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Gabapentin Inhibits Multiple Steps in the Amyloid Beta Toxicity Cascade.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-09-04 , DOI: 10.1021/acschemneuro.0c00414 Juliana González-Sanmiguel 1 , Carlos F Burgos 1 , Denisse Bascuñán 1 , Eduardo J Fernández-Pérez 1 , Nicolás Riffo-Lepe 1 , Subramanian Boopathi 2 , Arturo Fernández-Pérez 3 , Catalina Bobadilla-Azócar 1 , Wendy González 2, 4 , Maximiliano Figueroa 5 , Benjamín Vicente 6, 7 , Luis G Aguayo 1, 7
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-09-04 , DOI: 10.1021/acschemneuro.0c00414 Juliana González-Sanmiguel 1 , Carlos F Burgos 1 , Denisse Bascuñán 1 , Eduardo J Fernández-Pérez 1 , Nicolás Riffo-Lepe 1 , Subramanian Boopathi 2 , Arturo Fernández-Pérez 3 , Catalina Bobadilla-Azócar 1 , Wendy González 2, 4 , Maximiliano Figueroa 5 , Benjamín Vicente 6, 7 , Luis G Aguayo 1, 7
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Oligomeric β-amyloid peptide (Aβ) is one of the main neurotoxic agents of Alzheimer’s disease (AD). Oligomers associate to neuronal membranes, forming “pore-like” structures that cause intracellular calcium and neurotransmitter dyshomeostasis, leading to synaptic failure and death. Through molecular screening targeting the C terminal region of Aβ, a region involved in the toxic properties of the peptide, we detected an FDA approved compound, gabapentin (GBP), with neuroprotective effects against Aβ toxicity. At micromolar concentrations, GBP antagonized peptide aggregation over time and reduced the Aβ absorbance plateau to 28% of control. In addition, GBP decreased Aβ association to membranes by almost half, and the effects of Aβ on intracellular calcium in hippocampal neurons were antagonized without causing effects on its own. Finally, we found that GBP was able to block the synaptotoxicity induced by Aβ in hippocampal neurons, increasing post-synaptic currents from 1.7 ± 0.9 to 4.2 ± 0.7 fC and mean relative fluorescence intensity values of SV2, a synaptic protein, from 0.7 ± 0.09 to 1.00 ± 0.08. The results show that GBP can interfere with Aβ-induced toxicity by blocking multiple steps, resulting in neuroprotection, which justifies advancing toward additional animal and human studies.
中文翻译：
加巴喷丁抑制淀粉样β毒性级联反应的多个步骤。
寡聚β-淀粉样肽（Aβ）是阿尔茨海默氏病（AD）的主要神经毒性药物之一。低聚物与神经元膜结合，形成“孔状”结构，引起细胞内钙和神经递质动态平衡，导致突触衰竭和死亡。通过针对AβC末端区域（涉及该肽的毒性特性的区域）的分子筛查，我们检测到FDA批准的化合物加巴喷丁（GBP），具有抗Aβ毒性的神经保护作用。在微摩尔浓度下，GBP随时间拮抗肽聚集，并将Aβ吸收平台降低至对照组的28％。此外，GBP使Aβ与膜的结合降低了近一半，并且Aβ对海马神经元细胞内钙的作用被拮抗，而不会自行引起作用。最后，我们发现，GBP能够阻断Aβ诱导的海马神经元的突触毒性，使突触后电流从1.7±0.9增至4.2±0.7 fC，平均突触蛋白SV2的相对荧光强度值从0.7±0.09增至1.00 ±0.08。结果表明，GBP可以通过阻断多个步骤来干扰Aβ诱导的毒性，从而导致神经保护作用，从而有理由进一步开展动物和人体研究。
更新日期：2020-10-07
中文翻译：
加巴喷丁抑制淀粉样β毒性级联反应的多个步骤。
寡聚β-淀粉样肽（Aβ）是阿尔茨海默氏病（AD）的主要神经毒性药物之一。低聚物与神经元膜结合，形成“孔状”结构，引起细胞内钙和神经递质动态平衡，导致突触衰竭和死亡。通过针对AβC末端区域（涉及该肽的毒性特性的区域）的分子筛查，我们检测到FDA批准的化合物加巴喷丁（GBP），具有抗Aβ毒性的神经保护作用。在微摩尔浓度下，GBP随时间拮抗肽聚集，并将Aβ吸收平台降低至对照组的28％。此外，GBP使Aβ与膜的结合降低了近一半，并且Aβ对海马神经元细胞内钙的作用被拮抗，而不会自行引起作用。最后，我们发现，GBP能够阻断Aβ诱导的海马神经元的突触毒性，使突触后电流从1.7±0.9增至4.2±0.7 fC，平均突触蛋白SV2的相对荧光强度值从0.7±0.09增至1.00 ±0.08。结果表明，GBP可以通过阻断多个步骤来干扰Aβ诱导的毒性，从而导致神经保护作用，从而有理由进一步开展动物和人体研究。
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