Department of Chemistry, University College London, London, UK.
Inflamm Res. 2010 Mar;59 Suppl 2:S231-3. doi: 10.1007/s00011-009-0136-1.
The effects of the endogenous antioxidant alpha-lipoic acid on guinea pig colon smooth muscle contraction (Gpcc) induced by hydrogen peroxide were examined. Having previously shown that the histone deacetylase (HDAC) benzamide inhibitor MGCD0103 inhibits guinea-pig smooth muscle contraction, as do various sulfur-containing antioxidants, we asked whether hybrid compounds possessing both alpha-lipoic acid-derived antioxidant properties and HDAC inhibitory activity could inhibit Gpcc.
Guinea pig colon (Gpc) was incubated at 37 degrees C with Krebs buffer; the four stimulants-hydrogen peroxide, carbachol, histamine, and sodium fluoride-were added independently. The response to each stimulant alone was compared with that in the presence of each of the test compounds: MGCD0103, alpha-lipoic acid, and two of their hybrids, UCL M084 and UCL M109.
NaF (10 mM), carbachol (0.05 microM), histamine (0.1 microM), and hydrogen peroxide (1 microM) produced Gpcc of about 50-60% above basal level. With the exception of MGCD0103 against hydrogen peroxide, all four test compounds at 1 microM-MGCD0103, alpha-lipoic acid, UCL M084, and UCL M109-produced a significant inhibition of 35-60% of Gpcc induced by hydrogen peroxide, NaF, and carbachol, although none reduced histamine or ovalbumin-induced Gpcc. Benzalkonium chloride (Bcl), a G-protein inhibitor, reduced the hydrogen peroxide-induced Gpcc by 35%.
Contraction by stimulants used to induce Gpcc is known to involve G-proteins. All four test compounds-MGCD0103, alpha-lipoic acid and two of their hybrids, UCL M084 and UCL M109-reduced Gpcc induced by NaF and carbachol, suggesting that G-protein pathway involvement is relevant to the action of the test compounds, as is also indicated by the Bcl-induced inhibition of hydrogen peroxide-induced contractions. Additionally, alpha-lipoic acid and the two hybrids showed >30% inhibition of hydrogen peroxide-induced contractions, consistent with the antioxidant properties of the 1,2-dithiolane ring.
研究内源性抗氧化剂 α-硫辛酸对过氧化氢诱导的豚鼠结肠平滑肌收缩（Gpcc）的影响。先前的研究表明，组蛋白去乙酰化酶（HDAC）苯甲酰胺抑制剂 MGCD0103 以及各种含硫抗氧化剂均能抑制豚鼠平滑肌收缩，我们想知道是否具有 α-硫辛酸衍生的抗氧化特性和 HDAC 抑制活性的混合化合物能够抑制 Gpcc。
将豚鼠结肠（Gpc）在 37°C 下用 Krebs 缓冲液孵育；分别加入四种刺激物-过氧化氢、卡巴胆碱、组胺和氟化钠。将每种刺激物单独作用的反应与每种测试化合物存在时的反应进行比较：MGCD0103、α-硫辛酸以及它们的两种混合物 UCL M084 和 UCL M109。
NaF（10mM）、卡巴胆碱（0.05μM）、组胺（0.1μM）和过氧化氢（1μM）使 Gpcc 增加约 50-60%，高于基础水平。除了 MGCD0103 对过氧化氢的作用外，所有四种测试化合物（MGCD0103、α-硫辛酸、UCL M084 和 UCL M109）在 1μM 浓度下均能显著抑制由过氧化氢、NaF 和卡巴胆碱诱导的 35-60%的 Gpcc，但没有一种化合物能降低组胺或卵清蛋白诱导的 Gpcc。G 蛋白抑制剂苯扎氯铵（Bcl）可使过氧化氢诱导的 Gpcc 减少 35%。
已知用于诱导 Gpcc 的刺激物引起的收缩涉及 G 蛋白。所有四种测试化合物-MGCD0103、α-硫辛酸及其两种混合物 UCL M084 和 UCL M109-均能降低由 NaF 和卡巴胆碱诱导的 Gpcc，这表明 G 蛋白途径的参与与测试化合物的作用有关，这也表明 Bcl 诱导的抑制作用对过氧化氢诱导的收缩是有效的。此外，α-硫辛酸和两种混合物对过氧化氢诱导的收缩抑制率超过 30%，这与 1,2-二硫戊环的抗氧化特性一致。
