-AKT, and reduced Bax expression. Moreover apoptosis pathway study showed phospho-p38 expression was suppressed in the Noto R1 group. In the in vivo part, Noto R1 was administrated systemically to mice of MCAo followed by reperfusion. Behavior score and viability rate were assessed before sacrifice. TTC staining was performed for evaluating infarct area, volume and edema. H&E staining was applied for histological examination. TUNEL staining, IHC staining of Nestin, AQP4 and GFAP were performed. In the first part of Noto R1 of 40 mg/kg or PBS was injected into venous at the onset of blood vessel occlusion for 2 hours, and then followed by 22 hours of reperfusion. Results were all negative. In the second part, Noto R1 was injected intra-peritoneum for 10 days prior to MCAo which lasted for 1 hour 50 minutes, then reperfusion was allowed for 22 hours. Results showed Noto R1 improved behavior score and viability rate. Meanwhile Noto R1 significantly reduced ischemic area, volume and edema percentage. Moreover TUNEL-positive cells in the affected cortex were significantly decreased. Nestin-positive cell in the striatum were significantly increased in the Noto R1 group, and immunoactivity of AQP4 and GFAP was apparently decrease with Noto R1 treatment. In conclusion, this study showed that Noto R1 protected cultured neural stem cells against glutamate neurotoxicity in vitro via p38 MAPK pathway by inhibiting Bax protein expression and enhancing protein expression of Bcl-2 and phospho-AKT. Moreover, it also demonstrated significant preventive effects against ischemic stroke with mice model in vivo. In a word Noto R1 presents a highly potential candidate preventing ischemic stroke clinically in the future. / published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy