In elucidating the pathogenesis of AIDS peripheral neuropathy, we demonstrated by immunohistochemistry that subsets of rat dorsal root ganglia (DRG) express the CXCR4 receptor, the coreceptor for gp120IIIB; many of these neurons expressed Substance P immunoreactivity. We hypothesize: (a) rat neonatal DRG undergo apoptosis upon exposure to gp120IIIB; and (b) the apoptosis can be prevented by CEP-1347/KT7515, a specific inhibitor of the JNK signaling cascade. DRG were harvested from E15 and neonatal Holtzman rats and exposed to gp120IIIB, NMDA, or NGF-free media. DRG for calcium imaging were stained with FURA-2; apoptosis was assessed by immunocytochemistry using both neuron-specific enolase and the chromatin stain Hoechst 33342. Results reveal E15 DRG to be sensitive to NGF withdrawal but undergo no apoptosis to either gp120IIIB or NMDA, concurrent with the relative absence of calcium fluxes to the application of either. Neonatal DRG exhibited significant apoptosis to both gp120IIIB and NMDA, but not to NGF withdrawal; calcium imaging revealed calcium fluxes in response to administration of gp120IIIB and NMDA to neonatal DRG. CEP-1347/KT7515 at a concentration of 200 nM rescued DRG from their respective apoptosis inducers to approximately control levels. These results suggest activation of sensory neuron chemokine receptors by gp120IIIB may be directly responsible for the peripheral neuropathy suffered by patients with AIDS and AIDS peripheral neuropathy may be prevented by CEP-1347/KT7515.
|Original language||English (US)|
|Journal||Clinical Pharmacology and Therapeutics|
|State||Published - Dec 1 2001|
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