The role of PPARγ in chemotherapy-evoked pain

Abstract

Although millions of people are diagnosed with cancer each year, survival has never been greater thanks to early diagnosis and treatments. Powerful chemotherapeutic agents are highly toxic to cancer cells, but because they typically do not target cancer cells selectively, they are often toxic to other cells and produce a variety of side effects. In particular, many common chemotherapies damage the peripheral nervous system and produce neuropathy that includes a progressive degeneration of peripheral nerve fibers. Chemotherapy-induced peripheral neuropathy (CIPN) can affect all nerve fibers, but sensory neuropathies are the most common, initially affecting the distal extremities. Symptoms include impaired tactile sensitivity, tingling, numbness, paraesthesia, dysesthesia, and pain. Since neuropathic pain is difficult to manage, and because degenerated nerve fibers may not grow back and regain normal function, considerable research has focused on understanding how chemotherapy causes painful CIPN so it can be prevented. Due to the fact that both therapeutic and side effects of chemotherapy are primarily associated with the accumulation of reactive oxygen species (ROS) and oxidative stress, this review focuses on the activation of endogenous antioxidant pathways, especially PPARγ, in order to prevent the development of CIPN and associated pain. The use of synthetic and natural PPAR а agonists to prevent CIPN is discussed.

1. Introduction

Cancer continues to be a leading cause of death worldwide, second only to cardiovascular disease. Thankfully, sensitive tests for early diagnosis and powerful chemotherapeutic treatments have increased cancer survival significantly. However, chemotherapies are associated with serious side effects that cause additional suffering for patients and reduce their quality of life. Drug resistance and the side effects of chemotherapy, particularly painful peripheral neuropathy, represent major obstacles to the successful treatment of cancer. Here we review the roles of reactive oxygen species and oxidative stress in the development of chemotherapy-induced painful peripheral neuropathy, and the activation of endogenous antioxidant pathways, specifically peroxisome proliferator-activated receptor γ (PPARγ) signaling, as a potential approach to protect peripheral nerves from the damage caused by chemotherapy.

Many chemotherapeutic agents cause damage to the peripheral nervous system [1]. There are six classes of chemotherapies that cause nerve damage. These are platinum-based drugs, vinca alkaloids, taxanes, epothilones, proteasome inhibitors and immunomodulatory therapies. The platinum-based agents, taxanes, epothilones, and proteasome inhibitors are the most toxic to the nervous system. Chemotherapy-induced peripheral neuropathy (CIPN) represents a variety of neuropathies that involve large and small nerve fibers, and can include sensory, motor and autonomic fibers, often resulting in demyelination and axonal degeneration. Sensory neuropathy is the most common type of neuropathy from chemotherapy [2,3]. Sensory symptoms are most intense distally in the feet and hands with a “glove and stocking” distribution. Symptoms typically include impaired tactile sensation and numbness, tingling, paresthesia and dysesthesia [4]. Moreover, the neuropathy can be painful with sensations of burning, shooting or electric shock-like pains as well as mechanical or thermal hyperalgesia that result from activation and sensitization of nociceptors [5–9]. Motor symptoms occur less frequently than sensory symptoms and include muscle weakness, as well as disturbances in gait, balance and movement [10]. Collectively, these symptoms are the major dose-limiting side effect of chemotherapy [11] and can persist for years after chemotherapy treatment has ended [12].

The prevalence and severity of CIPN is dependent on many factors including the chemotherapeutic agent, combinations of chemotherapies, single and cumulative doses, duration of therapy, age, coexisting neuropathy (for example, diabetic neuropathy), genetic susceptibility, and alcohol abuse. The incidence and severity of CIPN vary considerably among agents when administered alone or in combination, but for vincristine, cisplatin, oxaliplatin, and paclitaxel, estimates for the occurrence of CIPN are as high as 90% or more [13–16]. Approximately 68% of patients receiving chemotherapy develop CIPN within the first month of treatment [2]. Since there is no generally accepted effective method to prevent the development of CIPN or reverse nerve damage once it occurs, a better understanding of the mechanisms that cause CIPN is needed so that therapeutic approaches can be developed.

