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 cisplatininduced 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 0.5 mM caused irreversible loss of neuronal activity, accompanied by cell death. Pretreatment with D-Met, at a concentration of 1.0 mM, prevented the cisplatin-induced excitation at 0.10-0.25 mM, caused sustained excitation without occurrence of cell death at 0.5 mM, 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 0.1 mM cisplatin, and proved ineffective at a concentration of 0.5 mM cisplatin. Pre-exposure time of D-Met was associated with the protective effects at 0.1 and 0.5 mM 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.

Curcumin alleviates cisplatin-induced learning and memory impairments

“…Oxidative stress may be the most important mechanism among these mechanisms that are proposed to explain neurotoxicity, and in this regard, targeting oxidative stress can limit cisplatininduced neurotoxicity while preserving anticancer efficacy. Therefore, several antioxidant molecules such as coenzyme Q10 (da Silva , walnut (Shabani et al, 2012b), D-Methionine (Gopal et al, 2012), alpha lipoic acid (Tuncer et al, 2010), melatonin (Tuncer et al, 2010), and curcumin (Al Moundhri et al, 2013;Mendonca et al, 2013) have been used to in an effort to either mitigate or prevent cisplatin-induced neurotoxicity.…”

Antioxidants l-carnitine and d-methionine modulate neuronal activity through GABAergic inhibition

“…The concept of excitotoxicity, the disturbance of membrane ionic balance that leads to degeneration-such as that induced by excess glutamate in Huntington Disease symptoms or methamphetamine-activated dopamine surge (Virmani et al 2003;Vamos et al 2010)-may be more relevant in the discussion of the protective action of L-carnitine within the framework of the inhibitory neurotransmitter system. Likewise, we suspect that perhaps the protective mechanism of D-methionine against platinum toxicity observed in our previous study (Gopal et al 2012) may partly be a counteracting measure against excitotoxicity by GABAergic inhibition.…”

“…Our previous studies were among the first to adapt functional studies of neuronal networks for testing the protective properties of L-carnitine and D-methionine (Wu et al 2011;Gopal et al 2012). We observed that both compounds elicited consistent inhibitory responses in neuronal networks.…”

“…Our studies previously alluded to the inhibitory effects of L-carnitine and D-methionine on neuronal activity, as both compounds attenuated over-excitation (Wu et al 2011;Gopal et al 2012). We suggest that inhibitory neurotransmission driven by the GABAergic system may be a direct cause of activity attenuation.…”

“…Several antioxidants such as sodium thiosulfate, D-methionine, and N-acetylcysteine have been reported to reduce oxidative stress in cochlear tissues and ameliorate hearing loss induced by noise or chemical insults (Blakley et al 2002;Lorito et al 2011). Our previous study focused on the neuroprotective properties of D-methionine, and showed that this compound was protective against cisplatin-induced toxicity in cortical networks (Gopal et al 2012).…”