Table 1.
Summary of the selected articles, together with high throughput screening feasibility.
| Animal Model Scientific name (n = Sample size) | Strain | Epileptogenic insult type (parameters) | Experimental findings | Possibility of high-throughput screening (HTS) | References |
|---|---|---|---|---|---|
| Fruitfly Drosophila melanogaster (n = 5–100) | GEFS+ SCN1A mutation | •High temperature (40°C) •PTZ (0–0.4 mM) |
•GEFS+ flies exhibit a heat-induced seizure phenotype •Blockade of GABA receptors increases sensitivity to heat-induced seizures in GEFS+ flies |
Yes (Stilwell et al., 2006) | Sun et al., 2012 |
| Canton Special (CS) | High frequency stimulation (0.5 ms pulses at 200 Hz for 300 ms) | •Acute feeding of potassium bromide ameliorates bss phenotypes •Acute feeding of Top1 inhibitors does not eliminate seizure-like behaviors, but did reduce the mean recovery time (MRT) of BS mutants |
Song et al., 2008 | ||
| parabss1 | High-frequency electrical brain stimulation (0.5-ms pulses at 300 Hz for 400 ms) | •Recovery time from BS paralysis for parabss1 varies with genetic background, age, and other factors •Recovery time appears to be primarily dependent on the number of bouts of tonic–clonic like activity |
Howlett et al., 2013 | ||
| •Easily shocked (eas) •Bang senseless (bss) •Technical knockout (tko) |
•70 ml fly vials •VWR VortexGenie (10 s) |
•The atu mutation reduces SLA and shortens the recovery time in BS mutants | Stone et al., 2013 | ||
| Drosophila melanogaster | •Fly vials (10 s) •39°C water bath •C4162 High Power Strobe, Chaney Electronics (10 Hz for 10 s) |
•Glia endogenously express both Dube3a and ATPα proteins •Overexpression of Dube3a in glia using repo-GAL4 results in seizure susceptibility •Glial Dube3a overexpression alters neuronal architecture •Glial-specific overexpression of Dube3a causes reduced intercellular K+ in glial cells |
Hope et al., 2017 | ||
| Wild type Oregon-R | PTZ (3.48, 0.33, and 5 mg/ml) | •Convulsions were not observed, visual examination found hyperkinetic behavior in PTZ treated flies •NaVP and LEV alleviates PTZ induced climbing speed deficit in flies •LEV exerted a long-term effect |
Mohammad et al., 2009 | ||
| pksple1/pksple1 | Fly vials (20 s followed by 10 s) | •Drosophila with homozygous prickle mutations display seizures | Tao et al., 2011 | ||
| •Easily shocked(eas) •Bang senseless (bss) •Technical knockout (tko) |
70 ml fly vials (10 s) | •Acute exposure (10 s) to 100% CO2 caused SLA in all three BS mutants •Refractory period following acute gas exposure •Susceptibility to SLA and anaesthetization following hypercapnia •Ability of hypoxia to trigger SLA •Prolonged exposure to anesthetic gases delayed SLA |
Whelan et al., 2010 | ||
| •Canton-S (wild-type) •Technical knockout (tko) •sesB •easalaE13 BS mutants |
Enclosed square recording arena with Vortex Genie2 (10 s) | •The ketone body β-hydroxybutyrate (β-HB) reduces SLA in the eas BS strain •The anticonvulsant effects of β-HB on SLA are partially mediated by both KATP channels and GABAB signaling |
Li et al., 2017 | ||
| Wild type Canton S | PTX (5 μM) 4-aminopyridine (3 mM) | •Exposure to proconsulvants heightens stimulation of neuronal activity •Exposure to Gbp reduces synchronicity |
Streit et al., 2016 | ||
| •Bang senseless •W1118 •elav-Gal4 •UAS-MRP1 •UAS-MRP1: elav-Gal4 |
