Neuroprotective agents in HIV-1 associated dementia

描述(由申请人提供)：感染人类免疫缺陷病毒-1(HIV)的患者中的一部分会发展为获得性免疫缺陷综合症痴呆症复合体(ADC)或HIV相关痴呆症(HAD)，这是一种以运动障碍和认知功能障碍为特征的疾病。在这些患者中，可以看到整个大脑的神经元和纤维严重丧失。尽管关于决定HAD缓慢但进行性神经元死亡的复杂因素的知识有了巨大的扩展，但还没有出现有效的药物治疗来逆转或延缓这种损伤。因此，发现减少HAD神经元变性的新化合物是至关重要的。神经营养因子是一种多肽，具有广泛的生物学作用，包括神经元保护和恢复突触接触。脑源性神经营养因子(BDNF)是一种典型的营养因子，可减少HIV包膜蛋白gp120诱导的神经元凋亡，用于产生HAD的实验模型。因此，BDNF可能是治疗HAD患者的一种理想的治疗方法，以最大限度地减少神经元损伤。不幸的是，全身给药的脑源性神经营养因子并没有到达受损的神经元。最近，我们发现LIGA20，一种口服后进入大脑的半合成鞘磷脂，具有类似于BDNF的神经营养特征。LIGA20的体外神经保护作用与其激活TrkB的能力有关，TrkB是一种BDNF受体，调节这种神经营养因子的神经保护作用。这些初步数据导致假设LIGA20可能具有类似于BDNF的神经保护特性。这项提案的总体目标是在体内建立LIGA20的药理和神经保护概况。特别是，我们建议在急性和亚慢性HAD动物模型中检验LIGA20防止细胞凋亡和神经元丢失的假设。这些措施包括：在小鼠和注射艾滋病毒感染的人单核细胞来源的巨噬细胞的小鼠中急性纹状体内注射gp120。神经细胞的凋亡、多巴胺的丢失和炎症反应将通过组织学和生化手段来确定。这项建议中获得的数据可能具有重要的治疗意义，因为LIGA20可能被用来替代BDNF来预防HAD患者的神经细胞死亡。

DESCRIPTION (provided by applicant): A subset of patients infected with human immunodeficiency virus-1 (HIV) develop Acquired Immunodeficiency Syndrome Dementia Complex (ADC) or HIV-associated dementia (HAD), a disorder characterized by motor impairments and cognitive dysfunctions. A severe loss of neurons and fibers throughout the brain is seen in these patients. Despite the enormous expansion of knowledge regarding the complex factors that determine slow but progressive neuronal death in HAD, no effective drug therapy to reverse or delay this damage has yet emerged. Thus, the discovery of new compounds that reduce neuronal degeneration in HAD is crucial. Neurotrophic factors are polypeptides that exhibit a broad spectrum of biological actions, including neuronal protection and restoration of synaptic contacts. Brain-derived neurotrophic factor (BDNF) is a prototypical trophic factor that reduces neuronal apoptosis evoked by the HIV envelope protein gp120, used to generate an experimental model of HAD. Thus, BDNF could be an ideal therapy for HAD patients to minimize neuronal damage. Unfortunately, BDNF administered systemically does not reach the injured neurons. Recently, we have discovered that LIGA20, a semi-synthetic sphingolipid that enters the brain after oral administration, has a neurotrophic profile similar to BDNF. The neuroprotective property of LIGA20 in vitro is related to its ability to activate TrkB, the BDNF receptor that modulates the neuroprotective property of this neurotrophic factor. These preliminary data lead to the hypothesis that LIGA20 may have a neuroprotective property similar to BDNF. The overall goal of this proposal is to establish the pharmacological and neuroprotective profile of LIGA20 in vivo. In particular, we propose to test the hypothesis that LIGA20 prevents apoptosis and neuronal loss in acute and subchronic animal models of HAD. These include: acute intrastriatal injection of gp120 in mice and mice injected with HIV-infected human monocytes-derived macrophages. Neuronal apoptosis, loss of dopamine and inflammatory responses will be determined by histological and biochemical means. The data obtained in this proposal could have important therapeutic implications because LIGA20 may be used instead of BDNF to prevent neuronal cell death in HAD individuals.