Rat dorsal root ganglia exhibit developmental dependent response to GP120_IIIB-induced apoptosis

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 gp120_IIIB; many of these neurons expressed Substance P immunoreactivity. We hypothesize: (a) rat neonatal DRG undergo apoptosis upon exposure to gp120_IIIB; 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 gp120_IIIB, 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 gp120_IIIB or NMDA, concurrent with the relative absence of calcium fluxes to the application of either. Neonatal DRG exhibited significant apoptosis to both gp120_IIIB and NMDA, but not to NGF withdrawal; calcium imaging revealed calcium fluxes in response to administration of gp120_IIIB 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 gp120_IIIB may be directly responsible for the peripheral neuropathy suffered by patients with AIDS and AIDS peripheral neuropathy may be prevented by CEP-1347/KT7515.