Suwanna Nirut, Thangnipon Wipawan, Soi-Ampornkul Rungtip
Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhonpathom, Thailand.
Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhonpathom, Thailand.
Neurosci Lett. 2014 Aug 22;578:44-9. doi: 10.1016/j.neulet.2014.06.029. Epub 2014 Jun 21.
Alzheimer's disease is a major cause of dementia in the elderly that involves a β-amyloid peptide (Aβ)-induced cascade of an increase in oxidative damage and inflammation. The present study demonstrated the neuroprotective effects of diarylpropionitrile (DPN), a non-steroidal estrogen receptor β selective ligand, against 10 μM Aβ1-42-induced oxidative stress and inflammation in primary rat cortical cell culture. Pre-treatment with 1-100 nM DPN significantly decreased neuronal cell death by increasing cell viability through a significant attenuation in the reactive oxygen species level, downregulation of pro-apoptotic activated caspase-3 and Bax, and upregulation of anti-apoptotic Bcl-2, thereby mitigating apoptotic morphological alterations. DPN pre-treatment decreased the expression levels of pro-inflammatory cytokines IL-1β and IL-6 through attenuation of Aβ1-42-induced phosphorylation of mitogen-activated protein kinases JNK and p38. In addition, DPN enhanced ERK1/2 and Akt phosphorylation depressed by Aβ1-42. These findings suggest that DPN protects neurons from Aβ1-42-induced neurotoxicity through a variety of mechanisms, ranging from anti-oxidation, anti-apoptosis, through to anti-inflammation.
阿尔茨海默病是老年人痴呆症的主要病因，涉及β-淀粉样肽（Aβ）诱导的氧化损伤和炎症增加的级联反应。本研究证明了二芳基丙腈（DPN），一种非甾体雌激素受体β选择性配体，对原代大鼠皮质细胞培养中10 μM Aβ1-42诱导的氧化应激和炎症具有神经保护作用。用1-100 nM DPN预处理可通过显著降低活性氧水平、下调促凋亡的活化半胱天冬酶-3和Bax以及上调抗凋亡的Bcl-2来增加细胞活力，从而显著降低神经元细胞死亡，进而减轻凋亡形态学改变。DPN预处理通过减弱Aβ1-42诱导的丝裂原活化蛋白激酶JNK和p38的磷酸化来降低促炎细胞因子IL-1β和IL-6的表达水平。此外，DPN增强了被Aβ1-42抑制的ERK1/2和Akt磷酸化。这些发现表明，DPN通过多种机制保护神经元免受Aβ1-42诱导的神经毒性，从抗氧化、抗凋亡到抗炎。
