An evolving cellular pathology occurs in dorsal root ganglia, peripheral nerve and spinal cord following intravenous administration of paclitaxel in the rat

Abstract

Paclitaxel (Taxol®) is a frontline antineoplastic agent used to treat a variety of solid tumors including breast, ovarian, or lung cancer. The major dose limiting side effect of paclitaxel is a peripheral sensory neuropathy that can last days to a lifetime. To begin to understand the cellular events that contribute to this neuropathy, we examined a marker of cell injury/regeneration (activating transcription factor 3; ATF3), macrophage hyperplasia/hypertrophy; satellite cell hypertrophy in the dorsal root ganglion (DRG) and sciatic nerve as well as astrocyte and microglial activation within the spinal cord at 1, 4, 6 and 10 days following intravenous infusion of therapeutically relevant doses of paclitaxel. At day 1 post-infusion there was an up-regulation of ATF3 in a subpopulation of large and small DRG neurons and this up-regulation was present through day 10. In contrast, hypertrophy of DRG satellite cells, hypertrophy and hyperplasia of CD68+ macrophages in the DRG and sciatic nerve, ATF3 expression in S100β+ Schwann cells and increased expression of the microglial marker (CD11b) and the astrocyte marker glial fibrillary acidic protein in the spinal cord were not observed until day 6 post infusion. The present results demonstrate that using the time points and markers examined, DRG neurons show the first sign of injury which is followed days later by other neuropathological changes in the DRG, peripheral nerve and dorsal horn of the spinal cord. Understanding the cellular changes that generate and maintain this neuropathy may allow the development of mechanism-based therapies to attenuate or block this frequently painful and debilitating condition.

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

“…CD68 is a glycoprotein found in cytoplasmic granules in many cells of macrophages lineage. Sections of sciatic nerves from paclitaxel-treated animals showed a significant increase in density of CD68-immunoreactive macrophages within the endoneurium compared to non-treated rats consistent with Peters et al, 2007 [42] . The presence of many macrophages could be explained by proliferation of resident macrophages or migration of hematogenous macrophages [47] .…”

“…Noteworthy, myleinopathy or demyelination commonly followed axonal affections [42] ,whereas, the myelin membrane is susceptible to toxic substances that can result in structural changes like edematous splitting and disruption [43] .…”

The Effect of Anakinra on Paclitaxel-Induced Peripheral Neuropathic Pain in Rats

“…It has been reported in several studies that paclitaxel is responsible for the development of peripheral neuropathic pain by increasing proinflammatory IL-1β expression (8)(9)(10)(11)(12). The IL-1β gene expression level increased in the paclitaxel group (PAC) compared to that in the HG and decreased in the groups in which anakinra was administered.…”

“…It has been found in numerous studies that reactive oxygen species (ROS) cause nerve injury-related pain and inflammatory pain (7). Paclitaxel has also been reported to activate proinflammatory cytokine expression (8)(9)(10)(11). Thus, the administration of paclitaxel results in the production of interleukin-1 beta (IL-1β) and other proinflammatory cytokines and their release from microglial cells.…”

Inactivation of GABAA receptor is related to heat shock stress response in organism model Caenorhabditis elegans

“…Thereafter, head and body areas in C. elegans were outlined, and then, integrated optical density (IOD) was measured. IOD is a parameter describing the average fluorescence intensity per area or volume of fluorescence (IOD = area × fluorescence intensity) (Belelli and Lambert 2005;Peters et al 2007). All values obtained were normalized to the untreated control mean and expressed as a percent of change.…”