Jansone Baiba, Kadish Inga, van Groen Thomas, Beitnere Ulrika, Plotniece Aiva, Pajuste Karlis, Klusa Vija
Department of Pharmacology, Faculty of Medicine, University of Latvia, Riga, Latvia.
Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA.
Pharmacol Res. 2016 Nov;113(Pt B):781-787. doi: 10.1016/j.phrs.2016.06.020. Epub 2016 Jun 21.
The prevalence of Alzheimer's disease (AD) is higher in females than in males, and causes more severe cognitive, memory and behavioral impairments. Previously, in male transgenic (Tg) APPSweDI mice, we reported that the novel lipophilic 1,4-dihydropyridine (DHP) derivative AP-12 crossed the blood-brain barrier, blocked neuronal and vascular calcium channels, changed brain protein expression and improved behavior. In this study, we used female Tg APPSweDI mice to assess the effects of AP-12 on behavior, and brain protein expression, with a particular focus on those of the GABAergic system. The results showed that in female Tg mice, similar to male Tg mice, AP-12 improved spatial learning/memory performance in the water maze test and demonstrated anxiolytic effect in the elevated zero maze (after single administration of AP-12) and elevated plus maze (after chronic injections of AP-12). In addition, we demonstrated upregulated expression of glutamate decarboxylase 67 (GAD67) and vesicular GABA transporter (VGAT) in the cingulate cortex and hippocampus, pointing to the role of the GABAergic system as one of the neural networks dysregulated in AD. In both female and male mice, AP-12 did not change the expression of hippocampal Homer-1, a protein which is involved in synaptic plasticity. However, in cingulate cortex, the staining density of Homer-1 was significantly increased in female mice. Further, female mice (similar to male mice) did not show changes in brain AChE expression and in the amyloid beta load in the hippocampus and cingulate cortex. In conclusion, the memory enhancing, anxiolytic and protein expression effects of AP-12 did not show sex specificity in APPSweDI mice. Considering the ability of AP-12 to block brain calcium channels and improve memory by enhancing the GABAergic and synaptic plasticity processes, AP-12 is a promising compound which merits further pre-clinical studies to investigate its usefulness in the treatment of AD.
阿尔茨海默病（AD）在女性中的患病率高于男性，且会导致更严重的认知、记忆和行为障碍。此前，在雄性转基因（Tg）APPSweDI小鼠中，我们报告称新型亲脂性1,4 - 二氢吡啶（DHP）衍生物AP - 12可穿越血脑屏障，阻断神经元和血管钙通道，改变脑蛋白表达并改善行为。在本研究中，我们使用雌性Tg APPSweDI小鼠来评估AP - 12对行为和脑蛋白表达的影响，特别关注γ-氨基丁酸能（GABAergic）系统的影响。结果表明，在雌性Tg小鼠中，与雄性Tg小鼠类似，AP - 12在水迷宫试验中改善了空间学习/记忆能力，并在高架零迷宫（单次给予AP - 12后）和高架十字迷宫（长期注射AP - 12后）中表现出抗焦虑作用。此外，我们证明了扣带回皮质和海马中谷氨酸脱羧酶67（GAD67）和囊泡GABA转运体（VGAT）的表达上调，表明GABAergic系统作为AD中失调的神经网络之一所起的作用。在雌性和雄性小鼠中，AP - 12均未改变海马中参与突触可塑性的蛋白Homer - 1的表达。然而，在扣带回皮质中，雌性小鼠中Homer - 1的染色密度显著增加。此外，雌性小鼠（与雄性小鼠类似）在脑乙酰胆碱酯酶（AChE）表达以及海马和扣带回皮质中的淀粉样β负荷方面未显示出变化。总之，AP - 12的记忆增强、抗焦虑和蛋白表达作用在APPSweDI小鼠中未表现出性别特异性。鉴于AP - 12能够阻断脑钙通道并通过增强GABAergic和突触可塑性过程来改善记忆，AP - 12是一种有前景的化合物，值得进一步进行临床前研究以探究其在AD治疗中的效用。
