Nucleoside analogue Reverse Transcriptase Inhibitors (NRTIs) are an essential component of HAART (Highly Active AntiRetroviral Therapy), substantially reducing the morbidity and mortality of HIV-1 infection. However, the use of many of these drugs, including ddC, ddl and d4T has been associated with a painful sensory polyneuropathy (Antiretroviral Toxic Neuropathy, ATN) that often necessitates drug discontinuation by the patient. There has been no reliable in vitro or in vivo animal models of NRTI neurotoxicity. We propose to develop a robust and reliable in vitro model of NRTI neurotoxicity to study the cellular mechanism of toxicity and initiate screening of preventative or therapeutic drugs. Dorsal root ganglion (DRG) sensory neurons are the main targets for NRTI toxicity in humans. Therefore, primary DRG sensory neurons from rats will be used to develop this model. We will examine the effects of various NRTIs that are known to cause ATN in humans. Established morphological criteria will be used as primary outcome measures of neurotoxicity. Additionally we will develop biochemical and molecular assays of neurotoxicity using the expression of axonal outgrowth associated genes. These will be validated against the primary morphological criteria and used in development of high-throughput assays. Our preliminary data suggests that the toxicity from NRTIs may be mediated through mitochondria. We observed mitochondrial energy failure associated with necrotic cell death. We will study the mechanism of this neurotoxicity by examining the roles of ATP generation, reactive oxygen species and mitochondria-specific heat-shock proteins. The ultimate goal of these studies will be to find compounds that may ameliorate the neurotoxicity of NRTIs. Nonimmunosuppressive neuroimmunophilin ligands will be used in this screening. Our screening program may yield clinically useful neuroprotective compounds that can be given in conjunction with the NRTIs as part of their HAART regimen. This is an ideal situation for a neuroprotective paradigm, because the neuroprotective drugs can be given in advance or in conjunction with the neurotoxic drugs. Furthermore, this assay system may be useful in development of NRTIs without the neurotoxic side effects. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043991-03
Application #
6798794
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Nunn, Michael
Project Start
2002-09-30
Project End
2006-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
3
Fiscal Year
2004
Total Cost
$310,650
Indirect Cost
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Cashman, Christopher R; Höke, Ahmet (2015) Mechanisms of distal axonal degeneration in peripheral neuropathies. Neurosci Lett 596:33-50
Höke, Ahmet (2014) Augmenting glial cell-line derived neurotrophic factor signaling to treat painful neuropathies. Proc Natl Acad Sci U S A 111:2060-1
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Melli, Giorgia; Höke, Ahmet (2009) Dorsal Root Ganglia Sensory Neuronal Cultures: a tool for drug discovery for peripheral neuropathies. Expert Opin Drug Discov 4:1035-1045

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