How do we choose the appropriate animal model for antiseizure therapy development?

Figures & data

Figure 1. Approach to the identification and differentiation of promising antiseizure drugs

Table 1. Common preclinical models of acute and chronic seizure in use for early ASD development, as well as innovative models of pharmacoresistant chronic seizures.

Animal Model	Acute vs. Chronic Seizures	Induction Protocol	Seizure Endpoints	Pharmacoresistant Model?	Translational Relevance	ASD Identified to Validate the Model	Effective ASDs at Non-Motor Impairing Doses
Maximal Electroshock (MES)	Acute	60 Hz 0.2 second alternating 50 mA current (mouse) or 150 mA (rat)	Tonic hindlimb extension seizure	No	Model for generalized tonic-clonic seizures; highly reproducible	PHT	PHT ^a; CBZ ^a; LTG ^f; VPA ^a,f; PB ^a; FBM ^a; GBP ^a,f; TPM ^f; EZG ^c; CBD ^d
Subcutaneous Pentylenetetrazol (s.c. PTZ)	Acute	Subcutaneous injection of chemoconvulsant pentylenetetrazol at dose known to elicit seizure in >97% of rodent strain (85 mg/kg in male CF-1 mice from Charles River)	Clonic spasms	No	Some translational relevance to absence seizures	ESM	ESM ^a; VPA ^a,f; BZD ^a; EZG ^f; FBM ^a; GBP ^a; PB ^a; TGB ^f; VGB ^f; CBD ^d
Corneal Kindled Mouse (50/60 Hz; traditional)	Chronic	50/60 Hz 3 mA 3 second stimulus delivered to anesthetized corneas	Presence of Racine stage seizures and/or mean seizure score	No	Model of chronic secondarily generalized focal seizures with clear behavioral and neuropathological deficits	Potentially LEV	PHT ^a; CBZ ^a; LTG ^f; LEV ^f; TGB ^f; EZG ^c,f; VGB ^f; GBP ^a; PB ^a,e; FBM ^a; VPA ^a,c,e,f; BDZ ^a,c,e,f; CBD ^d
6 Hz Corneal Kindled Mouse ^b	Chronic	6 Hz 3 sec stimulation of various current intensity (strain-dependent) delivered to anesthetized corneas for 2–4 weeks	Forelimb clonus	Yes	Model of pharmacoresistant chronic secondarily generalized focal seizures	To be determined	CLZ ^b; VPA ^b; CBZ ^b
Lamotrigine-Resistant Corneal Kindled Mouse ^e	Chronic	60 Hz 3 mA 3 second stimulus delivered to anesthetized corneas; mice receive lamotrigine pretreatment during 3–4 week kindling acquisition period	Presence of Racine stage seizures and/or mean seizure score	Yes	Model of pharmacoresistant chronic secondarily generalized focal seizures	To be determined	VPA ^e; DZP ^e; LEV ^e

a – Based on data available within the NINDS PANAChE database, accessed 04/2019.

b – Based on Leclercq et al., Epilepsy Research 2014.

c – Based on Barker-Haliski et al., Neurochemical Research. 2017.

d – Based on Patra et al., Epilepsia 2019.

e – Based on Koneval et al., Epilepsia 2018.

f – Based on Rowley and White, Epilepsy Research 2010.

Table 2. Comparative efficacy of prototype ASDs in electrically kindled rodent models of chronic seizures.

Antiseizure Drug	Amygdala-kindled rat*	Hippocampal kindled rat	Corneal kindled mouse (60 Hz)	Corneal kindled mouse (6 Hz)
Benzodiazepines	+	+ ^A	+ ^A, B, C	+ ^D
Brivaracetam	+	ND	ND	ND
Cannabidiol	ND	ND	+ ^E	ND
Carbamazepine	+	+ ^F	+ ^F	+ ^D
Eslicarbazepine acetate	+	ND	+ ^G	ND
Ethosuximide	NE	NE ^A	NE ^A, F	ND
Felbamate	+	+ ^A	+ ^A, E	ND
Gabapentin	+	NE ^A	+ ^A	ND
Lacosamide	+	+ ^G	ND	ND
Lamotrigine	+	+ ^F	+ ^C, F	ND
Levetiracetam	+	50% effective ^F	+ ^C, F	+ ^D
Oxcarbazepine	+	ND	ND	ND
Perampanel	+	ND	ND	ND
Phenobarbital	+	+ ^A	+ ^C	ND
Phenytoin	+	NE	+ ^F	ND
Pregabalin	+	+ ^I	ND	ND
Retigabine (ezogabine)	+	ND ^F	+ ^C	ND
Tiagabine	+	+ ^F	+ ^F	ND
Topiramate	+	NE ^F	50% effective ^F	ND
Valproate	+	+ ^F	+ ^B, C, F	+ ^D
Vigabatrin	+	ND ^F	+ ^F, J	ND
Zonisamide	+	ND	ND	ND

+ indicates compounds that are effective in the kindling model. NE indicates ‘not effective’. ND indicates ‘no published data’. Bold text indicates compounds that are ineffective in the kindling model. Italic text indicates compounds that demonstrate a pharmacological profile different from the clinically validated amygdala-kindled rat.

* Efficacy data of amygdala-kindled rats adapted from data presented in Table 2 of Klein et al., Epilepsia 2017 [5], with permission of John Wiley & Sons.

A – from NINDS PANAChE database (https://panache.ninds.nih.gov), accessed June 2019.

B – from Barker-Haliski et al., Neurochemical Research 2017.

C – from Koneval et al., Epilepsia 2018.

D – from Leclercq et al., Epilepsy Research 2014.

E – from Patra et al., Epilepsia 2019.

F – from Rowley and White, Epilepsy Research 2010.

G – from Potschka et al., Epilepsy Research 2014.

H – from Stohr et al., Epilepsy Research 2007.

I – from Vartanian et al., Epilepsy Research 2006.

J – from Klitgaard and Matagne, Epilepsy Research 1998.

Klein P, Dingledine R, Aronica E, et al. Commonalities in epileptogenic processes from different acute brain insults: do they translate? Epilepsia. 2018 Jan;59(1):37–66. Epub 2017 Dec 15.

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