Oxidative stress and nerve damage: role in chemotherapy induced peripheral neuropathy

Abstract

Peripheral neuropathy is a severe dose limiting toxicity associated with cancer chemotherapy. Ever since it was identified, the clear pathological mechanisms underlying chemotherapy induced peripheral neuropathy (CIPN) remain sparse and considerable involvement of oxidative stress and neuroinflammation has been realized recently. Despite the empirical use of antioxidants in the therapy of CIPN, the oxidative stress mediated neuronal damage in peripheral neuropathy is still debatable. The current review focuses on nerve damage due to oxidative stress and mitochondrial dysfunction as key pathogenic mechanisms involved in CIPN. Oxidative stress as a central mediator of apoptosis, neuroinflammation, metabolic disturbances and bioenergetic failure in neurons has been highlighted in this review along with a summary of research on dietary antioxidants and other nutraceuticals which have undergone prospective controlled clinical trials in patients undergoing chemotherapy.

Keywords: Chemotherapy; Mitochondria; Mitotoxicity; Nutraceuticals; Oxidative stress; Peripheral neuropathy.

Graphical abstract

Fig. 1

Pathobiology of peripheral neuropathy induced by several chemotherapeutic agents: peripheral nerve damage associated with taxanes, vinca alkaloids and bortezomib is characterized by various mechanisms like microtubular damage, mitochondrial dysfunction, neuronal apoptosis etc. . Damage to the microtubules causes impairment in axonal transmission and mitochondrial dysfunction. The mitochondrial dysfunction is due to opening of mitochondrial permeability transition pore (mPTP), swollen and vacuolated mitochondria which brings Ca²⁺ deregulation and activation of caspases thus driving the neuronal cell towards apoptosis . These changes consequently stimulate microglia cells which releases the proinflammatory mediators and growth factors to the damaged areas leading to peripheral sensitization thus causing spontaneous discharge and hyper excitability . Further proinflammatory mediators are also capable of damaging myelin sheath . Platinum compounds like cisplatin and oxaliplatin can affect mitochondrial DNA, leading to mitochondrial dysfunction and also induces neuronal apoptosis through activation of mitogen activated protein kinase (MAPK) pathway. These chemotherapeutic agents are also reported to cause peripheral sensitization by the up regulation of N-methyl D-aspartate (NMDA) receptors, transient receptor potential vanilloid (TRPV) channels, and protein kinase C (PKC) .Oxaliplatin also alters the Na⁺ channel conductance through chelation of Ca²⁺. All these effects can damage the sensory neurons such as Aδ and C fibers, which leads to neuropathic pain characterized by hyperalgesia and allodynia.

Fig. 2

Susceptibility of peripheral nervous system (PNS) to chemotherapeutic insult and oxidative stress: structural architecture of peripheral sensory and motor neurons makes them more susceptible to drug induced nervous damage . Dorsal root ganglion lacks an efficient vascular barrier and hence, drugs like chemotherapeutics and other neurotoxins can gain easy access to cell bodies of the sensory neurons. Unlike the central nervous system, the PNS doesn't have an analogy of blood brain barrier, and hence allows contact with some dangerous drug molecules, toxins and other blood proteins. Further, the absence of lymphatic system and cerebrospinal fluid around the peripheral nerves makes the potential dangerous substances to accumulate in the extracellular matrix around nervous tissue, which exacerbates the neuropathic damage . Chemotherapeutics accumulate in this manner can cause oxidative stress in the neurons directly by forming DNA adducts or indirectly by mitochondrial impairment of electron transport chain . Oxidative stress generated can cause nerve damage through microtubular disruption and or demyelination .

Fig. 3

Role of oxidative stress in chemotherapy induced peripheral neuropathy (CIPN): the chemotherapeutic agents can form mitochondria DNA adducts and brings defects in electron transport chain proteins leading to mitochondrial dysfunction . This is accompanied with an imbalance in the intracellular redox potential and elevation of reactive oxygen species especially superoxide. These major reactive species can elicit various alterations in peripheral neurons like redundant mitochondrial damage leading to apoptosis, inflammation and finally neurodegeneration. These reactive species are also reported to cause damage to bio molecules like phospholipids that result in demyelination, oxidation of proteins, releasing carbonyl bye products which can sensitize TRPV channels, inactivate antioxidant enzymes, and damage microtubules . Nuclear DNA adducts and peroxynitrite creates strand breaks therefore activates PARP and p53, which forces the neuronal cell towards apoptosis . Intracellular oxidative stress can also cause peripheral nociceptor sensitization by elevating the levels of proinflammatory mediators . All these metabolic, bioenergetic and functional deficits in neuron lead to the development of peripheral neuropathic damage.

Fig. 4

Mitochondrial dysfunction in CIPN and role of its pharmacological modulation: the common factors associated with oxidative stress induced mitochondrial dysfunction are disruption of calcium homeostasis, increased mitochondrial outer membrane permeability (MOMP), defective mitochondrial ATP synthesis, alteration in the mitochondrial membrane potential (↓ΔΨ_m), induction of mPTP, release of Cyt c (since it loose its binding ability by oxidative induced damage to the cardiolipin), mitochondrial swelling etc. . All these steps occur together or one orchestrates with other and forms a vicious cycle which further disrupts mitochondrial function. This finally leads to the cell death via apoptosis or necrosis. Pharmacological manipulation of mitochondrial toxicity with mitochondria-targeted antioxidants could help us to get the better therapeutic outcome in CIPN through alleviation of mitochondria mediated oxidative stress , , .

Fig. 5

Role of nutraceutical antioxidants in the treatment of chemotherapy induced peripheral neuropathy (CIPN): nutraceutical antioxidants exhibited significant neuroprotection towards chemotherapy induced neurotoxicity by decreasing cellular oxidative stress through their inherent free radical scavenging property (glutathione , , melatonin , n-acetyl cysteine , ω-3 fatty acids , α-lipoic acid etc) and indirectly by increasing whole blood concentrations of antioxidant enzymes (glutamine , n-acetyl cysteine [42]), normalizing mitochondrial functions (n-acetyl carnitine , α-lipoic acid [30]), attenuating the production of proinflammatory mediators (ω-3 fatty acids [43]) etc. Totally these nutraceutical antioxidants normalize the cellular functions, rescue mitochondrial impairment, inhibit neuronal inflammation, apoptosis and therefore diminish the sensory nerve degeneration , .