Introduction Chemotherapy induced peripheral neuropathy (CIPN) remains one of the major limitations in oncology clinics due to increasing number of cancer patients, lack of effective treatment strategy, relapse of disease [1]. Around 30–40% of patients undergoing chemotherapy develop peripheral neuropathy and experience symptoms of pain and sensory disturbances [2]. According to National Cancer Institute (NCI), CIPN is one of the major reasons responsible for cessation of treatment, and hence is responsible for decreased chemotherapeutic efficacy and higher relapses [3]. Symptoms of peripheral nerve damage range from sensorimotor deficits (tingling sensation, burning pain in the arms, allodynia and hyperalgesia) to various functional deficits (impaired axonal transmission and reduced nutritive blood flow to nerves [4]). The most frequent agents causing CIPN are platinum compounds, taxane derivatives, vinca alkaloids, epothilones, thalidomide and bortezomib, which adversely affect the peripheral nervous system through dissimilar mechanisms summarized in Fig. 1 [5]. Although, the molecular pathomechanism and severity may vary with the inducing agent, physical damage to the neurons by chemotherapeutic agent is a common mechanism underlying the disease pathology [4]. The physical damage by chemotherapeutic drugs leads to functional impairment in neurons through oxidative stress, inflammation, apoptosis and electrophysiological disturbances. The scope of the present review is to present a basic idea on the possible role of oxidative stress and related pathomechanisms in CIPN based upon the existing experimental evidences. Susceptibility of peripheral nervous system (PNS) to oxidative stress It is a recognized fact that antineoplastic agents produce reactive oxygen species (ROS) to induce apoptosis in cancer cells [6]. However, ROS generated during chemotherapy may interfere with the normal cells and tissues and may be associated with the various toxic events like cardio toxicity, nephrotoxicity, neurotoxicity, etc. Certain structural and functional attributes of peripheral nervous system (PNS) make it more susceptible for accumulation of chemotherapeutics and some neurotoxins (Fig. 2) [5]. Lack of an efficient vascular barrier and absence of lymph drainage make the PNS more prone to toxic chemical insults. In addition mammalian nerves are known to be more susceptible to oxidative stress because of their high content of phospholipids, mitochondria rich axoplasm and also due to weak cellular antioxidant defences [7]. It has also been recently observed that structural and functional impairment caused by anti-cancer drugs enhances mitochondrial free radical production. Oxidative stress generated in this regard causes physical damage to neurons by demyelination, mitochondrial dysfunction, microtubular damage and apoptosis [8]. Role of oxidative stress in the neuronal damage and incidence of neuropathic pain Although neurotoxicity caused by different classes of chemotherapeutic drugs differs to a significant extent, peripheral neuronal degeneration or small fiber neuropathy remains the end result of all CIPNs. It is been suspected that this might occur by a common mechanism i.e. increased neuronal oxidative stress as presented in Fig. 3. In fact, oxidative stress is identified to be responsible for the neuronal damage in different models of neuropathies such as diabetic neuropathy, acrylamide induced neuropathy and Charcot–Marie neuropathy [9–12]. These observations laid the foundation for investigating possible involvement of oxidative stress in CIPN. Chemotherapy induced mitochondrial dysfunction and corresponding oxidative stress generation mediate the peripheral nerve damage. Oxidative stress mediated neurodegeneration can execute through bioenergetic failure, depletion of antioxidant defences, bio molecular damage, microtubular disruption, ion channel activation, demyelination, neuroinflammation, mitophagy impairment and neuronal death through apoptosis [13–15]. The redox imbalance produced in neuronal cells can be pharmacologically modulated through adjustment of nuclear erythroid factor-2 related factor and nuclear factor kappa light chain enhancer of B cells balance (Nrf2–NF-κB axis), and hence these modulators have been tested for their efficacy in animal models of peripheral neuropathy [16,17]. An attempt has been made to test peroxynitrite scavengers, PARP inhibitors in animal models of CIPN, based on previous reports of their beneficial effect in diabetic neuropathy [18,19]. Attenuation of symptoms of CIPN by the usage of peroxynitrite scavengers and PARP inhibitors further supports a role of nitrosative–oxidative stress in CIPN [15,20]. Mitochondrion: an emerging target in CIPN Several prospective experimental studies in animal models suggested that mitochondrial dysfunction is associated with chemotherapy and axonal mitotoxicity contributes to neuropathic symptoms