Cellular targets of chemotherapeutic drugs differ among classes of agents and include DNA damage, disruption of microtubules and axonal transport, altered ion channel activity, damage to myelin, immunological changes and neuroinflammation [17]. For example, platinum-based therapies cause damage to nuclear and mitochondrial DNA [18–20] whereas taxanes cause microtubule disruption [21]. A common consequence of chemotherapeutic agents [e.g, paclitaxel [22,23]; vincristine [24]; cisplatin [25] is the increased formation of reactive oxygen species (ROS) and oxidative stress. Indeed, most chemotherapeutics elevate intracellular levels of ROS in cancer cells, and their effectiveness for reducing tumor growth is associated with ROS-mediated injury and apoptosis [26]. However, somatosensory neurons in the peripheral nervous system are particularly sensitive to chemotherapeutics because dorsal root ganglia (DRG) lack a blood brain barrier to restrict access of the drugs and they have lower capacity to manage ROS [27]. Elevated ROS can lead to apoptosis in peripheral sensory neurons by activating a mitochondrial-associated apoptotic pathway that includes activation of caspase and dysregulation of calcium homeostasis [28,29].

2. ROS signaling

In aerobic metabolism, the incomplete, partial, or monovalent reduction of molecular oxygen gives rise to ROS that have one or more unpaired electrons making them free radicals and powerful oxidants. ROS can be formed non-enzymatically by chemical, photochemical and electron transfer reactions, or as the byproducts of endogenous enzymatic reactions, phagocytosis, and inflammation [30]. Generation of ROS occurs in subcellular compartments such as the mitochondria [31], the endoplasmic reticulum [32], the plasma membrane [33], peroxisomes [34], cytoplasm and lysosomes [35]. A number of cellular metabolic enzymes, such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, xanthine oxidase, nitric oxide synthase (NOS), flavoproteins, CYP enzymes, oxidases, and myeloperoxidase are directly involved in the production of ROS [36]. Cytochrome P450 (CYP450) also generates ROS, in particular, ^•O₂⁻ and H₂O₂. ROS can be produced during oxidation of arachidonic acid to prostaglandins, thromboxanes, and leukotrienes by membrane associated enzymes such as cyclooxygenase and lipoxygenase [37].

The occurrence of ROS in biological systems was first described in 1954 [38]. In the same year, the toxic effects of oxidizing free radicals under conditions of high oxygen tension was demonstrated as well [39]. ROS regulate a variety of cellular responses that range from prosurvival pathways (antimicrobial and tumor inhibition) to “antisurvival” pathways [40]. Under normal physiological conditions, the intracellular level of ROS is maintained at a steady and low level by the equilibrium between their production and elimination by an endogenous antioxidant system. Endogenous antioxidants include low-molecular-weight antioxidants (e.g., ascorbic acid, vitamin E, and glutathione) and antioxidant enzymes (e.g., superoxide dismutase, catalase, glutathione peroxidase, and thioredoxins). In the central nervous system, ROS are generated downstream to activation of NMDA receptors by glutamate and play a role as intracellular messengers through the activation of protein kinases and other intracellular enzymes [41].

