Time dependent cisplatin dosing differences on hypoalgesia focusing on oxidative stress

• Published in: European journal of pharmacology 2023-03, Vol.942, p.175519-175519, Article 175519
• Main Authors: Seto, Yoshihiro, Niwa, Kentaro, Okazaki, Fumiyasu, To, Hideto
• Format: Article
• Language: English
• Subjects: Animals; Circadian rhythm; Cisplatin; Cisplatin - administration & dosage; Oxidative Stress; Peripheral Nervous System Diseases - chemically induced; Peripheral neuropathy; Rats; Superoxide Dismutase - metabolism; Thiobarbituric Acid Reactive Substances
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2023.175519

Although cisplatin is a key drug in cancer chemotherapy, it often causes sensory peripheral neuropathy, presenting as allodynia in the early stage and hypoalgesia in the serious stage. Chronotherapy has previously been shown to ameliorate cisplatin-induced peripheral neuropathy that was severe enough to cause hypoalgesia in rats. It also has adverse effects such as renal dysfunction and ototoxicity, which are induced by oxidative stress. Here, we show that oxidative stress causes severe cisplatin-induced peripheral neuropathy, and that differences in oxidative stress occur depending on the dosing time of cisplatin. Cisplatin was administered to rats at 5:00 or 17:00 every seven days for four weeks. The antioxidant agent, 1,3-Dimethylthiourea (DMTU), was administered before and after the administration of cisplatin. The hot plate test was used to assess hypoalgesia. Oxidative stress in the sciatic nerve was assessed from thiobarbituric acid reactive substances (TBARs) and superoxide dismutase (SOD) activity. Nerve apoptosis was analysed with qRT-PCR. We observed an increase in TBARs and a decrease in SOD activity with the development of cisplatin-induced hypoalgesia, which was ameliorated by DMTU treatment. Furthermore, differences in the dosing time of cisplatin caused differences in oxidative stress which were correlated with cisplatin-induced hypoalgesia. Severe oxidative stress caused cisplatin-induced hypoalgesia, and chronotherapy with cisplatin ameliorated hypoalgesia by reducing oxidative stress. In the future, chronotherapy with cisplatin may contribute to the treatment of cancer in humans. •Chronotherapy, which involves dosing cisplatin at 5:00, ameliorated severe cisplatin-induced peripheral neuropathy with hypoalgesia in rats.•Severe oxidative stress caused cisplatin-induced hypoalgesia, chronotherapy with cisplatin ameliorated hypoalgesia by reducing oxidative stress.•Chronotherapy with cisplatin can contribute to cancer treatment in humans.