Abstract
Sensory neuropathy is a dose-limiting side effect of oxaliplatin-based cancer treatment. This study investigated the antinociceptive effect of amifostine and its potential neuroprotective mechanisms on the oxaliplatin-related peripheral sensory neuropathy in mice. Oxaliplatin (1 mg/kg) was injected intravenously in Swiss albino male mice twice a week (total of nine injections), while amifostine (1, 5, 25, 50, and 100 mg/kg) was administered subcutaneously 30 min before oxaliplatin. Mechanical and thermal nociceptive tests were performed once a week for 49 days. Additionally, c-Fos, nitrotyrosine, and activating transcription factor 3 (ATF3) immunoexpressions were assessed in the dorsal root ganglia. In all doses, amifostine prevented the development of mechanical hyperalgesia and thermal allodynia induced by oxaliplatin (P<0.05). Amifostine at the dose of 25 mg/kg provided the best protection (P<0.05). Moreover, amifostine protected against neuronal hyperactivation, nitrosative stress, and neuronal damage in the dorsal root ganglia, detected by the reduced expression of c-Fos, nitrotyrosine, and ATF3 (P<0.05 vs the oxaliplatin-treated group). In conclusion, amifostine reduced the nociception induced by oxaliplatin in mice, suggesting the possible use of amifostine for the management of oxaliplatin-induced peripheral sensory neuropathy.
Highlights
Oxaliplatin is a third-generation platinum compound commonly used for the treatment of metastatic colon cancer [1]
Effect of amifostine on the mechanical nociceptive threshold in mice submitted to oxaliplatin-induced peripheral sensory neuropathy
Subcutaneous administration of amifostine, at doses of 1, 5, 25, 50, and 100 mg/kg, prevented this increase of the variation from the 21st day until the 49th day (Po0.05), compared to the group treated with oxaliplatin (Figure 1A)
Summary
Oxaliplatin is a third-generation platinum compound commonly used for the treatment of metastatic colon cancer [1]. Long-term treatment may affect proprioception, causing motor impairment [1]. Symptoms of neuropathy, such as tingling, numbness in hands and feet, and pain, are common in patients treated with oxaliplatin, which may persist for more than five years [6]. There is no fully effective drug in preventing or reducing these symptoms, or even therapy capable of modifying the development of such toxicity. There is limited and controversial clinical evidence of the effects of this drug on platinum compounds-related neuropathy [15,16]. This study investigated the antinociceptive effect of amifostine and the possible neuroprotective mechanism on the experimental peripheral sensory neuropathy induced by oxaliplatin in mice
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