Fly vials that were vortexed at VORTEX-5 for 10 s | •PHT reduces mean recovery time of three control groups containing the bss mutation •PHT and VPA caused negative effects on eclosion rate but positive effect on seizure behavior |
Bao et al., 2011 | ||
| Wild-type | High-frequency stimulation 0.5 ms pulses at 200 Hz for 300 ms using oscilloscope Minimal voltage: 2 V | •During induction of seizure, oscilloscope shows seizure-like activity •Presence of 7 min refractory period in flies after high frequency stimulation •If seizure is still induced, refractory period increases to 17 min |
Howlett and Tanouye, 2009 | ||
| •Wild-type •parabss1 •eas •sda |
High-frequency stimulation 0.5-ms pulses at 200 Hz for 400 ms using electrodes | •Injection of saline control caused a slight increase in seizure threshold whereas injection of 25 mM valproate saline solution caused a significant increase •Seizure sensitivity of parabss1 is the most difficult to suppress |
Howlett and Tanouye, 2013 | ||
| •easPC80 •sda iso70.8 |
High-frequency electrical brain stimulation (0.4-msec pulses at 200 Hz for 300 ms using electrodes) | •shits1 mutation in flies contributes to suppressing seizures •Seizure-like activity is related to the synaptic depletion •Disruption of synaptic transmission in excitatory neurons results in action potentials that are linked with seizures |
Kroll et al., 2015 | ||
| •Stress sensitive B (sesB9Ed−4) •bss paralytic mutant with loss of ANT •Seizure (seits) •Temperature-sensitive paralytic mutant •UAS-sesB31320 •UAS-sesB36661 |
Sleep deprivation Fly vials (10 s) and vortex machine | •Sleep deprivation can further influence seizure activity when sesB is disrupted •VPA can decrease susceptibility to sleep deprivation-enhanced seizure in sesB9Ed−4 •The effect of sleep deprivation on seizure activity can be observed using mechanical stimuli •In early development, sleep deprivation can increase susceptibility to sleep deprivation-enhanced seizure |
Lucey et al., 2015 | ||
| •Canton-S wild-type •Cry03homozygotes29 •Larvae |
Electroshock (10–30 V) Direct current pulse, created | •Exposure to pulsed blue light increased seizure duration •100 mT magnetic field increased the effect of blue light on seizure severity and is light dependent •Antiepileptic drugs can prevent prolongation of seizure due to their effect on neuronal activity |
Marley et al., 2014 | ||
| •Canton-S wild-type •Bang senseless •eas |
High-frequency electrical brain stimulation (0.5-ms pulses at 200 Hz for 300 ms) | •Mechanical shock results in six specific seizure phases in flies •Genetic background can influence seizure duration •bss flies have lower seizure threshold •The behavior of bss mutants is similar to other BS mutants such as easPC80, sdaiso7.8, and tko25t |
Parker et al., 2011 | ||
| •parabss1 •easPC80 •sda iso7.8 |
High frequency brain stimulation (0.5 ms-pulses at 200 Hz for 300 ms using tungsten electrodes) | •cacTS2 acts as a general seizure-suppressor mutation and can revert the effects of mutations such as sda, eas and parabss1 •cacTS2 is a seizure-resistant mutant at room temperature but a seizure-sensitive mutant at high temperature |
Saras and Tanouye, 2016 | ||
| •easPC80 •sda iso7.8 •topo I |
High frequency brain stimulation (0.5 ms-pulses at 200 Hz for 300 ms using tungsten electrodes) | •top1JS mutation is a general seizure-suppressor •top1JS mutation increases seizure thresholds and reduces the recovery time of eas flies |
