In vitro neuroprotective properties of the novel cholinergic channel activator (ChCA), ABT-418
In vitro neuroprotective properties of the novel cholinergic channel activator (ChCA), ABT-418
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DOI：
10.1016/0006-8993(96)00063-7
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发表时间：
1996-05-06
期刊：
影响因子：
2.9
通讯作者：
Sullivan, JP
中科院分区：
文献类型：
--
作者：
DonnellyRoberts, DL;Xue, IC;Sullivan, JP
最近的文献表明，与神经元烟碱型乙酰胆碱受体(NAChRs)相互作用的化合物在体外和体内都具有潜在的神经保护作用。ABT-418是一种新型的CHCA，它选择性地刺激不同亚型的nAChRs，并显示出认知增强活性。在本研究中，在谷氨酸(Glu)诱导的细胞毒性实验中，采用原代大鼠皮质神经元或人分化细胞系，研究了ABT-418和(-)-尼古丁的神经保护作用，以乳酸脱氢酶(LDH)释放为指标。LMR 32。ABT-418和(-)-尼古丁的神经保护作用具有时间和浓度依赖性，其最适浓度为10 mU M，最适预处理时间为2小时，亚急性暴露7天后，ABT-418对大鼠皮层细胞无细胞毒性，仍具有神经保护作用。保护似乎是通过与nAChRs的相互作用而介导的，可能是α(7)亚型，因为神经保护TVA被α-银环蛇毒素(α-BGT)和甲基琥珀酸碱(MLA)所阻止，这两种α(7)拮抗剂都是选择性的。细胞外钙离子的去除可阻止ABT-418和(-)-尼古丁的神经保护作用，这与已知的α(7)nAChRs调节钙动力学的能力一致。这些数据支持这样的观点，即ABT-418不仅可以增强认知，而且可能会减缓神经退化过程的进展。
Recent Literature has shown that compounds interacting with neuronal nicotinic acetylcholine receptors (nAChRs) have the potential to be neuroprotective both in vitro and in vivo. ABT-418 is a novel ChCA that selectively stimulates discrete subtypes of the nAChRs and exhibits cognitive enhancing activity. In the present study, the neuroprotective effects of ABT-418 and (-)-nicotine, as measured by the release of lactate dehydrogenase (LDH) into the media, were investigated in a glutamate (Glu)-induced cytotoxicity assay using either primary rat cortical neurons or a human differentiated cell line. LMR 32. The neuroprotection elicited by ABT-418 and(-)-nicotine is both time and concentration dependent with an optimal concentration of 10 mu M and an optimal pretreatment time of 2 h. ABT-418 remained neuroprotective and not cytotoxic to rat cortical cells following subacute exposure for 7 days. Protection appears to be mediated via an interaction with nAChRs, possibly the alpha(7) subtype, since the neuroprotection tvas prevented by alpha-bungaratoxin (alpha-Bgt) and methyllycaconitine (MLA), both selective alpha(7) antagonists. Removal of extracellular Ca2+ prevented the neuroprotective effects of ABT-418 and(-)-nicotine, consistent with the known ability of alpha(7) nAChRs to modulate calcium dynamics. These data support the idea that ABT-418 not only enhances cognition, but may possibly slow the progression of the neurodegenerative process.