PNAS：封闭受损神经元小孔有助于阻止神经元死亡

两种新发现的化合物可能通过封闭受损神经元的小孔从而有助于阻止阿兹海默病典型的神经元损伤。
被称为淀粉样缩氨酸原纤维的小蛋白质在患有阿兹海默症的人们的大脑中聚集，并导致了神经元死亡。尽管神经死亡的准确方式还不清楚，科学家发现这些原纤维在神经元的外层制造出了小的通道，这可以让钙进入并导致细胞死亡。
Harvey Pollard及其同事发现了两种小分子阻滞剂，它们可以通过封闭这些通道并防止钙的进入从而防止细胞死亡。这组科学家证明了这两种化合物都可以在类似的浓度下阻断这些通道，而且效果几乎是100%。然而，其中一种化合物能不可逆地阻断通道，而另一种的效果很容易逆转。这组作者得出结论说，这两种化合物都有潜力用于治疗阿兹海默症，而且可能代表了一种治疗该病的新方法。（ 生物谷 Bioon.com）
生物谷推荐原始出处：
PNAS Published online before print February 9, 2009, doi: 10.1073/pnas.0813355106
Small molecule blockers of the Alzheimer Aβ calcium channel potently protect neurons from Aβ cytotoxicity
Juan Carlos Diaza,1, Olga Simakovaa,1, Kenneth A. Jacobsonb, Nelson Arispea and Harvey B. Pollarda,2
aDepartment of Anatomy, Physiology and Genetics, Uniformed Services University School of Medicine, Bethesda, MD 20814; andbMolecular Recognition Section, Laboratory of Biooganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892
Abstract
Alzheimer's disease (AD) is a common, chronic neurodegenerative disease that is thought to be caused by the neurotoxic effect of the Amyloid beta peptides (Aβ). We have hypothesized that the intrinsic Aβ calcium channel activity of the oligomeric Aβ polymer may be responsible for the neurotoxic properties of Aβ, and that Aβ channel blockers may be candidate AD therapeutics. As a consequence of a rational search paradigm based on the model structure of the Aβ channel, we have identified two compounds of interest: MRS2481 and an enatiomeric species, MRS2485. These are amphiphilic pyridinium salts that both potently block the Aβ channel and protect neurons from Aβ toxicity. Both block the Aβ channel with similar potency (≈500 nM) and efficacy (100%). However, we find that inhibition by MRS2481 is easily reversible, whereas inhibition by MRS2485 is virtually irreversible. We suggest that both species deserve consideration as candidates for Alzheimer's disease drug discovery.