Abstract
Peripheral neuropathy is the most common neurological symptom in patients with acquired immunodeficiency syndrome (AIDS). Here, we examine possible mechanisms of gp120 and nucleoside reverse transcriptase inhibitors (NRTIs) in the pathogenesis of AIDS peripheral neuropathy. Neonatal dorsal root ganglion (DRG) neurons were found to undergo apoptosis in response to chronic treatment with gp120IIIB, an effect enhanced by the co-application of hCD4, as well as upon exposure to the nucleoside reverse transcriptase inhibitor (NRTI), 2′,3′-dideoxyinosine (ddI). DRG neurons were rescued from the neurotoxic effects of these agents by CEP-1347, an inhibitor of the mixed lineage kinases (MLKs), upstream activators of the c-Jun N-terminal kinase (JNK) signaling pathway. In addition, gp120- or ddI-mediated toxicity were also inhibited by neuronal expression of dominant negative versions of the MLKs. Our results suggest that both gp120 and the NRTIs cause sensory neuron apoptosis through the activation of the JNK pathway, and that CEP-1347-like compounds may serve as a therapeutic option in patients with AIDS-associated peripheral neuropathy.
Original language | English (US) |
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Pages (from-to) | 246-253 |
Number of pages | 8 |
Journal | Experimental Neurology |
Volume | 188 |
Issue number | 2 |
DOIs | |
State | Published - Aug 2004 |
Funding
This work was supported by Grants NIH NS43095, DA13141, MH40165, NS33826, and NS21442 to RJM. The authors wish to thank Ghanashyam Ghadge (University of Chicago) for providing the adenovirus constructs and gratefully acknowledge the expert technical assistance of Christopher P. Mauer.
Keywords
- AIDS
- Apoptosis
- HAART
- HIV-1
- JNK signaling
- Mixed lineage kinases
- NRTI
- Peripheral neuropathy
- Sensory neuron
- gp120
ASJC Scopus subject areas
- Neurology
- Developmental Neuroscience