Mefloquine Damage Vestibular Hair Cells in Organotypic Cultures

Abstract

Mefloquine is an effective and widely used anti-malarial drug; however, some clinical reports suggest that it can cause dizziness, balance, and vestibular disturbances. To determine if mefloquine might be toxic to the vestibular system, we applied mefloquine to organotypic cultures of the macula of the utricle from postnatal day 3 rats. The macula of the utricle was microdissected out as a flat surface preparation and cultured with 10, 50, 100, or 200 μM mefloquine for 24 h. Specimens were stained with TRITC-conjugated phalloidin to label the actin in hair cell stereocilia and TO-PRO-3 to visualize cell nuclei. Some utricles were also labeled with fluorogenic caspase-3, -8, or -9 indicators to evaluate the mechanism of programmed cell death. Mefloquine treatment caused a dose-dependent loss of utricular hair cells. Treatment with 10 μM caused a slight reduction, 50 μM caused a significant reduction, and 200 μM destroyed nearly all the hair cells. Hair cell nuclei in mefloquine-treated utricles were condensed and fragmented, morphological features of apoptosis. Mefloquine-treated utricles were positive for the extrinsic initiator caspase-8 and intrinsic initiator caspase-9 and downstream executioner caspase-3. These results indicate that mefloquine can induce significant hair cell degeneration in the postnatal rat utricle and that mefloquine-induced hair cell death is initiated by both caspase-8 and caspase-9.

Addition of Exogenous NAD+ Prevents Mefloquine-Induced Neuroaxonal and Hair Cell Degeneration through Reduction of Caspase-3-Mediated Apoptosis in Cochlear Organotypic Cultures

“…It is thought that degeneration of auditory nerve axons occurs early and proceeds quickly after mefloquine exposure [10-13], and the first cytotoxic effect of mefloquine is thought to result from free heme accumulation that is responsible for its antimalarial effects [55]. Consistent with this report, it is well-established that free heme is a cytotoxic iron compound that causes the formation of ROS [56].…”

“…Mefloquine (Lariam ®) is an antimalarial drug that is widely used for prophylactic and therapeutic treatment of malaria [4-6]; however, it can induce a range of neurological side effects such as anxiety, panic attacks, nightmares, dizziness, tremor, headache, fatigue, grand mal seizures, suicidal ideation, balance disturbance, and hearing loss [7-9]. Several in vitro studies have revealed that mefloquine selectively damaged cochlear and vestibular hair cells and spiral ganglion neurons through apoptosis [10-13]. Moreover, mefloquine is also known to cause primary rat cortical neuron degeneration, neuronal calcium homeostasis disruption in embryonic rat neurons, and significant axonal degeneration [14-16].…”

Carbaryl-induced ototoxicity in rat postnatal cochlear organotypic cultures

“…Cochlear organotypic cultures were prepared from P3 SASCO Sprague Dawley rats (Charles River Laboratories, Wilmington, MA) following protocols similar to those described previously (Yu et al, ; Liu et al, ; Wang et al, ). P3 rats were decapitated and the cochlea removed and immersed in HBSS solution.…”

Stimulation of Suicidal Erythrocyte Death by the Antimalarial Drug Mefloquine

“…The use is limited by various side effects [4] including neuropsychiatric disorders [10,11,12,13,14], skin reactions [15] as well as risk of miscarriage and stillbirth [16]. Mefloquine triggers apoptosis [17,18,19,20,21] and may sensitize tumor cells for cytostatic treatment [20].…”

“…Mefloquine triggers apoptosis [17,18,19,20,21] and may sensitize tumor cells for cytostatic treatment [20]. Mechanisms involved in mefloquine induced apoptosis include oxidative stress [10,18,21], ceramide formation [22] and caspase activation [14,18]. …”