d-Methionine protects against cisplatin-induced neurotoxicity in cortical networks.
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.
University of North Texas, Department of Speech & Hearing Sciences, United States. gopal@unt.edu
Kamakshi V
KV
Gopal
Calvin
C
Wu
Bibesh
B
Shrestha
Kathleen C M
KC
Campbell
Ernest J
EJ
Moore
Guenter W
GW
Gross
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001303:Auditory Cortex / Q000187:drug effects* / Q000196:embryology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D008715:Methionine / Q000008:administration & dosage / Q000627:therapeutic use*; D051379:Mice; D008813:Mice, Inbred ICR; D008839:Microelectrodes; D009415:Nerve Net / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000517:prevention & control*; D013237:Stereoisomerism
D000970:Antineoplastic Agents; D018696:Neuroprotective Agents; D008715:Methionine; D002945:Cisplatin