Protective effects of phosphatidylcholine on oxaliplatin-induced neuropathy in rats
Introduction
Oxaliplatin is a third-generation platinum-based antineoplastic agent, which is commonly used in treating advanced colorectal cancer, and as adjuvant therapy in several types of cancer [12]. Although oxaliplatin has less ototoxicity and nephrotoxicity than other platinum-based chemotherapeutic agents, it causes acute and chronic peripheral neurotoxicity [1], [13]. Acute neuropathy can be observed in almost all patients. This neuropathy occurs within hours of injection, and can be resolved within days [4], [18]. On the other hand, chronic neuropathy is observed in 10–15% of patients after cumulative injection of oxaliplatin, which cannot be resolved easily [10], [16]. It is one of the main reasons that patients do not continue their cancer treatments; therefore, it is important to protect cancer patients from chemotherapy-induced neuropathic pain.
Developing effective treatments to attenuate peripheral neuropathy is difficult because knowledge about the mechanism of oxaliplatin-induced neuropathy is still insufficient [13]. Many studies suggest that oxidative stress associated with oxaliplatin is a direct cause of neuropathy. It is generally known that chemotherapeutic agents generate reactive oxygen species (ROS) to induce apoptosis in cancer cells [11]. However, ROS also affects normal cells and tissues and may be associated with neurotoxicity. In particular, peripheral nerves can be physically damaged by demyelination, mitochondrial dysfunction, inflammation, and apoptosis [26]. Thus, levels of glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD), and activities of mitochondrial enzymes are good biomarkers for determining neuropathy. A recent study suggests that the spinal cord and its subpopulation are directly damaged by oxaliplatin, and oxidative stress is the major reason for this neuronal damage [7].
To ameliorate oxaliplatin-induced neuropathy, various treatments have been suggested including acetyl-l-carnitine, vitamin E, vitamin C, glutathione, and amifostine [2], [3], [15]. Among these treatments, antioxidants (glutathione, N-acetylcysteine, and vitamin E) are known for their neuron-protecting actions, alleviating functional impairments of neurons [6], [8], [9], [22]. However, their abilities to relieve pain have proven to be insufficient. There are several reasons that can explain this weakness: 1) irreversibility of established oxidative damage; 2) radical specificity of antioxidants; and 3) interference with oxidation-reduction signaling pathways [17].
Phosphatidylcholine (PC, 1,2-diacyl-sn-glycero-3 phosphocholine) is a major component of biological membranes and several studies suggest that PC has antioxidant effects and prevents lipid peroxidation [23], [27]. In our previous study, the treatment with PC resulted in a significant attenuation on the increase in serum levels of TNF-α and IL-6, pro-inflammatory cytokines in lipopolysaccharide-induced acute inflammation in multiple organ injury, suggesting that PC may be a functional material for its use as an anti-inflammatory agent [20]. In addition, decreases in choline level are associated with oxidative damage, resulting in cellular injury and necrosis [30]. Therefore, we evaluated the protective effect of PC in rats by recording the thermal nociceptive threshold changes in oxaliplatin-induced peripheral neuropathy by conducting paw pressure, hot-plate and tail-flick tests. Then, we examined quantity of MDA, total GSH, glutathione peroxidase (GPx) activity and superoxide dismutase activity to determine the oxidative stress level. We used histopathological and immunohistochemical methods to observe neuronal damage and glial activation in sciatic nerves and lumbar spinal cords.
Section snippets
Chemicals
Oxaliplatin (5 mg/ml) was purchased from the Sanofi-Aventis pharmaceutical company. Phosphatidylcholine was purchased from Lipoid GmbH (Phospholipon90G). MDA, SOD activity, total GSH and GPx activity assay kits were purchased from Biovision Inc. (San Francisco, CA, USA). All other essential chemicals were purchased from Sigma-Aldrich chemical Co. (St. Louis, MO, USA).
Animals
Male Sprague–Dawley rats, 5 weeks old and weighing about 180 g, were purchased from Samtako Biotechnology (Osan, Republic of Korea).
Effect of PC on body weights in oxaliplatin-treated rats
Body weight changes of all groups are shown in Fig. 1A. On day 0, there were no significant differences in body weights between groups. Body weights of the oxaliplatin and oxaliplatin + PC groups were significantly lower than those of the control group on days 7, 14, 21 and 28 (p < 0.01 on days 7 and 14; p < 0.001 on days 21 and 28). However, there were no significant differences in body weights between the oxaliplatin group and the oxaliplatin + PC group.
Effect of PC on the mechanical nociceptive threshold in oxaliplatin-treated rats
Mechanical nociceptive threshold changes in the
Discussion
In the present study, we demonstrated the protective effects of PC on oxaliplatin-induced peripheral neuropathy using behavioral tests, biochemical tests, and histopathological and immunohistochemical evaluations. Previous studies show that symptoms of oxaliplatin-induced peripheral neuropathy are characterized by pain, numbness, dysesthesia and thermal-related hyperalgesia, and these symptoms occur when 4 mg/kg of oxaliplatin is injected intraperitoneally to rats twice a week for 4 weeks [1],
Conclusion
In conclusion, PC administration ameliorated the oxaliplatin-induced behavioral, biochemical and histopathological changes in rats. The PC-mediated effects in this study may be attributed to its antioxidant and neuroprotection properties. However, further study is needed to evaluate the effect of PC on several symptoms of oxaliplatin-induced peripheral neuropathy. To get more conclusive results, a larger number of rats in each group and more elaborate techniques are needed.
Conflict of interest statement
The authors declare that there are no conflicts of interest.
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These authors contributed equally to this work and share the first authorship.