Esteban Gerard, Van Schoors Jolien, Sun Ping, Van Eeckhaut Ann, Marco-Contelles José, Smolders Ilse, Unzeta Mercedes
Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Institute of Neurosciences, Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain.
Department of Pharmaceutical Chemistry and Drug Analysis (FASC), Experimental Pharmacology, Center for Neurosciences (C4N), Vrije Universiteit Brussel, Jette, Belgium.
J Pharm Pharmacol. 2017 Mar;69(3):314-324. doi: 10.1111/jphp.12697. Epub 2017 Jan 30.
To evaluate the in-vitro and in-vivo effects on monoaminergic neurotransmission of ASS234, a promising multitarget-directed ligand (MTDL), for Alzheimer's disease (AD) therapy.
In vitro was explored the effect of ASS234 on the monoaminergic metabolism in SH-SY5Y and PC12 cell lines, and remaining activity of both monoamine oxidase (MAO) isoforms was assessed. The corresponding dopamine (DA), homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) and noradrenaline (NA) levels were determined by HPLC-ED. In-vivo experiments were carried out Wistar rats and intracerebral guide cannulas were implanted in the hippocampus and in the prefrontal cortex by sterotaxic coordinates. The day after microdialysis samples were collected and levels of 5-HT, DA and NA were determined by (UHPLC) with electrochemical detector.
ASS234 induced a significant increase in serotonin (5-HT) levels in SH-SY5Y cells. In PC12 cells, ASS234 increased significantly the ratio of dopamine (DA)/(HVA + DOPAC), although no apparent differences in (NA) were observed. By in-vivo microdialysis, ASS234 showed a significant increase in the extracellular levels of 5-HT and NA in hippocampus whereas in the prefrontal cortex, DA and NA also increased significantly.
This study reveals the ability of ASS234 a MTDL compound, to enhance the monoaminergic neurotransmission supporting its potential use in AD therapy.
评估ASS234（一种有前景的多靶点导向配体（MTDL））对阿尔茨海默病（AD）治疗中单胺能神经传递的体外和体内作用。
在体外研究ASS234对SH-SY5Y和PC12细胞系中单胺能代谢的影响，并评估两种单胺氧化酶（MAO）同工型的剩余活性。通过高效液相色谱-电化学检测法（HPLC-ED）测定相应的多巴胺（DA）、高香草酸（HVA）、3,4-二羟基苯乙酸（DOPAC）和去甲肾上腺素（NA）水平。在体内实验中，对Wistar大鼠进行实验，通过立体定位坐标将脑内引导套管植入海马体和前额叶皮质。在微透析样本采集后的第二天，通过超高效液相色谱（UHPLC）和电化学检测器测定5-羟色胺（5-HT）、多巴胺（DA）和去甲肾上腺素（NA）的水平。
ASS234可使SH-SY5Y细胞中的血清素（5-HT）水平显著升高。在PC12细胞中，ASS234显著提高了多巴胺（DA）/（HVA + DOPAC）的比值，尽管未观察到去甲肾上腺素（NA）有明显差异。通过体内微透析，ASS234使海马体中5-HT和NA的细胞外水平显著升高，而在前额叶皮质中，DA和NA也显著增加。
本研究揭示了MTDL化合物ASS234增强单胺能神经传递的能力，支持其在AD治疗中的潜在应用。
