Johnson Shakevia, Duncan Jeremy, Hussain Syed A, Chen Gang, Luo Jia, Mclaurin Channing, May Warren, Rajkowska Grazyna, Ou Xiao-Ming, Stockmeier Craig A, Wang Jun Ming
Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, Mississippi.
Alcohol Clin Exp Res. 2015 Mar;39(3):476-84. doi: 10.1111/acer.12650. Epub 2015 Feb 19.
Brain cell death is a major pathological consequence of alcohol neurotoxicity. However, the molecular cascades in alcohol-induced brain tissue injury are unclear.
Using Western blot and double immunofluorescence, we examined the expression of interferon (IFN)-induced protein kinase R (PKR), phosphorylated-PKR (p-PKR), and IFN gamma (IFNγ) in the prefrontal cortex (PFC) of postmortem brains from subjects with alcohol use disorders (AUD).
The protein levels of PKR, p-PKR, and IFNγ were significantly increased in subjects with AUD compared with control subjects without AUD, and a younger age of onset of AUD was significantly correlated with higher protein levels of p-PKR. In addition, elevated PKR- and p-PKR-IR were observed in both neurons and astrocytes in the PFC of subjects with AUD compared to subjects without AUD.
The activation of the IFNγ-PKR pathway in PFC of humans is associated with chronic excessive ethanol use with an age of onset dependent manner, and activation of this pathway may play a pivotal role in AUD-related brain tissue injury. This study provides insight into neurodegenerative key factors related to AUD and identifies potential targets for the treatment of alcohol-induced neurotoxicity.
脑细胞死亡是酒精神经毒性的主要病理后果。然而，酒精诱导的脑组织损伤中的分子级联反应尚不清楚。
我们使用蛋白质免疫印迹法和双重免疫荧光法，检测了酒精使用障碍（AUD）患者死后大脑前额叶皮质（PFC）中干扰素（IFN）诱导的蛋白激酶R（PKR）、磷酸化PKR（p-PKR）和IFNγ的表达。
与无AUD的对照受试者相比，AUD患者中PKR、p-PKR和IFNγ的蛋白水平显著升高，且AUD发病年龄越小，p-PKR蛋白水平越高。此外，与无AUD的受试者相比，AUD患者PFC中的神经元和星形胶质细胞中PKR和p-PKR免疫反应性均升高。
人类PFC中IFNγ-PKR途径的激活与慢性过量乙醇使用有关，且具有发病年龄依赖性，该途径的激活可能在AUD相关的脑组织损伤中起关键作用。本研究深入了解了与AUD相关的神经退行性关键因素，并确定了治疗酒精诱导神经毒性的潜在靶点。