produced by various chemotherapeutic agents such as taxanes, vinca alkaloids, platinum compounds and bortezomib [21–25]. In fact histological and microscopic observation of peripheral nerve sections of chemotherapeutic drug treated animals showed swollen and vacuolated mitochondria. These features indicate neuronal apoptosis that may be through pathways like caspase activation and Ca2+ dysregulation. Paclitaxel induced apoptosis is mainly due to cytochrome c (Cyt c) release and Ca2+ dysregulation through the opening of mPTP of mitochondria [26,27]. Frataxin deficiency, mt DNA damage, formation of defective electron transport chain (etc) components and loss in antioxidant defense enzymes has been demonstrated as mechanism for platinum compounds induced neuropathy [27]. Accumulation of dysfunctional mitochondria due to inefficient mitophagy further increases the free radical leakiness and this vicious cycle of oxidative damage to the bio molecules and mitochondria provides a feed-forward mechanism, that leads to further accumulation of ROS and RNS in the neurons during the development and progression of CIPN (Fig. 4). These experimental evidences clearly indicate that oxidative stress induced mitochondrial dysfunction is a central mediator of redox imbalance, apoptotic, autophagic and bioenergetic failure in peripheral neurons. It has also been widely observed that accumulation of oxidant damaged proteins and organelles due to inefficient autophagic pathway might be responsible for neurodegeneration, and hence therapeutic alleviation of Autophagy/Mitophagy is an unexplored potential target in peripheral neuropathies associated with nerve damage [28]. Oxidative stress in CIPN: biomarkers and therapeutic strategies Experimental evidences support the involvement of mitochondria mediated oxidative, nitrosative stress in development of peripheral nerve damage. Identification of these mechanisms might be helpful in identifying newer biomarkers for the CIPN and thus increases the chances of getting improved therapeutic strategies. Currently diagnosis is based mainly on clinical examination and electrophysiological changes to monitor CIPN, hence identification of newer disease pathomechanisms will be helpful in identifying new candidate biomarkers through which disease progression can be identified at an earlier stage [3]. Oxidative damage to peripheral neurons can cause damage to myelin sheath, mitochondrial proteins and other antioxidant enzymes. Hence, identification of levels of malondialdehyde, glutathione (GSH), superoxide dismutase (SOD) and activities of mitochondrial enzymes such as citrate synthase and ATP synthase can be helpful in monitoring the course of peripheral neuropathy and response of neuropathy to the treatment. Due to the wide range of safety and tolerability, some of the dietary antioxidants and nutraceuticals have been tested for their clinical efficacy against chemotherapy induced peripheral neuropathy in large scale controlled clinical trials (Table 1). These agents were reported to have clinical utility by their protective action on neurons and they were found to alleviate functional disturbances of neurons by improving the mitochondrial function and physiology as shown in Fig. 5 [29,30]. Despite their wide usage and clinical efficacy, the available antioxidants present so far could only provide mild to moderate pain relief in peripheral neuropathy [31]. Failure of antioxidants in clinical trials might be due to their inability to reverse established oxidative damage, radical specificity and interference with physiological redox signaling pathways [28]. Targeted delivery of antioxidants and employing the mechanism based approach, clinical pathology and concentration dependent dosage schedule in antioxidant trials will help us to develop better understanding and might help us in devising newer strategies in CIPN [32]. Another possible explanation of translational failures of these trials are the common toxicity criteria (CTC) assessment scales used in CIPN trials, which should be remodified to include necessary parametric measures, that will ensure accurate quantification of the drug induced effect [33]. Summary This review highlighted the possible involvement of oxidative stress as a vital pathogenic mechanism of CIPN. Molecular insight into oxidant induced neuronal damage can probe a chance of getting an alternative therapy for CIPN in the form of natural phyto antioxidants or synthetic radical traps. Further, identification of antioxidant molecules having pleiotropic activity on other pathophysiological pathways involved in the CIPN could aid in the development of improved therapies. Since mitochondria are found to be a primary source of cellular ROS, pharmacological interventions targeted at maintenance of mitochondrial health and function is an alternative therapeutic approach for CIPN over direct scavengers of free radicals for the treatment of CIPN.
