Levin Robert M, Schuler Catherine, Leggett Robert E, Hass Martha A
Stratton Va Medical Center, Albany, NY, USA.
Albany College of Pharmacy and Health Services, Albany, NY, USA.
Turk J Urol. 2018 Dec 20;45(4):289-295. doi: 10.5152/tud.2018.48154. Print 2019 Jul.
Obstructive bladder dysfunction (OBD) caused by benign prostatic hyperplasia is a common medical problem in ageing men. As the prostate enlarges and compresses the urethra, the bladder wall thickness and the bladder is termed "compensated" because its function is still relatively normal. Subsequently, bladder function begins to fail and this change is termed "decompensation." The extent of decompensation progresses from mild through severe. Bladder decompensation is mediated by cyclical ischemia followed by reperfusion (I/R) resulting in an increased generation of free radicals and oxidative stress. Previous studies demonstrated that both vitamin E (tocopherol) and alpha-lipoic acid (LA) showed significant antioxidant activity in experimental urinary bladder oxidative stress models. We hypothesized that co-drugs derived from these antioxidants would result in enhanced antioxidant activity relative to either individual compound for the treatment of oxidative stress in the lower urinary tract.
Two ester co-drugs of TOC and LA, tocopherol ester (α-TOCE) and δ-TOCE were synthesized. Six adult male New Zealand White (NZW) rabbits were divided into two groups of three rabbits each. Eight full thickness strips from each rabbit bladder were taken for in vitro I/R experiments. The strips from the first set were control rabbits (24 strips). Six strips were not incubated, while the remaining strips were incubated in α-TOCE dissolved in 1% (n=6) or 2.5% ethanol (n=6) solutions. These strips were not subjected to in vitro I/R. The strips from the second set were processed as follows: 6 strips were not incubated, while the remaining strips were incubated in α-TOCE dissolved in 1% (n=6) or in δ-TOCE dissolved in 2.5% ethanol. These strips were subjected to 1 hour in vitro ischemia followed by two hours reperfusion.
Preliminary studies demonstrated that neither antioxidant had any effect on the contractile responses to 1% or 2.5% ethanol. Neither antioxidant had any effect on the control contractile responses. Both antioxidants protected the tissue from the initial effects of ischemia. Both antioxidants had significant protective effects on the contractile responses to all forms of stimulation after the reperfusion period.
Incubation with both antioxidants had similar protective effects on responses both to ischemia and to reperfusion.
良性前列腺增生引起的梗阻性膀胱功能障碍（OBD）是老年男性常见的医学问题。随着前列腺增大并压迫尿道，膀胱壁厚度增加，此时膀胱被称为“代偿性”，因为其功能仍相对正常。随后，膀胱功能开始衰退，这种变化被称为“失代偿”。失代偿程度从轻到重逐渐发展。膀胱失代偿是由周期性缺血后再灌注（I/R）介导的，这会导致自由基生成增加和氧化应激。先前的研究表明，维生素E（生育酚）和α-硫辛酸（LA）在实验性膀胱氧化应激模型中均表现出显著的抗氧化活性。我们假设，相对于单独的化合物，由这些抗氧化剂衍生的联合药物在治疗下尿路氧化应激方面会具有增强的抗氧化活性。
合成了生育酚（TOC）和LA的两种酯类联合药物，生育酚酯（α-TOCE）和δ-TOCE。将6只成年雄性新西兰白兔分为两组，每组3只。从每只兔膀胱取8条全层组织条用于体外I/R实验。第一组的组织条为对照兔（24条）。6条未孵育，其余组织条在溶解于1%（n = 6）或2.5%乙醇（n = 6）溶液中的α-TOCE中孵育。这些组织条未进行体外I/R处理。第二组的组织条处理如下：6条未孵育，其余组织条在溶解于1%乙醇的α-TOCE（n = 6）或溶解于2.5%乙醇的δ-TOCE中孵育。这些组织条先进行1小时体外缺血，然后再灌注2小时。
初步研究表明，两种抗氧化剂对1%或2.5%乙醇的收缩反应均无影响。两种抗氧化剂对对照收缩反应均无影响。两种抗氧化剂均保护组织免受缺血的初始影响。两种抗氧化剂在再灌注期后对所有形式刺激的收缩反应均有显著保护作用。
两种抗氧化剂孵育对缺血和再灌注反应均有相似的保护作用。
