School of Pharmacy and Biomolecular Sciences, University of Brighton, Moulsecoomb, Brighton BN2 4GJ, UK.
School of Pharmacy and Biomolecular Sciences, University of Brighton, Moulsecoomb, Brighton BN2 4GJ, UK.
Neuropeptides. 2019 Oct;77:101931. doi: 10.1016/j.npep.2019.05.002. Epub 2019 May 3.
Angiotensin IV (ang IV) is known to improve learning and memory in animal models but the mechanism is unclear. We have previously demonstrated sex differences in the pro-cognitive effects of ang IV, and that prenatal alcohol exposure (PAE) abolishes these effects. This study aimed to explore a possible mechanism underlying the sex differences and the effects of PAE in male mice. Mouse breeding harems received 5% ethanol in drinking water throughout pregnancy and lactation in a two-bottle schedule. The effects of ang IV were assessed in offspring at 4 months of age using the open field test, novel object recognition test and elevated plus maze. Aminopeptidase activity of brain insulin-regulated aminopeptidase (IRAP), a putative target of ang IV, was determined. As seen in a previous similar study, ang IV administered immediately after the second training trial significantly improved novel object recognition 24 h later in male mice but not female. PAE abolished this pro-cognitive effect in males. PAE also increased anxiety-like behaviour in male but not female offspring. Ang IV decreased the aminopeptidase activity of brain IRAP in control male, but not female, mice; PAE abolished this inhibitory effect. Ang IV improved memory consolidation in male but not female mice and PAE abolished this effect in the males. While the effects of PAE may be related to increased anxiety; ang IV decreased the aminopeptidase activity in male but not female mice and PAE abolished this inhibitory effect. The results therefore suggest that improvements in learning and memory induced by peripheral administration of ang IV correlate with a reduction of the enzyme activity of IRAP. This is the first demonstration that ang IV administered peripherally can induce long-term (24 h) changes in IRAP function which are probably not simple competitive inhibition and the first demonstration that PAE alters IRAP activity.
血管紧张素 IV（ang IV）已知可改善动物模型的学习和记忆，但机制尚不清楚。我们之前已经证明了 ang IV 在认知方面的促效作用存在性别差异，而产前酒精暴露（PAE）会消除这些作用。本研究旨在探索雄性小鼠中 ang IV 促效作用性别差异和 PAE 作用的可能机制。在母鼠妊娠和哺乳期，通过双瓶饮水方案，让繁殖 harems 一直饮用 5%乙醇。在 4 个月大的幼鼠中，通过旷场试验、新物体识别试验和高架十字迷宫评估 ang IV 的作用。测定脑胰岛素调节氨基肽酶（IRAP）的氨基肽酶活性，IRAP 是 ang IV 的一个假定靶点。如先前类似的研究所示，在雄性小鼠中，ang IV 在第二次训练后立即给药，可显著改善 24 小时后的新物体识别，但对雌性小鼠没有影响。PAE 消除了这种认知促进作用。PAE 还增加了雄性但不是雌性幼鼠的焦虑样行为。ang IV 降低了对照组雄性小鼠脑 IRAP 的氨基肽酶活性，但对雌性小鼠没有影响；PAE 消除了这种抑制作用。ang IV 改善了雄性但不是雌性小鼠的记忆巩固，而 PAE 消除了雄性小鼠的这种作用。虽然 PAE 的作用可能与焦虑增加有关；ang IV 降低了雄性但不是雌性小鼠脑 IRAP 的氨基肽酶活性，而 PAE 消除了这种抑制作用。因此，结果表明，外周给予 ang IV 可改善学习和记忆，与降低 IRAP 的酶活性相关。这是首次证明外周给予 ang IV 可诱导 IRAP 功能的长期（24 小时）变化，这可能不仅仅是简单的竞争性抑制，也是首次证明 PAE 改变了 IRAP 活性。
