We show that paclitaxel can induce degeneration of the central axons of DRG neurons, building on previously described degenerative effects of taxanes on sensory neurons and axons. Previous work demonstrated that paclitaxel causes peripheral neuropathy that manifests as degeneration of afferent sensory axons . The degree and reversibility of chemotherapy-induced peripheral neuropathy is dependent on the dose and treatment schedule of the chemotherapy agent; recovery is likely due to repair and regenerative capacities of peripheral sensory nerves, resulting in the restoration of some function [1, 2]. However, central axons have limited capacity to repair and regenerate and any functional loss is unlikely to recover . Our work on the mouse model of CIPN, therefore, highlights the critical need for novel approaches of central axonal protection from chemotherapy agents, as opposed to the development of regenerative strategies for peripheral axons only.
DRG neurons have a unique feature of possessing both central and peripheral axonal branches; thus, once inside a neuron, paclitaxel in sufficient doses would be expected to affect microtubules in the cell body and in both axonal branches. Our data suggest that this prediction holds in mouse models. The observation that degeneration is restricted to the dorsal column where DRG axons reside in the spinal cord suggests that paclitaxel does not affect spinal cord axons uniformly and probably does not directly enter the central nervous system in sufficient amounts to cause a uniform toxicity. Indeed, paclitaxel has been shown in relatively low concentrations in the spinal cord compared to sciatic nerve and DRG in mice [2, 19]. Therefore, it is likely that paclitaxel can either be transported from the periphery or directly affect DRG cell bodies to cause degeneration of axons in the dorsal column. Our data cannot distinguish between these two routes, but support the notion that paclitaxel can exert degenerative effects on sensory axons irrespective of whether the axons are in the central or peripheral nervous systems.
A potential explanation for the degeneration of central DRG axons is that at the dose used in this study, paclitaxel may cause massive death of DRG neurons. However, our data argues against this notion as we did not observe degenerating neuronal cells bodies in the DRG of mice intoxicated with paclitaxel (Fig. 5). Other studies also report the absence of massive degeneration of DRG neurons following high dose intoxication . Therefore, in the paclitaxel-induced neuropathy mouse model examined, the degenerative effects of paclitaxel are exerted in part on central sensory axon branches. Importantly, the dose used in this study, 30 mg/kg 3 times a week for 2 weeks, is equivalent to a mg/m2 human dose. Paclitaxel is dosed in human at 175–300 mg/m2 every 2–3 weeks; thus, the high dose investigated in this study remained within the range that is administered in human. In future studies, it would be interesting to test if similar effects are observed at different doses of paclitaxel intoxication.
In mouse dorsal column and likely in that of human, ascending mechanosensory axons are segregated from axons that transmit proprioceptive information in a medial to lateral pattern . Our data suggest that both types of afferent axons degenerate as we observed degenerated axons in both medial and lateral regions of the dorsal column, and at all levels of the spinal cord of paclitaxel-intoxicated mice. Our findings are consistent with observed effects of taxanes on both mechanoreception and proprioception in human cases .
Paclitaxel binds to microtubules and stabilizes them, which interferes with normal cellular function including cell division and microtubule-dependent intra-cellular and axonal transport [4, 6]. Through the aggregation of intracellular microtubules, taxanes affect both the soma of sensory neurons as well as axons . Microtubule-dependent transport is critical for axonal function and health, both in the central and peripheral nervous systems; as such, disruption of axonal transport is implicated in various central nervous system disorders and peripheral neuropathies . Agents such as paclitaxel that disrupt microtubule-dependent transport would be expected to affect both central and peripheral axons given that the agents have access to axons, either directly or via DRG cell bodies.
Involvement of non-neuronal cells in peripheral neuropathy caused by paclitaxel in rodent models has been previously documented [11, 12]. Whether the adverse effect on non-neuroral cells within the nervous system is a primary contributor or a secondary response to axonal injury, however, is an open question. Our data suggest that activated macrophages in paclitaxel-treated nerves are in response to degenerated axons and therefore, at least one cell type, macrophages, mediates secondary effects to the insult of paclitaxel on axons. Foamy phagocytic macrophages were associated with degenerating fibers, but not intact myelinated axons. This pattern of macrophage infiltration has been described in other human peripheral neuropathies, including axonal neuropathies . Therefore, macrophages in paclitaxel-treated nerves might be clearing debris of degenerated axons and myelin, thus allowing for regeneration and recovery over time, and facilitating the resolution of peripheral neuropathy from taxanes in some cases.
Though our data is restricted to the mouse model of CIPN, the results have implications for patients undergoing aggressive chemotherapy treatment. In a few cases, degeneration of central axons has been reported in patients treated with chemotherapy agents. For example, degeneration of the dorsal column of the spinal cord has been described in a patient treated with bortezomib, a proteasome inhibitor that is a very effective chemotherapy agent for multiple myeloma . A limiting factor in identifying cases presenting with dorsal column degeneration has been the requirement for autopsy tissue. However, with the availability of MRI imaging capable of detecting damage to the spinal cord , it is now possible to ascertain degeneration in the spinal cords of patients undergoing aggressive treatment. The data in our mouse model of CIPN argue for such examination.