Abstract
Zebrafish have recently emerged as an attractive in vivo model for epilepsy. Seven-day-old zebrafish larvae exposed to the GABAA antagonist pentylenetetrazol (PTZ) exhibit increased locomotor activity, seizure-like behavior, and epileptiform electrographic activity. A previous study showed that 12 out of 13 antiepileptic drugs (AEDs) suppressed PTZ-mediated increases in larval movement, indicating the potential utility of zebrafish as a high-throughput in vivo model for AED discovery. However, a question remained as to whether an AED-induced decrease in locomotion is truly indicative of anticonvulsant activity, as some drugs may impair larval movement through other mechanisms such as general toxicity or sedation. We therefore carried out a study in PTZ-treated zebrafish larvae, to directly compare the ability of AEDs to inhibit seizure-like behavioral manifestations with their capacity to suppress epileptiform electrographic activity. We re-tested the 13 AEDs of which 12 were previously reported to inhibit convulsions in the larval movement tracking assay, administering concentrations that did not, on their own, impair locomotion. In parallel, we carried out open-field recordings on larval brains after treatment with each AED. For the majority of AEDs we obtained the same response in both the behavioral and electrographic assays. Overall our data correlate well with those reported in the literature for acute rodent PTZ tests, indicating that the larval zebrafish brain is more discriminatory than previously thought in its response to AEDs with different modes of action. Our results underscore the validity of using the zebrafish larval locomotor assay as a rapid first-pass screening tool in assessing the anticonvulsant and/or proconvulsant activity of compounds, but also highlight the importance of performing adequate validation when using in vivo models.
Highlights
Epilepsy is a common neurological disorder marked by episodic seizures as a result of abnormal electrical activity in the brain
Embryo medium prepared with DMSO to a final concentration of 1% w/v served as a vehicle control (VHC)
We considered an antiepileptic drugs (AEDs) positive if there were more than one point that showed a statistically significant decline in total movement compared to the VHC+PTZ treated group (Table 1, Figure 3)
Summary
Epilepsy is a common neurological disorder marked by episodic seizures as a result of abnormal electrical activity in the brain. The condition of patients that show drug-resistant seizures can sometimes be improved by non-pharmacological treatment, but even after surgery, 10% of patients continue to experience seizures [2] For these reasons, the discovery of novel anticonvulsant compounds and the subsequent development of new, alternative AEDs remains an important area of research. Subcutaneous (s.c.) PTZ administration produces a characteristic behavioral pattern of events: ear twitch, vibrissae twitch, straub tail, myoclonic twitch, forelimb clonus, falling and tonic hind limb extension [4]. These seizure behaviors correlate with spiking activity and spike-wave discharges in the cortex as measured by electroencephalography (EEG) [4]. The predictive value of the acute PTZ test is high, rodent models have certain disadvantages for large-scale screening applications in comparison with smaller vertebrates, namely: higher cost, lower throughput, the requirement for appreciable amounts of compound, as well as regulatory and ethical considerations
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
