Effect of antiepileptic drug levetiracetam on cochlear function

Highlight

• Levetiracetam (LEV) has little or no effect on the function of the outer hair cells.

• High dose LEV can decrease cochlear neural response and increase its threshold.

• High dose LEV can enhance the forward masking of cochlear neural response.

• Clinical dose of LEV can prolong the latency of cochlear neural response.

• Delayed cochlear response may contribute to the treatment of audiogenic seizures.

Abstract

Background

Levetiracetam (LEV, 5–100 mg/kg) has been shown to prevent audiogenic seizures in a dose-dependent manner. This chemical is known to bind to synaptic vesicle protein 2A and inhibit l-type calcium channels, affecting neurotransmitter release. We hypothesize that the drug prevents audiogenic seizures partially by affecting cochlear neural response.

Methods

To test this hypothesis, rats were given 1000, 500, 50, or 0 mg/kg (saline control) LEV-injection. Distortion product otoacoustic emissions (DPOAE), reflecting outer hair cell (OHC) function, and cochlear compound action potentials (CAP), reflecting cochlear neural output, were recorded and compared pre- and post-LEV.

Results

1000 mg/kg LEV-injection did not significantly affect DPOAE. The high dose LEV-injection, however, significantly reduced CAP amplitude resulting threshold shift (TS), prolonged CAP latency, and enhanced CAP forward masking. CAP latency and forward masking were significantly affected at the 500 mg/kg dose, but CAP-TS remained unchanged after LEV-injection. Interestingly, CAP latency wassignificantly prolonged, at least at the low stimulation levels, although the amplitude of CAP remained constant after a clinical dose of LEV-injection (50 mg/kg).

Discussion

Since the clinical dose of LEV-injection does not reduce CAP amplitude, the reduction of cochlear neural output is unlikely to be the underlying mechanism of LEV in the treatment of audiogenic seizure. The delayed cochlear neural response may be partially related to the prevention of audiogenic seizure. However, neuropharmacological changes in the central nervous system must play a major role in the treatment of audiogenic seizure, as it does in the treatment of focal epilepsy.

Introduction

Levetiracetam (LEV) is a widely used antiepileptic drug (Keppra®) approved by the Food and Drug Administration for use in adults and as an adjunctive medication for treatment of focal onset seizures in infants and children (Capovilla et al., 2004; Aeby et al., 2005; Gurses et al., 2008; Mruk et al., 2015; Ahmad et al., 2017; Akiyama et al., 2018; Akter et al., 2018; Han et al., 2018; Kanemura et al., 2018; Ahrens et al., 2019; Rosche et al., 2019; Wani et al., 2019; Zhou et al., 2019; Akhondian et al., 2020; Chu et al., 2020; Liu et al., 2020a; Sadleir et al., 2020; Sarangi et al., 2020). It has also been used to treat startle epilepsies in humans and suppress audiogenic seizures in animals (Gower et al., 1995; Luef and Loscher, 2007; Gurses et al., 2008; Vinogradova and van Rijn, 2008; Dreissen and Tijssen, 2012; Lowrie et al., 2016; Wu et al., 2019). Similar to the audiogenic seizures observed in the animals, musicogenic seizures were observed in humans which were triggered by musical stimuli ranging from simple tones to complex symphonic music (Kaplan, 2003; Cheng, 2016; Maguire, 2017; Tseng et al., 2018; Jesus-Ribeiro et al., 2020), although there are no reports about LEV in the treatment of musicogenic seizures.

The mechanisms by which LEV acts to suppresses seizures are not fully understood. The most likely mechanism is that the drug reduces seizures by binding to synaptic vesicle protein 2A (SV2A) (Kaminski et al., 2012; Loscher et al., 2016; Wu et al., 2019). LEV is known to be the ligand of SV2A (Lynch et al., 2004; Gillard et al., 2006; Nowack et al., 2011), and the synaptic vesicle protein 2 is required to maintain a pool of vesicles available for calcium-stimulated exocytosis regulating neurotransmission (Xu and Bajjalieh, 2001; Madeo et al., 2014). In addition, LEV has been reported to suppress voltage-operated L-type calcium channels and potassium channels in the isolated hippocampal neurons (Madeja et al., 2003; Yan et al., 2013) leading to a decrease in the total number of action potentials and prolonging the latency between spikes (Madeja et al., 2003).

LEV application in the rat brain slice has been reported to inhibit glutamate release, reducing the amplitude of the excitatory postsynaptic currents (EPSCs) (Lee et al., 2009). Glutamate serves as the neurotransmitter between the inner hair cells (IHCs) and the cochlear afferent nerve fibers (Peppi et al., 2012). The release of the neurotransmitter from the IHCs is regulated by L-type calcium channels (Zhang et al., 1999; Robertson and Paki, 2002), which mainly presents in the IHCs and pillar cells (Layton et al., 2005) and a small amount in the outer hair cells (OHCs) (Chen et al., 1995). Blockage of L-type calcium channels has been shown to reduce the cochlear compound action potential (CAP) (Chen et al., 2006). Therefore, treatment with LEV is expected to alter the neural output of the cochlea. The expected LEV-induced reductions in the neural output of the cochlea could potentially aid in the suppression of audiogenic seizures that occur in many strains of rodents and other mammals (Maxson et al., 1977; Henry, 1984; Loscher, 1984; Reigel and Faingold, 1993; Faingold et al., 1994; Lowrie et al., 2017) or suppression of musicogenic seizures observed in humans (Kaplan, 2003; Cheng, 2016; Maguire, 2017; Tseng et al., 2018; Jesus-Ribeiro et al., 2020).

To determine the effects of LEV on the cochlear functions, we treated rats with different doses of LEV and measured CAP generated by the auditory nerve to determine the extent to which the drug altered the neural output of the cochlea. To test the possible nonspecific effects of LEV on OHCs, distortion product otoacoustic emissions (DPOAE), which provide a noninvasive method for assessing OHC electromotility and functional integrity of the OHCs (Abdala and Visser-Dumont, 2001) were also evaluated.