Song et al., 2007 | ||
| Medicinal leech Hirudo verbana | Stage IV larvae (cca-1 mutant) | PTZ (4–10 mM) | No seizures in T-type Ca2+ channel (cca-1) mutant worms | No data found | Hahn and Burrell, 2015 |
| Planaria (n = 8–20) | Brown D. tigrina | NMDA (1, 3, 10 mM) PTX (0.01–5.0 mM) Nicotine (0.1–10 μM) | Planaria exhibit an increasing number of sudden asynchronous convulsive movements in a dose dependent manner when exposed to proconvulsants | No data found | Ramakrishnan and DeSaer, 2011 |
| Brown D. tigrina | Glutamate (0.6 mM) NMDA(1.4 mM) Semicarbazide (4.5 mM). | •Riluzole reverses I-glutamate, NMDA and semicarbazide induced PSLA •(+)-MK-801 reverses I-glutamate and NMDA induced PSLA |
Ramakrishnan et al., 2013 | ||
| Dugesia dorotocephala | NMDA (0.01, 0.1, 1, 3, 10 mM) or water | •NMDA produced PSLA •MK-801 or DNQX antagonizes NMDA-induced PSLA •Topiramate antagonizes PSLA induced by NMDA or AMPA |
Rawls et al., 2009 | ||
| Roundworm Caenorhabditis elegans (n = 4–6) | Stage IV larvae (wild type N2) | High temperature (26°C-28 ± 1°C) | Seizure frequency was significantly decreased by Baccoside A | Yes (O'reilly et al., 2014) | Pandey et al., 2010 |
| Stage IV larvae (cca-1 mutant) | No seizures in T-type Ca2+ channel (cca-1) mutants | ||||
| •Bristol N2 •CB156 unc-25(e156) •CB382 unc-49 (e382) |
Electrical shock (200 Hz, 3.5 ms, 47 V) PTZ (72.0 mM) | Electric shock induces paralysis and convulsions in C. elegans | Risley et al., 2016 | ||
| Tadpole Xenopus laevis | Albino Xenopus laevis (n = 20) | PTZ (15 mM) Bicuculline Picrotoxin Kainic acid (0.25 mM) Pilocarpine (75 mM) 4-ami-nopyridine, 4-AP (1 mM) | •All proconvulsants caused seizures which are divided into classes; (I) Rapid swimming, (II) Behavior arrest, (III) Loss of posture, (IV) Repetitive side-to-side lateral movement of head, (V) Fast, alternating contractions of axial musculature •A low number of TUNEL-positive and PI-positive cells were present, indicating progressive cell-loss within normal brain growth |
No data found | Hewapathirane et al., 2008 |
| Wild type | PTZ (10 mM or 15 mM) | •PTZ induces seizures in tadpoles, causing uncontrolled tail bends and excessive turning •Seizure susceptibility decreases when the level of putrescine increases •Endogenous protective mechanisms prevent long-term cell damage due to the presence of polyamine |
Bell et al., 2011 | ||
| Zebrafish Danio rerio | Larvae, 7 d.p.f, Ekkwill strain | PTZ (40 mM) | •PTZ induces agitation (Stage I) before degrading into occasional body-stiffening and loss of posture (Stages II and III) •TPR, VPA, LTG •reduces PTZ-induced movement as to compare with VHC+PTZ, within 30 min. •GBP increases PTZ-induced movement •Other AEDs were inactive at their MTC |
Yes - embryo (Liu et al., 2012) | Afrikanova et al., 2013 |
| •Adult, wild type (n = 6) | PTZ (220 mg/kg) | •The PTZ-treated group had an increase in distance, velocity, mobility, and circular rotations •GBP prevented PTZ-induced increases in zebrafish •cephalic field potential |
Banote et al., 2013 | ||
| Larvae (n = 5) | PTZ (15 mM) | •SC-560 reduces c-fos mRNA expression compared to PTZ group whereas SC-236 has no effect •SC-560 prevents PTZ-induced increase of locomotor activity whereas SC-236 had no effect |