The abundance of ROS causes irreversible changes in proteins, lipids, carbohydrates, and nucleic acids that lead to cell damage with subsequent effects on cell activity and survival [42]. The specific effects of ROS occur in part through the covalent modification of specific cysteine residues found within redox-sensitive target proteins resulting in the modification of enzymatic activity [43]. For example, through the oxidation of redox-sensitive cysteine residues ROS activates p38a MAPK, promoting neuroinflammation and subsequently neurotoxicity [44]. A causal relationship between oxidative stress and peroxisome proliferator-activated receptor γ (PPARγ) a nuclear receptor involved in limiting ROS, was also shown. Following cisplatin treatment PPARγ protein was reduced in DRG and was associated with oxidative stress [25]. Thus ROS lead to aberrant cell dysfunction and cell death, and thereby contribute to disease development. Oxidative stress is implicated in the initiation and progression of neurodegenerative diseases such as Alzheimer’s disease [45], Parkinson’s disease [46], and multiple sclerosis [47]. An excess of ROS also contributes to peripheral neuropathy in diabetes [48], acrylamide toxicity [49], and Charcot-Marie syndrome [50,27], as well as the pathophysiology of somatic [51,52] and visceral pain [53]. ROS mediate their effects in part via activation of nuclear factor-κB (NF-κB), protein-1 (AP-1), and signal transducer and activator of transcription (STAT)-1 and STAT3 transcription factors leading to up-regulation of proinflammatory genes and cytokines that include TNF-α, interleukin 1 (IL-1), IL-6, IL-8, and transcription of other inflammatory genes [54–59]. These changes, as well as increased expression of COX-2 [60] and iNOS [61] which are both regulated in part by NF-kB [62], are relevant to pain.

Oxidative stress and ROS are also associated with chronic pain and hyperalgesia. Oxidative stress pathways parallel those that contribute to pain associated with central sensitization, leading to increased responses of nociceptive spinal neurons to innocuous and noxious stimuli (i.e., secondary hyperalgesia) [63–67]. Reducing ROS decreased secondary hyperalgesia and central sensitization produced by capsaicin [68] as well as long term potentiation in the spinal cord [69]. In the periphery, ROS contribute to hyperalgesia following acute inflammation [70,71]. ROS may also play a direct role in activation of transient receptor potential (TRP) channels that underlie transduction of sensory stimuli (TRPV1 [72]; TRPA1 [73]) or enhance their activity [74]. Increasing the activity of these channels in DRG neurons can alter the excitation of neurons and the propagation of nociceptive sensory signals. In an animal model of neuropathic pain, spinal (i.e., intrathecal) administration of ROS scavengers phenyl-N-tert-butylnitrone (PBN) and 5,5-dimethylpyrroline-N-oxide (DMPO) was more efficacious than systemic or intracerebroventricular administration [75,76] in attenuating mechanical hyperalgesia. Following nerve injury, ROS in the spinal cord might contribute to pain by decreasing GABAergic transmission [77] or by increasing excitatory synaptic strength (e.g. mitochondrial superoxide) [78].

In patients and in preclinical models, neuropathic pain produced by chemotherapy was dependent on oxidative stress and accumulation of ROS in the periphery and/or the spinal cord depending on the chemotherapeutic agent [3,22,27,67]. In some cases the accumulation of ROS was due to decreased activity of antioxidant enzymes [22,25]. Recent studies indicate that ROS are pivotal in CIPN by decreasing axonal outgrowth and promoting abnormal impulse transmission, hyperexcitability, spontaneous or ectopic discharge, and pain [5,7,25,79,80]. For example, oxidative stress contributed to cisplatin-induced hyperalgesia and a corresponding decrease in the electrical threshold of Aδ and C fibers [80]. Systemic administration of the ROS scavenger PBN blocked the accumulation of ROS and attenuated cisplatin-induced hyperalgesia [25,80]. In addition to a likely systemic effect, experiments in vitro demonstrated that ROS generated by cisplatin sensitized small DRG neurons directly and co-incubation with PBN reversed the effect of cisplatin [25]. Paclitaxel-induced painful neuropathy is also associated with an increase in mitochondrial ROS in DRG [22,81], and ROS scavengers decreased ROS in DRG and attenuated hyperalgesia. However, clinical studies combining nutraceuticals with antioxidant properties and chemotherapy have been disappointing. Use of vitamin E, acetyl-L-carnitine, glutamine, glutathione, vitamin B6, omega-3 fatty acids, magnesium, calcium, α-lipoic acid and n-acetyl cysteine as adjuvants to cancer treatments showed controversial results [82–87]. For example, dietary beta carotene, a precursor of vitamin A, increased the incidence and mortality of lung cancer [88], and vitamin E supplements increased the risk of prostate cancer in healthy men [89]. Moreover, the adjunct use of antioxidants also reduced the efficacy of chemotherapy and radiation therapy in some forms of cancer [90]. Thus, there is no clinical evidence to recommend ROS scavengers for the treatment or prophylaxis of CIPN.

