Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, United States.
Department of Anesthesiology, University of Illinois, Chicago, IL 60614, United States; Jesse Brown VA Medical Center, Chicago, IL 60614, United States.
Brain Res. 2019 Jan 1;1702:29-37. doi: 10.1016/j.brainres.2017.12.028. Epub 2017 Dec 21.
Damage to noradrenergic neurons in the Locus coeruleus (LC) occurs contributes to neuropathology and behavioral deficits in Alzheimer's disease (AD); methods to reduce LC damage may therefore be of benefit. We previously showed that vindeburnol, a derivative of the plant alkaloid vincamine, reduced neuroinflammation, amyloid burden, and LC damage in a mouse model of AD; however, effects on behavior were not tested. We now tested the effects of vindeburnol on anxiety-like behavior in 5xFAD mice which develop robust amyloid burden at early ages. During novel object recognition testing, we observed that 5xFAD mice spent more time exploring than wildtype littermates, and that time was reduced by vindeburnol. Vindeburnol also reduced hyperlocomotion in the 5xFAD mice which may have contributed to their increased exploration times. In an open field test, vindeburnol normalized the increase of time spent in the center, and the decrease of time spent near the walls in 5xFAD mice. Vindeburnol reduced amyloid burden in the hippocampus and cortex, areas that contribute to regulation of anxiety-like behavior. In vitro, vindeburnol increased neuronal BDNF expression in a cAMP-dependent manner; and inhibited phosphodiesterase activity with an EC near 50 μM. These findings suggest that cAMP-mediated increases in neurotrophic factors contribute to beneficial effects of vindeburnol within the context of LC damage, which may be of value for treatment of some neuropsychiatric symptoms of AD.
蓝斑（LC）去甲肾上腺素能神经元损伤导致阿尔茨海默病（AD）的神经病理学和行为缺陷；因此，减少 LC 损伤的方法可能是有益的。我们之前曾表明，vin-deburnol 是 vincamine 植物生物碱的衍生物，可减少 AD 小鼠模型中的神经炎症、淀粉样蛋白负担和 LC 损伤；然而，尚未测试其对行为的影响。我们现在测试了 vindeburnol 对 5xFAD 小鼠焦虑样行为的影响，5xFAD 小鼠在早期就会出现明显的淀粉样蛋白负担。在新物体识别测试中，我们观察到 5xFAD 小鼠比野生型同窝仔鼠花费更多的时间探索，而 vindeburnol 减少了它们的探索时间。Vindeburnol 还减少了 5xFAD 小鼠的过度活动，这可能导致它们的探索时间增加。在开放场测试中，vindeburnol 使 5xFAD 小鼠在中央区域花费的时间增加和靠近墙壁区域花费的时间减少恢复正常。Vindeburnol 减少了海马体和皮质中的淀粉样蛋白负担，这些区域有助于调节焦虑样行为。体外实验中，vindeburnol 以 cAMP 依赖的方式增加神经元 BDNF 表达；并以接近 50 μM 的 EC 抑制磷酸二酯酶活性。这些发现表明，cAMP 介导的神经营养因子增加可能有助于 vindeburnol 在 LC 损伤背景下的有益作用，这对于治疗 AD 的某些神经精神症状可能具有价值。
