Spatiotemporal localization of injury potentials in DRG neurons during vincristine-induced axonal degeneration

Abstract

The distal to proximal degeneration of axons, or "dying back" is a common pattern of neuropathology in many diseases of the PNS and CNS. A long-standing debate has centered on whether this pattern of neurodegeneration is due to an insult to the cell body or to the axon itself, although it is likely that mechanisms are different for specific disease entities. We have addressed this question in a model system of vincristine-induced axonal degeneration. Here, we created a novel experimental apparatus combining a microfluidic divider with a multielectrode array substrate to allow for independent monitoring of injury-induced electrical activity from dorsal root ganglion (DRG) cell bodies and axons while isolating them into their own culture microenvironments. At specified doses, exposure of the cell body to vincristine caused neither morphological neurodegeneration nor persistent hyperexcitablility. In comparison, exposure of the distal axon to the same dose of vincristine first caused a decrease in the excitability of the axon and then axonal degeneration in a dying back pattern. Additionally, exposure of axons to vincristine caused an initial period of hyperexcitability in the cell bodies, suggesting that a signal is transmitted from the distal axon to the soma during the progression of vincristine-induced axonal degeneration. These data support the proposition that vincristine has a direct neurotoxic effect on the axon.

Cellular and functional evidence for a protective action of neurosteroids against vincristine chemotherapy-induced painful neuropathy

“…In agreement with our observations, axonal degeneration, IENF decrease or sensory terminal arbor dysregulation have previously been described in antineoplastic-treated animals or patients [12,34,35]. However, VINC-induced down-regulation of CNPase expression in peripheral nerves in vivo has never been demonstrated, and the present report constitutes the first one providing this crucial information.…”

Mechanisms of vincristine-induced neurotoxicity: Possible reversal by erythropoietin

“…We observed that the amplitude of the MCAP was significantly decreased, while its duration was significantly prolonged in the VCR group. This suggests that a significant number of sensory and motor fibers are affected by the drug as confirmed by reported histological studies, which showed VCR-induced axonal degeneration as well as disorganization of the axonal microtubule cytoskeleton and increase in the caliber of unmyelinated sensory axons (9,16). On the other hand, no significant change was observed in conduction velocity.…”

Progressive Motor Neuronopathy: A Critical Role of the Tubulin Chaperone TBCE in Axonal Tubulin Routing from the Golgi Apparatus

“…"Axonal" hypotheses postulated that the degenerative process is triggered in the axon itself: Vincristine, a chemotherapeutic agent used in human cancer therapy, causes a peripheral neuropathy with prominent distal axonal degeneration (Bradley et al, 1970). The axonal dying back process can be mimicked in neuronal cultures (Ravula et al, 2007) in which topic application of Vincristine at clinically relevant concentrations injures the axon but not the neuronal soma (Silva et al, 2006). Several genetic studies have also linked impaired retrograde axonal transport to motor neuron degeneration.…”