3. Neuroprotective role of PPARγ and its ligands

A promising approach to potentially reduce chemotherapy-induced oxidative stress and CIPN is to enhance endogenous antioxidant responses in healthy cells, including neurons. Mammalian cells have evolved a unique metabolic strategy to protect themselves against oxidative damage induced by ROS: two transcription factors, PPARγ and nuclear factor erythroid 2p45-related factor 2 (Nrf2), play key roles in defending cells against oxidative stress [91].

PPARγ belongs to the family of PPAR nuclear receptors that also includes PPARα and PPARβ/δ. They share a common structure consisting of a DNA binding domain at the N-terminus and a ligand binding domain at the C-terminus. Of the three PPAR subtypes, PPARγ is the most studied and is further subdivided into the three isoforms: PPARγ1, PPARγ2, and PPARγ3. Each specific isoform is tissue- and function-specific. Although PPARγ1 is widely expressed among tissues, PPARγ2 occurs exclusively in adipose tissue [92] and PPARγ3 is expressed in hematopoietic stem and progenitor cells [93]. PPARγ is expressed throughout the central nervous system, in neurons and glia, as well as in DRG [94], but under physiological conditions expression is higher in neurons than in glia [95]. PPAR heterodimerizes with the retinoid X receptor (RXR) inducing a conformational change in the receptor that allows the PPAR:RXR complex to bind to a PPAR response element (PPRE) in the promoter region of a target gene. Co-activators are important in defining the pattern of genes activated by PPAR ligands. PGC-1α, a co-activator of PPARγ, contributes to the expression of genes involved in glucose, lipid and energy metabolism, and promotes mitochondrial biogenesis [96]. In the absence of a ligand, PPARγ:RXR can recruit a corepressor to the complex to suppress transcription of a gene. This keeps the basal levels of PPARγ-mediated transcription minimal [97]. In the presence of ligand, the corepressor dissociates and a coactivator binds to the PPAR:RXR complex to initiate mRNA synthesis.

PPAR signaling is directly related to PPAR expression, its interactions with ligands and post-translational modification. Different ligands bind to PPARγ in different ways, inducing different conformations and different transcription patterns [98,99]. For example, synthetic ligands not only compete for a hydrophobic binding pocket for PPARγ activation by endogenous ligands, but also bind to an alternative site that promotes PPARγ hyperactivation in vivo. Thus, allosteric regulation may explain the adverse effects of some synthetic ligands [100]. Genes controlled by PPARγ are differentially regulated not only by agonist binding but also by post-translational modifications that include phosphorylation, SUMOylation, and ubiquitination of PPARγ [98,101,102]. For example, phosphorylation by MAPK decreases PPARγ activity [103]. CDK5-mediated phosphorylation of PPARγ leads to reduced insulin sensitivity [98,99], and SUMOylation at Lys395 is strongly associated with PPARγ transrepression of nuclear factor NF-κB [102]. Thus blocking the activity of other transcription factors by this non-genomic mechanism may underlie some of the anti-inflammatory effects mediated by PPARγ [104].

