Paclitaxel alters sensory nerve biomechanical properties

Abstract

Paclitaxel is an effective chemotherapeutic that, despite its common use, frequently causes debilitating peripheral sensory neuropathy. Paclitaxel binds to and stabilizes microtubules, and through unknown mechanisms, causes abnormal microtubule aggregation. Given that microtubules contribute to the mechanical properties of cells, we tested the hypothesis that paclitaxel treatment would alter the stiffness of sensory nerves. Rat sural nerves were excised and soaked in Ringer's solution with or without paclitaxel. Nerves were secured between a force transducer and actuator, and linearly strained. Stress-strain curves were generated, from which elastic moduli were calculated. Paclitaxel treated nerves exhibited significantly higher moduli in both linear and transition regions of the curve. A composite-tissue model was then generated to estimate the stiffness increase in the cellular fraction of the nerve following paclitaxel treatment. This model was supported experimentally by data on mechanical properties of sural nerves stripped of their epineurium, and area fractions of the cellular and connective tissue components of the rat sural nerve, calculated from immunohistochemical images. Model results revealed that the cellular components of the nerve must stiffen 12x to 115x, depending on the initial axonal modulus assumed, in order to achieve the observed tissue level mechanical changes. Consistent with such an increase, electron microscopy showed increased microtubule aggregation and cytoskeletal packing, suggestive of a more cross-linked cytoskeleton. Overall, our data suggests that paclitaxel treatment induces increased microtubule bundling in axons, which leads to alterations in tissue-level mechanical properties.

Induction of cell cycle arrest by increasing GTP-RhoA levels via Taxol-induced microtubule polymerization in renal cell carcinoma

“…Taxol is an effective chemotherapeutic used to treat cancer patients; it binds to and stabilizes MT, causing abnormal MT aggregation (20). Immunofluorescent staining revealed that in the absence of Taxol, tubulin was widely distributed throughout the cytoplasm and accumulated in the perinuclear regions of cells.…”

Decoupled epineurial and axonal deformation in mouse median and ulnar nerves

“…The epineurium and perineurium are the most likely candidates for load‐bearing. In one study, peeling of the epineurium of rat sural nerves decreased nerve modulus by up to 5‐fold, with the perineurium intact . On the other hand, the perineurium—which consists of collagen, elastic fibers, and the basal lamina—has also been posited as the major load‐bearing layer of the nerve; indeed, rabbit tibial nerves lost most of their load‐bearing capabilities with perineurial breakage at strains of 27% beyond in‐situ strain .…”

“…In one study, peeling of the epineurium of rat sural nerves decreased nerve modulus by up to 5-fold, with the perineurium intact. 37 On the other hand, the perineurium-which consists of collagen, elastic fibers, and the basal lamina 1,39 -has also been posited as the major load-bearing layer of the nerve; indeed, rabbit tibial nerves lost most of their loadbearing capabilities with perineurial breakage at strains of 27% beyond in-situ strain. 41 In both of these studies, as well as others, 3,42 the endoneurium and axons were spared under nerve tension, suggesting that axons did not sense or bear the same loads as surrounding connective tissue.…”

Local Administration of Methylprednisolone Laden Hydrogel Enhances Functional Recovery of Transected Sciatic Nerve in Rat

“…The strongest connective tissue layers in peripheral nerves are the perineurium and, to a lesser extent, the epineurium. Changes in the epineurium and perineurium extracellular matrix composition are likely to have significant effects on the biomechanical properties of acellular nerve [32]. The connective tissue from the epineurium forms a layer of fiber membrane at the 3rd day postoperatively and then forms collagen at the 8th day.…”