Neurotrophin mimetic therapeutics for HIV-associated neural dysfunction

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DESCRIPTION (provided by applicant): Human immunodeficiency virus (HIV) rapidly penetrates into and infects the central nervous system (CNS). Inflammatory activity resulting from the interaction of HIV with macrophages and microglia in the nervous system leads to varying levels of neurological impairment and neuronal loss. While disease severity has been reduced with the advent of highly active antiretroviral therapy, CNS disease persists and is expected to exert an increasingly heavy toll as patients with HIV live longer. Currently there are no therapeutic treatments that effectively control the inflammatory interactions that disable and destroy neurons. Several studies have indicated that neurotrophin receptor activation and subsequent signaling through protein kinase B (commonly known as Akt) has substantial therapeutic potential for the treatment of HIV-associated CNS disease. However, it has been difficult to exploit this potential due to the poor penetration of peptides into the brain and difficulties in controlling the balance between neuroprotective and pro-apoptotic neurotrophin signaling. The recent identification of small, non-peptide molecules that cross the blood-brain barrier and mimic the actions of neurotrophins offers an important opportunity to develop the therapeutic potential of the neurotrophin-Akt signaling pathway. These compounds are targeted to specific epitopes of the p75 neurotrophin receptor (p75NTR) or receptor tyrosine kinase B (TrkB), thereby allowing a greater degree of control over signaling than seen with the endogenous ligands. Early work has shown that these compounds have potent neuroprotective properties. The proposed studies will use primary neural cultures to evaluate the therapeutic potential of three of these compounds. Protection against early neuronal damage will be tested by exposing rat neural cultures to conditioned medium from macrophages exposed to the HIV-1 envelope protein, gp120. Alterations in calcium homeostasis and microtubule-associated protein immunoreactivity will be used as sensitive indices of neuronal dysfunction. In addition, the direct anti- inflammatory properties of each compound will be assessed by measuring cytokine, chemokine and growth factor secretion in microglial and macrophage cultures. Assays are designed to generate basic pharmacological data needed to progress from culture experiments to pre-clinical whole animal studies. The proposed studies will establish dosing guidelines, mechanistic information and cellular targeting profiles necessary for therapeutic development of the neurotrophin mimetics.