3a. PPARγ ligands

Natural and synthetic PPARγ ligands have been identified and are of considerable scientific and clinical interest because PPARγ controls the expression of hundreds of genes. A number of putative natural ligands for PPARγ-dependent gene transcription have been identified on the basis of their ability to stimulate receptor activity, although their endogenous roles in vivo remain uncertain. PPARγ is activated by a range of endogenous bioactive lipids including polyunsaturated fatty acids (PUFAs), their lipoxygenase, cyclooxygenase and nitrated metabolites as well as lysophosphatidic acid, albeit at very high and possibly supraphysiological concentrations. Free polyunsaturated fatty acids activate PPARs with relatively low affinity, whereas fatty-acid derivatives show higher affinity and selectivity [105,106]. 15-deoxy-Δ12,14-prostaglandin J2 (PGJ2), an oxidized fatty acid, was recognized as the first natural ligand of PPARγ [107,108]. Subsequently, two oxidized fatty acids [9-hydroxyoctadecadienoic acid (9-HODE) and 13-hydroxyoctadecadienoic acid (13-HODE)] and two nitrated fatty acids [nitrated linoleic (LNO2) and oleic acids (OA-NO2)] were shown to activate PPARγ-dependent gene transcription with potency rivaling that of rosiglitazone [109–111]. Recently, resolvin E1 was determined to bind to the ligand binding domain of PPARγ with affinity comparable to rosiglitazone [106], a synthetic PPARγ agonist, suggesting its potential as an endogenous agonist. Using reporter gene assays, binding studies with selective antagonists in vitro and in vivo, and small interfering RNA (siRNA) knockdown, endocannabinoids such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG) have been identified as additional promising PPARγ ligands [112,113]. For example, AEA initiates transcriptional activation of PPARγ by binding to the PPARγ ligand binding domain in a concentration-dependent manner in multiple cell types [114]. In addition to AEA, 2-AG and 15-Deoxy-delta12,14-prostaglandin J2-glycerol ester, a putative metabolite of 2-AG, were shown to suppress expression of IL-2 in a reporter gene assay through binding to PPARγ [115,116]. Therefore, the interaction between endocannabinoids and PPARγ may include direct binding of endocannabinoids or their hydrolyzed or/and oxidized metabolites to PPARγ. The possible modulation of PPARγ-dependent gene expression down stream of intracellular signaling cascades initiated by activation of cannabinoid receptors cannot be excluded.

It is interesting to note that there is a feed forward loop in bioactive lipid signaling and PPARγ. Due to their hydrophobic nature, endogenous PPAR ligands are delivered to the receptors by fatty-acid-binding proteins (FABPs) [97]. Since the PPARγ response element is located in the promoters of fabp genes [117], it is not surprising that treatment with a PPARγ ligand increases PPARγ-dependent expression of FABP4 in monocyte-derived dendritic cells [118], and a large number of fatty acids transported by FABP5 stimulate PPARγ-dependent gene expression [119].

Synthetic PPARγ agonists consist of several subgroups: the thiazolidinediones (TZD, rosiglitazone, pioglitazone and troglitazone), the non-TZD agonists (ciglitazone, netoglitazone and rivoglitazone, the PPARα/γ dual and PPARα/γ/δ pan-agonists as well as the selective PPARγ modulators, [120]. Unexpectedly, non-steroidal anti-inflammatory drugs (flufenamic acid, ibuprofen, fenoprofen, and indomethacin A) are also weak PPARγ ligands. The TZDs were the first family of synthetic PPARγ ligands [121] and are the standard for full PPARγ agonist activity. Currently, TZDs are used clinically to improve glucose homeostasis, insulin sensitivity and lipid metabolism. Thus they have benefits for patients with diabetes [122] and cardiovascular disease [123,124].

