Peng Fuwang, Dhillon Navneet, Callen Shannon, Yao Honghong, Bokhari Sirosh, Zhu Xuhui, Baydoun Hicham H, Buch Shilpa
Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
J Neurovirol. 2008 Jan;14(1):62-72. doi: 10.1080/13550280701809084.
The human immunodeficiency virus (HIV)-1 envelope glycoprotein gp120 has been implicated in mediating neuronal apoptosis, a hallmark feature of HIV-associated dementia (HAD). Mitigation of the toxic effects of gp120 could thus be a potential mechanism for reducing HIV toxicity in the brain. In this study the authors hypothesized that neurotrophic factor, such as platelet-derived growth factor (PDGF), could protect the neurons against gp120-mediated apoptosis. SH-SY5Y cells treated with gp120 exhibited increased cell death when measured by lactate dehydrogenase (LDH) and deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) assay, with concomitant loss of neurites and increased cell rounding. Pretreatment with PDGF-BB, however, reduced gp120-associated neurotoxicity and rescued the neurite outgrowth. Additionally, gp120-mediated activation of caspase-3 was also significantly reduced in cells pretreated with PDGF-BB. Antiapoptotic effects of PDGF-BB were also confirmed by monitoring levels of anti- and proapoptotic genes, Bcl-xL and Bax, respectively. Furthermore, PDGF-mediated protection against gp120 involved the phosphoinositide (PI) 3-kinase/Akt pathway. Taken together these findings lead us to suggest that PDGF-BB could be considered as a therapeutic agent that can mitigate gp120-mediated neurotoxicity in HAD.
人类免疫缺陷病毒1型（HIV-1）包膜糖蛋白gp120被认为与介导神经元凋亡有关，这是HIV相关痴呆（HAD）的一个标志性特征。因此，减轻gp120的毒性作用可能是降低HIV对大脑毒性的一种潜在机制。在本研究中，作者假设神经营养因子，如血小板衍生生长因子（PDGF），可以保护神经元免受gp120介导的凋亡。通过乳酸脱氢酶（LDH）和脱氧核苷酸末端转移酶介导的dUTP缺口末端标记（TUNEL）检测，发现用gp120处理的SH-SY5Y细胞的细胞死亡增加，同时伴有神经突丧失和细胞变圆。然而，用PDGF-BB预处理可降低与gp120相关的神经毒性，并挽救神经突生长。此外，在PDGF-BB预处理的细胞中，gp120介导的半胱天冬酶-3激活也显著降低。通过分别监测抗凋亡基因和促凋亡基因Bcl-xL和Bax的水平，也证实了PDGF-BB的抗凋亡作用。此外，PDGF介导的对gp120的保护作用涉及磷酸肌醇（PI）3激酶/Akt途径。综上所述，这些发现使我们认为PDGF-BB可被视为一种治疗剂，它可以减轻HAD中gp120介导的神经毒性。
