d-Methionine protects against cisplatin-induced neurotoxicity in cortical networks

Abstract

Cisplatin is a platinum-based chemotherapeutic agent widely used for the treatment of various types of cancer. Patients undergoing cisplatin treatment often suffer from a condition known as "chemobrain", ototoxicity, peripheral neuropathy, weight loss, nausea, vomiting, nephrotoxicity, seizures, hearing loss and tinnitus. d-Methionine (d-Met), a sulfur-containing nucleophilic antioxidant, has been shown to prevent cisplatin-induced side effects in animals without antitumor interference. In this study, we have used an in vitro model of cortical networks (CNs), enriched in auditory cortex cells; to quantify cisplatin neurotoxicity and the protective effects of d-Met. Dissociated neurons from auditory cortices of mouse embryos were grown on microelectrode arrays with 64 transparent indium-tin oxide electrodes, which enabled continuous optical and electrophysiological monitoring of network neurons. Cisplatin at 0.10-0.25 mM induced up to a 200% increase in spontaneous spiking activity, while concentrations at or above 0.5mM caused irreversible loss of neuronal activity, accompanied by cell death. Pretreatment with d-Met, at a concentration of 1.0mM, prevented the cisplatin-induced excitation at 0.10-0.25 mM, caused sustained excitation without occurrence of cell death at 0.5mM, and delayed cell death at 0.75 mM cisplatin. l-Methionine, the optical isomer, showed lower potency and less efficacy than d-Met, was less protective against 0.1mM cisplatin, and proved ineffective at a concentration of 0.5mM cisplatin. Pre-exposure time of d-Met was associated with the protective effects at 0.1 and 0.5mM cisplatin, with longer pre-exposure times exhibiting better protection. This study quantifies as a function of concentration and time that d-Met protects central nervous system tissue from acute cisplatin toxicity.