Elsevier

Brain Research

Volume 1168, 7 September 2007, Pages 46-59
Brain Research

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

https://doi.org/10.1016/j.brainres.2007.06.066Get rights and content

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 ganglia (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 (GFAP) 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.

Introduction

Administration of the chemotherapeutic agent paclitaxel can induce a dose-dependent peripheral sensory neuropathy in a subset of patients receiving this therapy for breast, ovarian, and non-small cell lung cancer (Lee and Swain, 2006, Mielke et al., 2006). Following administration of paclitaxel patients may experience a range of positive sensory symptoms including spontaneous tingling, burning pain, joint and muscle pain (Postma et al., 1995, Quasthoff and Hartung, 2002, Dougherty et al., 2004) that often occur in the distal extremities in a “glove and stocking” distribution. These symptoms may increase in severity and be accompanied by sensory deficits including numbness, loss of vibratory sensation, decreased deep tendon reflexes and decreased proprioceptive abilities (Rowinsky et al., 1993, Postma et al., 1995). In many patients, these symptoms spontaneously resolve following discontinuation of therapy, while in others they may persist for weeks to a lifetime (Pignata et al., 2006). Despite the widespread incidence of paclitaxel-induced peripheral neuropathy (PIPN) and increasing use of paclitaxel in the treatment of various tumors (Giordano et al., 2006), there is currently no accepted standard of care to prevent/treat the pain or sensory dysfunction associated with this condition. The lack of standard treatment strategies is in part due to a lack of information regarding the cellular mechanisms responsible for the development of PIPN.

Recently, using a previously characterized model of PIPN (Cliffer et al., 1998), we reported pathological features in the dorsal root ganglia (DRG) and sciatic nerve 10 days following intravenous administration of paclitaxel in rats (Peters et al., 2007). This cellular pathology was accompanied by behavioral changes indicative of a sensory neuropathy including cold and mechanical allodynia as well as behavioral deficits in coordination (Peters et al., 2007). Examination of sensory ganglia at multiple levels of the neuroaxis revealed that the cellular pathology occurred in a length-dependent manner (Jimenez-Andrade et al., 2006) similar to the pattern of symptoms observed in patients treated with taxanes. What remains unknown is the time course of the evolution of cellular events that occur following intravenous paclitaxel administration. In the current study, we examined the time course of changes in markers of cell injury/regeneration (ATF3), activation of satellite cells (GFAP), macrophage hypertrophy and hyperplasia (CD68) and microglial and astrocyte activation/hypertrophy (CD11b and GFAP, respectively) within the DRG, sciatic nerve, and spinal cord following intravenous administration of paclitaxel in the rat.

Section snippets

Time course of neuronal and non-neuronal ATF3 expression in the DRG of paclitaxel-treated rats

In the current study, we examined immunohistochemically the levels of activating transcription factor 3 (ATF3) in the DRG of rats that received intravenous paclitaxel or vehicle. We administered two infusions of paclitaxel at a dose of 18 mg/kg (day 0 and day 3; 36 mg/kg cumulative dose). We examined ATF3 expression in fourth lumbar (L4) DRG at days 1, 4, 6 and 10 following the first infusion. The percentage of ATF3-immunoreactivity (IR) neuronal profiles significantly increased in

Impact of intravenous paclitaxel on sensory neurons in the DRG

PIPN is a continuing challenge in the treatment of cancer as it can have a significant impact on cancer patient's quality of life and survivorship (Mantyh, 2006). Despite the widespread incidence of this neuropathy, the cellular mechanisms responsible for its development are largely unknown. In the present study, the up-regulation of ATF3 by a subset of small, medium and large sensory neurons was the first cellular marker of those we examined to show a change following intravenous infusion of

Animals and drugs

All procedures were approved by the Institutional Animal Care and Use Committee at the University of Minnesota. Adult male Sprague Dawley rats (250–275 g; Harlan, Indianapolis, IN) were used in the present study. Paclitaxel was formulated by dissolving paclitaxel (Eton Bioscience, San Diego, CA) in Cremophor EL and dehydrated ethanol (1:1) to make a stock solution of 12 mg/ml. Prior to administration, the paclitaxel solution was further diluted with sterile saline (1:3). The paclitaxel solution

Acknowledgments

This work was supported by National Institutes of Health grants (NS23970, NS048021), a Merit Review from the Veterans Administration, and NIH Musculoskeletal Training grant T32 AR 050938-01.

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