3b. PPARγ and neuroprotection

PPARγ agonists mitigate neuroinflammation in two ways: 1) by direct inhibition of NF-kB and 2) by increasing expression of enzymes that decrease ROS. In multiple tissues, activation of PPARγ leads to upregulation of key antioxidant enzymes, including superoxide dismutase, glutathione peroxidase, and catalase [125–127]. In contrast to its role in ligand activation of gene expression by binding of the nuclear receptor to PPRE, PPARγ blocks expression of genes promoted by other classes of transcription factors [128]. PPARγ agonists reduce inflammation by promoting inhibition of pro-inflammatory transcription factors (e.g., NF-κB, STAT1, STAT3, AP-1 and NFAT) thereby decreasing synthesis of mRNA of enzymes and mediators that promote the formation of ROS, including COX-2, inducible nitric oxide synthase (iNOS), and proinflammatory cytokines [129]. The anti-oxidant activity of PPARγ in combination with its inhibition of NF-κB underlies the function of PPARγ in neuroprotection. Neuroprotective effects of PPARγ agonists have been reported in animal models of peripheral neuropathies including nerve injury-induced neuropathic pain, trigeminal neuropathic pain and diabetic neuropathy [130–132]. Ghosh and colleagues [133] reported that pioglitazone reduced mitochondrial ROS in a neuron-like cell line by up-regulating mitochondrial oxidative phosphorylation, mitochondrial biogenesis and antioxidant defense enzymes. In animal models, TZDs attenuated inflammation-associated chronic and acute neurological disorders such as stroke, spinal cord injury, and traumatic brain injury [134]. In diabetic neuropathy, pioglitazone reduced proinflammatory cytokines TNF-α and 1L-1B in the sciatic nerve, normalized expression of Nav1.7 channels that underlie neuronal excitability, and increased expression of the PPARγ gene in the spinal cord [132]. Similarly, pretreatment with pioglitazone protected cortical neurons from H₂O₂-mediated damage by the increasing the expression of PPARγ mRNA and protein and a downstream increase in catalase [135]. It is noteworthy that rosiglitazone also protected hippocampal and DRG neurons from experimentally induced mitochondrial damage by increasing the expression of the anti-apoptotic protein Bcl-2 [136]. Similarly, in auditory hair cells, pioglitazone blocked gentamicin toxicity by upregulating genes that decrease ROS and prevent apoptosis [137].

PPARγ does not act alone to reduce oxidative stress. PPARγ regulates Nrf2, a master redox-sensing transcription factor that binds the antioxidant response element (ARE) to activate antioxidant systems and mute the destructive effects of oxidative stress [91,138]. In addition to PPARγ-mediated modulation of the Nrf2/ARE pathway, Nrf2 also regulates PPARγ/PPRE, suggestive of a bidirectional loop [139]. Thus, there is a direct relationship between PPARγ and Nrf2: in the absence of Nrf2 PPARγ expression decreases, and vice versa. For example, PPARγ expression was markedly reduced in Nrf2 null mice compared to wild-type mice [139]. Furthermore, TZDs simultaneously upregulated expression of PPARγ and Nrf2 in animal models of oxidative stress [140]. Importantly, some antioxidant genes such as catalase, glutathione S-transferase and superoxide dismutase contain both a PPRE and an ARE and are regulated by both PPARγ and Nrf2 to elicit anti-oxidative effects. In addition, PPARγ and Nrf2 synergistically inhibited the NF-κB pathway to produce anti-inflammatory effects [142]. Thus, clinical benefits of TZDs in CIPN arise from their ability to reduce oxidative stress and inflammation. Similarly, the analgesic properties of PPAR agonists have been demonstrated in a variety of preclinical pain models [94].

