Antiseizure drug efficacy and tolerability in established and novel drug discovery seizure models in outbred vs inbred mice.

Abstract:

OBJECTIVE:Initial identification of new investigational drugs for the treatment of epilepsy is commonly conducted in well-established mouse acute and chronic seizure models: for example, maximal electroshock (MES), 6 Hz, and corneal kindling. Comparison of the median effective dose (ED50) of approved antiseizure drugs (ASDs) vs investigational agents in these models provides evidence of their potential for clinical efficacy. Inbred and outbred mouse strains exhibit differential seizure susceptibility. However, few comparisons exist of the ED50 or median behaviorally impairing dose (TD50) of prototype ASDs in these models in inbred C57Bl/6 vs outbred CF-1 mice, both of which are often used for ASD discovery. METHODS:We defined the strain-related ED50s and TD50s of several mechanistically distinct ASDs across established acute seizure models (MES, 6 Hz, and corneal-kindled mouse). We further quantified the strain-related effect of the MES ED50 of each ASD on gross behavior in a locomotor activity assay. Finally, we describe a novel pharmacoresistant corneal-kindling protocol that is suitable for moderate-throughput ASD screening and demonstrates highly differentiated ASD sensitivity. RESULTS:We report significant strain-related differences in the MES ED50 of valproic acid (CF-1 ED50: 90 mg/kg [95% confidence interval (CI) 165-214] vs C57Bl/6: 276 mg/kg [226-366]), as well as significant differences in the ED50 of levetiracetam in the pharmacoresistant 6 Hz test (CF-1: 22.5 mg/kg [14.7-30.2] vs C57Bl/6: >500 mg/kg [CI not defined]). There were no differences in the calculated TD50 of these ASDs between strains. Furthermore, the MES ED50 of phenobarbital significantly enhanced locomotor activity of outbred CF-1, but not C57Bl/6, mice. SIGNIFICANCE:Altogether, this study provides strain-related information to differentiate investigational agents from ASD standards-of-care in commonly employed preclinical discovery models and describes a novel kindled seizure model to further explore the mechanisms of drug-resistant epilepsy.

journal_name

Epilepsia

journal_title

Epilepsia

authors

Koneval Z,Knox KM,Memon A,Zierath DK,White HS,Barker-Haliski M

doi

10.1111/epi.16624

subject

Has Abstract

pub_date

2020-09-01 00:00:00

pages

2022-2034

issue

9

eissn

0013-9580

issn

1528-1167

journal_volume

61

pub_type

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