Zebrafish: A Predictive Model for Assessing Seizure Liability - Zebrafish: Methods for Assessing Drug Safety and Toxicity - page 159

Chapter 13

Zebrafish: A Predictive Model
for Assessing Seizure Liability

Demian Park, Joshua Meidenbauer, Breanne Sparta, Wen Lin Seng,
and Patricia McGrath
Phylonix, Cambridge, MA, USA

13.1 INTRODUCTION

Several marketed drugs have been associated with increased seizure risk and the
U.S. Food and Drug Administration (FDA) has included this end point in its Safety
Pharmacology Guidance for Industry (ICH, 2001). Using a quantitative video-based
motion tracking system, zebrafish has been shown to be a predictive animal model
for assessing compound-induced seizure-like movement (Baraban et al., 2005;
Winter et al., 2008). In a recent study, using methods similar to those reported
by others, we examined movement of 6 day post fertilization (dpf) zebrafish
after treatment with nine seizure inducing compounds, pentylenetetrazole (PTZ),
4-aminopyridine (4-AP), picrotoxin, strychnine hemisulfate, methoxychlor, amox-
apine, aminophylline hydrate, bicuculline methiodide, and enoxacin. After drug
treatment, distance traveled at high speed (greater than 20 mm/s) in 1 min intervals
( D ) for 60min was measured.
The longest distance traveled in a single 1 min interval (peak D )duringthe
60min recording period was identified at various concentrations. Then, peak D for
compound-treated animals was compared with D of carrier control at the same time
point and Student's t -test was used to determine if compound effects were significant
( P < 0.05). Using this criterion, eight of the nine seizure inducing compounds

caused significant effects on zebrafish movement and the negative control com-
pound did not induce high-speed movement. These and other results underscore the
potential value of incorporating this zebrafish assay in preclinical safety studies to
assess seizure liability.