Activation of c-Jun N-terminal kinase mediates gp120IIIB- and nucleoside analogue-induced sensory neuron toxicity.
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.
Bodner
Amos
A
Department of Molecular Pharmacology and Biological Chemistry, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611 USA.
Toth
Peter T
PT
Miller
Richard J
RJ
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D016049:Didanosine / Q000494:pharmacology; D004336:Drug Antagonism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology; D015699:HIV Envelope Protein gp120 / Q000633:toxicity*; D007211:Indoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D009475:Neurons, Afferent / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D051381:Rats; D011994:Recombinant Proteins / Q000633:toxicity
D002227:Carbazoles; D004791:Enzyme Inhibitors; D015699:HIV Envelope Protein gp120; D007211:Indoles; D011994:Recombinant Proteins; C106592:3,9-bis((ethylthio)methyl)-K-252a; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D016049:Didanosine