Mitochondrial abnormality in sensory, but not motor, axons in paclitaxel-evoked painful peripheral neuropathy in the rat

Abstract

The dose-limiting side effect of the anti-neoplastic agent, paclitaxel, is a chronic distal symmetrical peripheral neuropathy that produces sensory dysfunction (hypoesthesia and neuropathic pain) but little or no distal motor dysfunction. Similar peripheral neuropathies are seen with chemotherapeutics in the vinca alkaloid, platinum-complex, and proteasome inhibitor classes. Studies in rats suggest that the cause is a mitotoxic effect on axonal mitochondria. If so, then the absence of motor dysfunction may be due to mitotoxicity that affects sensory axons but spares motor axons. To investigate this, paclitaxel exposure levels in the dorsal root, ventral root, dorsal root ganglion, peripheral nerve, and spinal cord were measured, and the ultrastructure and the respiratory function of mitochondria in dorsal roots and ventral roots were compared. Sensory and motor axons in the roots and nerve had comparably low exposure to paclitaxel and exposure in the spinal cord was negligible. However, sensory neurons in the dorsal root ganglion had a very high and remarkably persistent (up to10 days or more after the last injection) exposure to paclitaxel. Paclitaxel evoked a significant increase in the incidence of swollen and vacuolated mitochondria in the myelinated and unmyelinated sensory axons of the dorsal root (as seen previously in the peripheral nerve) but not in the motor axons of the ventral root. Stimulated mitochondrial respiration in the dorsal root was significantly depressed in paclitaxel-treated animals examined 2-4 weeks after the last injection, whereas respiration in the ventral root was normal. We conclude that the absence of motor dysfunction in paclitaxel-evoked peripheral neuropathy may be due to the absence of a mitotoxic effect in motor neuron axons, while the sensory dysfunction may be due to a mitotoxic effect resulting from the primary afferent neuron's cell body being exposed to high and persistent levels of paclitaxel.

The Possible Role of Propolis in Ameliorating Paclitaxel-Induced Peripheral Neuropathy in Sciatic Nerve of Adult Male Albino Rats

“…Our study revealed swollen disrupted mitochondria in the affected myleinated axons, which coincides with many investigators who suggested that mitochondrial swelling is a characteristic sign in paclitaxel axonopathy [37,38] . This could be explained by affection of Mitochondrial permeability transition pore (mPTP) which is a high conductance channel in mitochondrial inner membrane that contains different proteins including adenine nucleotide translocator (ANT), mitochondrial phosphate carrier (PiC), voltage-dependent anion channel (VDAC), and cyclophilin-D (Cyp-D).…”

Animal Models of Peripheral Neuropathies

“…A similar low-dose regimen (2 mg/kg every other day for a total of 4 doses) also showed distal axonal degeneration, as evidenced by reduced intraepidermal nerve fiber densities and mitochondrial abnormalities [92,93]. Recent studies showed that mitochondria in sensory axons is more susceptible to the toxicity of paclitaxel compared to mitochondria in motor axons, providing a potential hypothesis as to fiber selectivity of paclitaxel-induced neuropathy [94].…”

Anti-Nociceptive Synergism of Pregabalin and Xylopic acid Co-administration in Paclitaxel induced Neuropathy: Isobolographic Analysis

“…21 Morphological changes such as swollen and vacuolated mitochondria as well as reduced respiration and energy production in axonal mitochondria that results from paclitaxel administration initiates apoptosis pathways by altering intracellular calcium levels. 4,22 Therefore, the neuropathy in this study after low dose paclitaxel administration was due to atypical (swollen and vacuolated) mitochondria in peripheral sensory axons, both C-fibers and myelinated axons as well as the loss of intraepidermal nerve fibres. Both agents may have acted centrally to produce analgesic synergism.…”

“…Evidence of swollen and vacuolated mitochondria in peripheral sensory axons, both C-fibers and myelinated axons has been reported. 4 Its use is limited by Myelossupression and peripheral neurotoxicity. 3 Clinically, the sensory neurotoxicity produced by paclitaxel include allodynia, numbness, tingling, and burning pain which often begin symmetrically in the feet and sometimes appear simultaneously in both hands and feet.…”