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. ? ? ?
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