兩種新發(fā)現(xiàn)的化合物可能通過(guò)封閉受損神經(jīng)元的小孔從而有助于阻止阿茲海默病典型的神經(jīng)元損傷。
被稱為淀粉樣縮氨酸原纖維的小蛋白質(zhì)在患有阿茲海默癥的人們的大腦中聚集,，并導(dǎo)致了神經(jīng)元死亡,。盡管神經(jīng)死亡的準(zhǔn)確方式還不清楚，科學(xué)家發(fā)現(xiàn)這些原纖維在神經(jīng)元的外層制造出了小的通道,，這可以讓鈣進(jìn)入并導(dǎo)致細(xì)胞死亡,。
Harvey Pollard及其同事發(fā)現(xiàn)了兩種小分子阻滯劑，它們可以通過(guò)封閉這些通道并防止鈣的進(jìn)入從而防止細(xì)胞死亡,。這組科學(xué)家證明了這兩種化合物都可以在類似的濃度下阻斷這些通道,，而且效果幾乎是100%。然而,，其中一種化合物能不可逆地阻斷通道,，而另一種的效果很容易逆轉(zhuǎn)。這組作者得出結(jié)論說(shuō),，這兩種化合物都有潛力用于治療阿茲海默癥,，而且可能代表了一種治療該病的新方法。（生物谷Bioon.com）
生物谷推薦原始出處：
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; and
bMolecular 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.
