Human immunodeficiency virus (HIV) rapidly penetrates into and infects the central nervous system (CMS). 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, CMS 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 of protein kinase B (commonly known as Akt) has substantial therapeutic potential for the treatment of HIV-associated CMS 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 at the p75 neurotrophin receptor (p75NTR) or receptor tyrosine kinase B (TrkB) offers an important opportunity to develop the therapeutic potential of the neurotrophin-Akt signaling pathway. These neurotrophin mimetics represent a new class of compounds that appear to have excellent neuroprotective and anti-inflammatory properties, are non-toxic and have good oral availability. The proposed studies will use primary neural cultures to evaluate the therapeutic potential of three of these compounds. Protection against inflammation and damage generated by exposing rat neural cultures to HIV-1 envelope proteins or feline neural cultures to feline immunodeficiency virus (FIV) will be assessed using conventional measures of cell death as well as newly developed techniques to assess alterations in calcium homeostasis. In addition, the anti-inflammatory properties of each compound will be assessed by measuring cytokine, chemokine and growth factor secretion in both mixed and purified microglial cultures. The proposed studies will determine the basic pharmacology and therapeutic potential of the non-peptide neurotrophin mimetics in assays specifically designed to maximize the efficiency of screening and allow rapid translation to in vivo models. ? ? ?
|Meeker, Rick B; Poulton, Winona; Clary, Gillian et al. (2016) Novel p75 neurotrophin receptor ligand stabilizes neuronal calcium, preserves mitochondrial movement and protects against HIV associated neuropathogenesis. Exp Neurol 275 Pt 1:182-98|
|Meeker, Rick B; Poulton, Winona; Feng, Wen-hai et al. (2012) Suppression of immunodeficiency virus-associated neural damage by the p75 neurotrophin receptor ligand, LM11A-31, in an in vitro feline model. J Neuroimmune Pharmacol 7:388-400|
|Meeker, Rick B; Poulton, Winona; Markovic-Plese, Silva et al. (2011) Protein changes in CSF of HIV-infected patients: evidence for loss of neuroprotection. J Neurovirol 17:258-73|