Investigation of the effect of mitochondrial ATP-sensitive potassium channel agonist diazoxide in a model of cisplatin-induced peripheral neuropathy

It has been shown that platinum-based drugs, particularly cisplatin, are among the most effective cancer treatments. Nevertheless, the drug has severe adverse effects. Due to its cytotoxic properties, cisplatin has a restricted use. Neurotoxicity is one of the most limited factors in cancer chemotherapy. In this study, a model of peripheral neuropathy was induced by chronic injection of 3 mg/kg cisplatin intraperitoneally (i.p.) once each week for five weeks. Diazoxide is a selective activator of the ATP-sensitive potassium channel in mitochondria. In this study, behavioral nociceptive experiments, nerve conduction velocity measurements, oxidative stress markers and proinflammatory cytokine levels, as well as hematoxylin-eosin and Masson trichrome staining and immunoblot analysis were performed to determine the potential effects of diazoxide on cisplatin neuropathy. In vitro cytotoxicity tests were also used to evaluate the potential effect of co-administration of diazoxide and cisplatin on the antitumor activity of cisplatin. Cisplatin-exposed animals exhibited mechanical allodynia (p<0.001), thermal hypoalgesia (p<0.001), and motor impairment (p<0.01). It also decreased the sciatic nerve's motoric conduction velocity (p<0.05) and increased the CMAP latency time (p<0.01). There was a significant increase in oxidative stress markers TOC (p<0.001), as well as proinflammatory cytokine markers TNF-alpha (p<0.001) and IL-6 (p<0.001). Histopathological examination revealed axon degeneration, edema, and fibrosis. The treatment with diazoxide alleviates these side effects caused by cisplatin. In vitro tests revealed that diazoxide has therapeutic effects without decreasing the anticancer activity of cisplatin (p<0.0001). In conclusion, it was established that diazoxide improved behaviorally, electrophysiologically, biochemically, and histopathologically the symptoms of cisplatin neuropathy. Keywords: Cisplatin neuropathy, diazoxide, ATP sensitive potassium channels, nerve conduction velocity, in vivo experiments