Interestingly, PPARγ agonists play an important role in overcoming neuronal insulin resistance in conditions of dysfunctional carbohydrate and lipid metabolism, although the contribution of insulin receptors to neuroprotection in CIPN is not known. Neurons are not dependent on insulin for glucose uptake as muscle or adipose tissue, but they are insulin-responsive [143]. Neuronal insulin receptors couple to two cellular signaling pathways, Akt and MAPK, that promote neuron survival and axonal growth [144]. Insulin receptors are especially high at the perikaryon of small-diameter sensory DRG neurons, suggesting the involvement of insulin signaling in nociceptive pathways [145]. Increased ROS levels are an important trigger for insulin resistance [146,147], but there is only one report of insulin resistance in C-fibers of cisplatin treated guinea pigs [148]. Because the occurrence of insulin resistance in CIPN has not been adequately addressed, we cannot exclude the possibility that a neuroprotective role of PPARγ agonists in CIPN is mediated by improved insulin receptor sensitivity.

Another important benefit of PPARγ is its potential use in cancer therapy and prevention. Activation of PPARγ by TZDs is tumor suppressive in human breast, prostate, colon, bladder and lung cancer, as well as in osteosarcoma and leukemia [149–152]. Since NF-KB signaling and insulin resistance are associated with an increased risk of several cancers, including breast, rectal, liver, and pancreatic cancers, PPARγ ligands can suppress tumors while reducing NF-KB and insulin resistance, resulting in cancer cell reprogramming, differentiation and survival [151,153].

4. Conclusion

Although the pharmacological agonists of PPARγ exhibit promising therapeutic properties in treatment of painful CIPN due to their profound ability to attenuate oxidative stress and inhibit ROS-related downstream pathways, recent interest in these nuclear receptors has faded. Several clinical trials have shown that it is difficult to develop a PPARγ ligand without concomitantly inducing unacceptable side-effects. Two TZDs (rosiglitazone and pioglitazone) are currently available in the United States but were suspended by the European Medicines Agency owing to concerns that the overall risks of rosiglitazone and pioglitazone exceed their benefits. Moreover, PPARγ ligands have been neuroprotective in animal models [154–156], but not in clinical settings [157,158]. In this regard, a thorough study of the role and potential benefits of endogenous PPARγ ligands may reveal new therapeutic and safe approaches for preventing CIPN with minimal risks. Tissue specific targeting also could pave the way to renewed interest and clinical use of PPAR ligands.

Figure 1.

Treatment with chemotherapeutic agents generates reactive oxygen species (ROS) and promotes oxidative stress. Although this is an underlying mechanism for reducing tumor growth, ROS can sensitize nociceptors that mediate pain directly as well as indirectly through increased expression of inflammatory mediators such as tumor necrosis factor-a (TNF-α), interleukins and oxidized lipids (e.g., prostaglandins) generated by cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). ROS activates pro-inflammatory transcription factors including nuclear factor-κB (NF-κB), protein-1 (AP-1), and signal transducer and activator of transcription (STAT)-1 and −3. See text for additional details.

Figure 2.

Pathways regulated by Peroxisome proliferator-activated receptor γ (PPARγ) reduce levels of reactive oxygen species (ROS). PPARγ heterodimerizes with the retinoid X receptor (RXR) to activate the PPAR response element (PPRE) on target genes. Activation of gene transcription increases the expression of genes such as catalase and superoxide dismutase that catabolize ROS. PPARγ also mediates transrepression of pro-inflammatory transcription factors such as nuclear factor-κB (NF-κB), protein-1 (AP-1), and signal transducer and activator of transcription (STAT)-1 and −3. PPARγ-mediated gene repression reduces levels of enzymes that generate ROS: cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Endogenous agonists for PPARγ include15-deoxy-Δ12,14-prostaglandin J2 (PGJ2), resolving E1 and endocannabinoids such as anandamide and 2-arachidonoylglycerol. Synthetic agonists include pioglitazone, a thioglitazone. See text for additional details.

Highlights.

• Peripheral neuropathy is a common side effect of many chemotherapeutic agents.

• Chemotherapy-induced peripheral neuropathy (CIPN) can be painful and long-lasting.

• Reactive oxygen species (ROS) are contributing factors to CIPN.

• Activating endogenous antioxidant pathways, particularly PPARγ, may prevent CIPN.