- 學位論文
探討牛磺酸減緩D-半乳糖造成之認知學習能力障礙與腦中氧化壓力
Effects of taurine on cognitive dysfunction and oxidative damage in the brain of D-galactose treated mice
摘要
世界人口持續增加同時老化人口比例亦隨之提升，失智症好發於老齡人口，進而影響記憶、思考、行為與日常生活能力。然而目前尚無有效的治療方式，但可以減緩症狀的方式來延長生命，因此預防及延緩失智症的發生越顯重要。 本研究目標為探討牛磺酸(taurine)在D-半乳糖(D-galactose)誘導小鼠老化模式下其改善認知學習能力與抗發炎之功效。使用45隻十二週齡雄性ICR小鼠隨機分為五組：(1)控制組(CON)：管灌蒸餾水+皮下注射生理食鹽水；(2) D-半乳糖處理組(DG)：管灌蒸餾水+皮下注射100 mg D-galactose/kg body weight (BW) day；(3) D-半乳糖處理補充低劑量牛磺酸組(DG_LT)：管灌100 mg taurine/kg BW day+皮下注射100 mg D-galactose/kg BW day；(4) D-半乳糖處理補充高劑量牛磺酸組(DG_HT)：管灌400 mg taurine/kg BW day+皮下注射100 mg D-galactose/kg BW day；(5) D-半乳糖處理補充胺胍(aminoguanidine)組(DG_AG)：管灌50 mg aminoguanidine/kg BW day+皮下注射100 mg D-galactose/kg BW day，進行實驗同時記錄小鼠採食量與體重變化，並於第九週進行行為試驗後犧牲採取其血清與腦(包含海馬迴與部分大腦皮質)進行分析。 在動物記憶學習試驗之結果顯示，D-半乳糖誘導下補充牛磺酸與胺胍之組別可縮短參考記憶試驗的搜尋時間(p<0.05)，且補充牛磺酸之組別更可在空間性探測試驗中延長於目標象限的搜尋時間(p<0.05)。由腦海馬迴切片中，可以看到DG組在齒狀迴區域有較多之細胞皺縮且細胞排列鬆散邊緣模糊，而補充牛磺酸與胺胍組別則皆有改善的現象。在腦中氧化壓力與抗氧能力之分析中，DG_HT之組別其小鼠腦中TBARS值顯著低於DG組(p<0.05)，抗氧化物質GSH含量則顯著高於DG組且在胺胍組有一樣的效果(p<0.05)。相較於DG組不論補充牛磺酸與胺胍之組別都可以顯著提升腦中抗氧化酵素超氧歧化酶、麩胱甘肽過氧化酶之活性(p<0.05)。在D-半乳糖誘導下補充牛磺酸不僅可減少腦中糖化終產物(advanced glycation end products, AGEs)之含量(p<0.05)，亦對AGEs下游發炎相關基因表現(Nox2、Nfκb、Il-1β、Il-6、Tnfα及Cox2)具調降作用(p<0.05)；此外對促細胞凋亡基因表現(Bax及Casp3)具調降作用(p<0.05)並具提升抑細胞凋亡基因(Bcl-2及Bcl-xL)之表現(p<0.05)。DG組之Cd11b與Gfap表現量皆顯著高於CON組(p<0.05)，而不論牛磺酸補充組或是DG_AG組皆顯著減少神經膠細胞活化標幟之表現(p<0.05)。 綜觀上述研究成果，牛磺酸可藉由調節抗氧化能力、抑制細胞凋亡與抗發炎來減少神經膠細胞之活化同時改善D-半乳糖誘發老化小鼠模式下之認知行為障礙。
並列摘要
The proportion of Taiwan elders is expected to rise up sharply, and hence, the geriatric diseases, i.e. dementia, are attracted an attention nowadays. Until now, there have not been effective therapeutics that can stop or reverse clinical progressions of dementia but some attenuated treatments. The D-galacotse treated model is generally used in pharmacological studies for aging studies. This study was to investigate if taurine could attenuate cognitive deficits and decrease oxidative stress/damage in brain of D-galactose treated mice. Forty-five 12 week-old-male ICR mice were used in the experiment and divided randomly into five groups: (i) Control group (CON): 0.3 ml of saline and 0.2 ml distilled water, (ii) D-galactose treated group (DG): 100 mg D-galactose/kg BW day, (iii) DG_LT: 100 mg D-galactose/kg BW day and 100 mg taurine/kg BW day, (iv) DG_HT: 100 mg D-galactose/kg BW day and 400 mg taurine/kg BW day and (v) DG_AG: 100 mg D-galactose/kg BW day and 50 mg aminoguanidine/kg BW day for 9 weeks. Saline and D-galactose were provided daily by subcutaneous injection on the back, respectively, while distilled water, taurine, and aminoguanidine were treated daily by an oral gavage. Results showed that D-galactose treated mice cotreated with taurine spent less searching time in the reference memory test than those without taurine (p<0.05), and taurine administration also extended the staying period around the target quadrant in the probe test (p<0.05). By an H&E staining, neuronal degeneration and nucleus shrinkage in hippocampus dentate gyrus area were also observed in D-galactose treated mice, but those were attenuated by taurine supplementation. The gene expressions of glial fibrillary acidic protein (Gfap) and cluster of differentiation marker Cd11b which related to brain damage were upregulated in D-galactose treated groups, but downregulated by taurine supplementation (p<0.05). Besides, taurine administration enhanced the antioxidant capacity in both of brain and sera (p<0.05). Moreover, the protective mechanism probably resulted from downregulating (p<0.05) inflammatory and upregulating (p<0.05) anti-apoptosis genes. Western blotting analyses also showed that a deposition of AGEs was significantly increased in DG group, whereas taurine supplementation could significantly prevent accumulation of AGEs in brain (p<0.05). Taken together, taurine shows preventive effects on the development of cognitive dysfunctions induced by D-galactose.
並列關鍵字
aging ； hippocampus ； D-galactose ； taurine ； reference memory test ； antioxidative capacity ； antiinflammation參考文獻
延伸閱讀
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