Background:  Distal symmetric polyneuropathy and antiretroviral toxic neuropathy from nucleoside analogues are the most frequent neurological complications in HIV/AIDS patients. The underlying pathology is “dying back” axonal degeneration with preservation of the neuronal cell bodies until late in the disease. This dying back phenomenon is similar to many other toxic and metabolic neuropathies. However, the nature of dying back and the site of initial toxicity is unknown. In recent years we have developed in vitro models of distal symmetric polyneuropathy and antiretroviral toxic neuropathy  using HIV envelope protein gp120 and nucleoside analogue dideoxycytidine (ddC), respectively. In this study we examined the site of action of gp120 and ddC using compartmentalized cell culture system.

Methods:  We plated embryonic sensory dorsal root ganglion neurons in compartmentalized chambers, also known as Campenot chambers. These chambers allow one to grow the axons of dorsal root ganglion neurons in isolation from the cell bodies. In these chambers we administered gp120 or ddC into the cell body compartment or to the side chamber housing the axons. Serially we monitored the axon length in the side chamber and examined apoptotic cell death in the cell body chamber after 72 hours. We used unpaired Student’s t-test for statistical comparison.

Results:  The antiretroviral drug ddC caused a significant reduction in axonal length when applied to the side chamber, but not when applied to the cell body chamber, indicating that the primary site of action is the axon. In contrast, gp120 caused similar reductions in axonal length when it was applied to the side axonal chamber or the center cell body chamber, suggesting that toxicity of gp120 could be mediated by binding to the neuronal cell body or the axon. There was no significant cell death in either condition at the doses used in the study.

Conclusions:  This study shows that although distal symmetric polyneuropathy and antiretroviral toxic neuropathy are similar to each other clinically and pathologically, the sites of action of gp120 and ddC, agents that model distal symmetric polyneuropathy and antiretroviral toxic neuropathy, respectively, are different. These studies suggest that strategies directed toward protection of the axons might be more fruitful in diseases where the primary action is at the axonal level, rather than the cell body level.

Keywords: neuropathy; compartmented culture; pathogenesis