Thesis (Ph. D.)--University of Queensland, 2002. / Includes bibliographical references.

Stroke is a serious cerebral vascular event and a leading cause of death and disability worldwide, and ischemic stroke is the most common type. Evidence from animal research in acute cerebral ischemia shows that a combination of neuroprotectants might be more efficacious than the single agent given individually. Both melatonin and electro-acupuncture (EA) have been suggested to be effective treatments against cerebral ischemia. However, it is unknown whether a combination of these two therapies could be beneficial against focal cerebral ischemia. In the first study, the effect of post-treatment with a combination of melatonin and EA on regional cerebral blood flow (rCBF), neurological deficit score and infarct volume was investigated in both permanent and transient middle cerebral artery occlusion (MCAO) models in rats. When compared with the single treatment of melatonin or EA, the combination therapy resulted in a significant improvement of neurological function and a dramatic reduction of infarct volume at 72 hr after transient MCAO. A significant upregulatory effect on rCBF has been exerted by the combined treatment. The effect of a combination of melatonin and EA on inflammatory reaction was investigated in the second study. Post-treatment of the combination therapy effectively inhibited neutrophil infiltration as well as the expression of some pro-inflammatory mediators, and increased the anti-inflammatory protein expression at 72 hr after transient MCAO. This beneficial effect may be due to the respective anti-inflammatory effects of melatonin and EA. In the third study, the effect of a combination of melatonin and EA on apoptosis was examined. When compared with the EA treatment alone, post-treatment of the combination therapy exerted a greater inhibitory effect on tissue apoptosis and expression of the pro-apoptotic proteins as well as an upregulatory effect on the anti-apoptotic protein expression. In the fourth study, the effect of continuous post-treatment of a combination of melatonin and EA on transient MCAO was investigated. The combination treatment significantly improved neurological function and decreased infarct volume at 7 days after transient MCAO. Cell proliferation and expression of the neurotrophic factor were increased by the combined treatment. The effect of pretreatment with a combination of melatonin and EA was examined in the fifth study. Neurological function was improved and infarct volume was reduced by the combination pretreatment at 24 hr after transient MCAO. The inflammatory and apoptotic reaction were inhibited by the combined pretreatment through the modulatory effect of the related proteins. In summary, our results show that, when compared with the single treatment of either melatonin or EA, post-treatment with a combination of melatonin and EA induced a complementary neuroprotective effect on improvement of neurological function and a dramatic reduction of infarct volume after transient MCAO. The complementary protection may be partially mediated via anti-inflammation and anti-apoptosis after transient cerebral ischemia. Pretreatment with a combination of melatonin and EA may be more effective in preventing ischemic brain injury after transient focal cerebral ischemia. / published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

Thesis (M.S.)--University of Hawaii at Manoa, 2007. / Includes bibliographical references (leaves 13-17). / vii, 17 leaves, bound ill. 29 cm

Thesis (M.S.)--University of Hawaii at Manoa, 2007. / Includes bibliographical references (leaves 40-51). / ix, 51 leaves, bound ill. (some col.) 29 cm

Thesis (doctoral)--Lund University, 1996. / Added t.p. with thesis statement inserted.

Thesis (doctoral)--Lund University, 1996. / Added t.p. with thesis statement inserted.

Thesis (M.Sc.)--Memorial University of Newfoundland, 2002. / Bibliography: leaves 72-92.

Thesis (Ph.D.)--Memorial University of Newfoundland, 2004. / Bibliography: leaves 140-153.

Global cerebral ischemia is an established animal model mimicking the effects of cardiac arrest in humans. It is characterized by selective neuronal damage in the hippocampus and significant behavioural and cognitive impairments. In this light, novel therapeutic compounds with numerous physiological targets as well as neuroprotective capabilities and the capacity to lessen residual cognitive deficits pose as great candidates in the treatment of ischemic pathology. The current thesis investigates the possible therapeutic properties of resveratrol (3, 4, 5´trihydroxystilbene), a naturally occurring phytoalexin present in the skin of grapes, against cerebral ischemia-induced neuronal degeneration and cognitive impairments, as well as elaborate on possible mechanisms of action of the compound in male Wistar rats. In Article 1, neuronal density assessment and behavioural testing following chronic pretreatment with resveratrol at two doses (1 and 10 mg/kg) revealed that the compound has important neuroprotective properties at short and long post-ischemic intervals. Despite comparable neuronal protection, the two resveratrol doses showed distinct behavioural effects, highlighting independent actions of the polyphenol on discrete physiological systems mediating cellular survival and behavioural recovery. Articles 2 and 3 investigated possible mechanisms of action of the polyphenol that have not yet been explored with regards to cerebral ischemia. Specifically, Article 2 demonstrated that resveratrol influences markers of plasticity in both ischemic and control animals as well as promotes angiogenesis in the hippocampal region postischemia. Further elaborating on documented effects attributing non-neuronal mechanisms of action of resveratrol in reducing glial activation postischemia, Article 3 highlighted important regulatory effects of resveratrol on mediating glial type-1 glutamate transporter expression at a short reperfusion interval. These findings support the notion of multiple biological targets by resveratrol and highlight its potential role in attenuating forebrain ischemia-induced neuronal degeneration through multiple physiological targets, while cautioning against possible dose-related effects on behaviour and in healthy controls.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第25006号 / 医博第5040号 / 新制||医||1070(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 高橋 淳, 教授 荒川 芳輝, 教授 林 康紀 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM