Neuroprotective agents in HIV-1 associated dementia

描述（由申请方提供）：感染人类免疫缺陷病毒-1（HIV）的一部分患者发生获得性免疫缺陷综合征痴呆综合征（ADC）或HIV相关痴呆（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神经元和纤维的严重损失。尽管关于决定HAD中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，但尚未出现逆转或延迟这种损伤的有效药物治疗。因此，发现减少HAD中神经元变性的新化合物至关重要。神经营养因子是具有广泛生物学作用的多肽，包括神经元保护和突触接触的恢复。脑源性神经营养因子（BDNF）是一种典型的营养因子，可减少由HIV包膜蛋白gp 120诱发的神经元凋亡，用于产生HAD的实验模型。因此，BDNF可能是HAD患者最小化神经元损伤的理想治疗方法。不幸的是，全身给予BDNF不能到达受损的神经元。最近，我们发现LIGA 20是一种口服后进入大脑的半合成鞘脂，具有与脑源性神经营养因子相似的神经营养作用。LIGA 20在体外的神经保护特性与其激活TrkB的能力有关，TrkB是调节这种神经营养因子的神经保护特性的BDNF受体。这些初步数据导致了这样的假设，即LIGA 20可能具有类似于BDNF的神经保护特性。该提案的总体目标是建立LIGA 20在体内的药理学和神经保护作用。特别是，我们建议测试的假设，LIGA 20防止细胞凋亡和神经元丢失的急性和亚慢性动物模型HAD。这些包括：急性纹状体内注射gp 120的小鼠和注射HIV感染的人单核细胞衍生的巨噬细胞的小鼠。将通过组织学和生物化学手段确定神经元凋亡、多巴胺损失和炎症反应。在这个提议中获得的数据可能具有重要的治疗意义，因为LIGA 20可以代替BDNF用于防止HAD个体的神经元细胞死亡。

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.