Caporello Emily, Nath Avindra, Slevin John, Galey David, Hamilton Greg, Williams Larry, Steiner Joseph P, Haughey Norman J
Department of Neurology, John Hopkins University School of Medicine, Baltimore, Maryland, USA.
J Neurochem. 2006 Jul;98(1):146-55. doi: 10.1111/j.1471-4159.2006.03863.x.
The dysfunction and death of neuronal cells is thought to underlie the cognitive manifestations of human immunodeficiency virus (HIV)-associated neurological disorders. Although HIV-infected patients are living longer owing to the effectiveness of anti-retroviral therapies, the number of patients developing neurological disorders is on the rise. Thus, there is an escalating need for effective therapies to preserve cognitive function in HIV-infected patients. Using HIV-protein-induced neurotoxicity as a model system, we tested the effectiveness of a non-immunosuppressive immunophilin ligand to attenuate gp120 and Tat-induced modification of neuronal function. The immunophilin ligand GPI1046 attenuated endoplasmic reticulum (ER) calcium release induced by gp120 and Tat and protected neurons from the lethal effect of these neurotoxic HIV proteins. Both inositol 1,4,5 trisphosphate (IP(3)) and ryanodine-sensitive ER calcium release was attenuated by pre-incubation with GPI1046. Using the sarco/endoplasmic reticulum calcium pump inhibitor thapsigargin to release ER calcium, we determined that GPI1046 reduced the total ER calcium load. These findings suggest that non-immunosuppressive immunophilin ligands may be useful neuroprotective drugs in HIV dementia.
神经元细胞的功能障碍和死亡被认为是人类免疫缺陷病毒（HIV）相关神经疾病认知表现的基础。尽管由于抗逆转录病毒疗法的有效性，HIV感染患者的寿命延长，但发生神经疾病的患者数量却在增加。因此，对于在HIV感染患者中维持认知功能的有效疗法的需求不断升级。我们以HIV蛋白诱导的神经毒性作为模型系统，测试了一种非免疫抑制性亲免素配体减轻gp120和Tat诱导的神经元功能改变的有效性。亲免素配体GPI1046减弱了gp120和Tat诱导的内质网（ER）钙释放，并保护神经元免受这些神经毒性HIV蛋白的致死作用。预先用GPI1046孵育可减弱肌醇1,4,5-三磷酸（IP(3)）和对ryanodine敏感的ER钙释放。使用肌浆/内质网钙泵抑制剂毒胡萝卜素释放ER钙，我们确定GPI1046降低了ER的总钙负荷。这些发现表明，非免疫抑制性亲免素配体可能是治疗HIV痴呆的有用神经保护药物。