Barbalho et al., 2016 | ||
| Larvae, WIK wild-type (n = 12) | PTZ (20 mM) | Oxcarbazepine, zonisamide and diazepam caused a decrease in locomotor activity | Berghmans et al., 2007 | ||
| •Adult, (AB), wild-type strain •Male (n = 8; 10 months) •Female (n = 9; 8 months) |
PTZ (15 mM) | •Zebrafish experienced 4.93 seizure events on average •Epileptiform discharges last for 85 s on average |
Cho et al., 2017 | ||
| Adult, WIK strain | PTZ (15 mM) | •Reactive gliosis manifests after PTZ-induced seizures •Total number of leukocytes increases after seizure •Increased cellular proliferation in ventricular zone and parenchyma |
Duy et al., 2017 | ||
| Adult, wild-type (4–5 months) | PTZ (2, 4, 6, and 8 mM) Caffeine (1, 10, or 30 μM) | •Lower concentration (2 mM) of PTZ evokes stage I (increased swim activity) •Higher concentrations (4, 6 and 8 mM) of PTZ evokes stages II and III (II—rapid whirlpool-like circling swim, III—clonus-like seizures) •Valproic acid, gabapentin, lacosamide and carbamazepine increases latency to all stages •Pregabalin was ineffective |
Gupta et al., 2014 | ||
| Larvae, 7 d.p.f | PTZ (15 mM) Picrotoxin Biculline | s334/Colbert mutant demonstrates inability to generate long duration epileptiform discharges in response to PTZ | Hortopan et al., 2010b | ||
| •Wild type larvae, 3 d.p.f •Wild-type (n = 22), mib mutant (n = 28) |
PTZ (15 mM) | •Stage 1 and 3 seizures were noted in mibhi904 mutants •93% of mibhi904 mutants acquire recurrent spontaneous multi-spike bursts > 1,000 ms in duration |
Hortopan et al., 2010a | ||
| •7 d.p.f., Larvae, wild-type (AB) •5 d.p.f morpholino-injected larvae (WT) •7 d.p.f scn1La mutant larvae (HO) |
PTZ (40 mM) | •PTZ-treated larvae suffered more seizures than VHC-treated larvae •PTZ-treated larvae had a longer seizure duration than VHC-treated larvae •Seizures per larvae in the HO group is higher than the WT group •Chemical models produced frequent and long seizures as to compared to genetic models |
Hunyadi et al., 2017 | ||
| Adult (3–4 months old) heterogenous WT stock | PTZ (170 mg/kg) | •PTZ group had seizures characterized by abnormal circular movements •PHY, RSV, OXC, GBP, and DZP provided resistance against PTZ |
Kundap et al., 2017 | ||
| •Larvae (n = 10) •Embryo |
Ginkgotoxin (40 mM) | Ginkgotoxin exposure induces seizure-like behavior within embryos | Lee et al., 2012 | ||
| Larvae (7, 15, and 30 d.p.f.) | Kainic acid (100, 300, and 500 μM) | •No locomotor or seizure activity recorded in 7 d.p.f. larvae •Locomotor activity detected in 15 d.p.f larvae •No locomotor or seizure activity recorded in 30 d.p.f. larvae |
Menezes et al., 2014 | ||
| Adult, 4–6 months (n = 12) | PTZ (5, 7.5, 10, and 15 mM) | •Zebrafish immersed in PTZ solution experienced seizures •Seizure scores of zebrafish increases as PTZ concentration increases |
Mussulini et al., 2013 | ||
| •Adult, wild-type TupLF strain •Adult, transgenic Tg[HuC:GFP] |
Loss of cln3 protein using a knockout model | •Using in situ hybridization, cln3 gene expression was shown in WT zebrafish •EEG reveals increased frequency activity and higher amplitude in cln3 ATG MO morphants, which reflects epileptiform activity •Loss of cln3 protein in zebrafish causes motor abnormalities |
Packer et al., 2016 | ||
| •Larvae, wild-type 7–14 d.p.f. (n = 5) •Danio rerio larvae, aldh7a1 mutants 7–14 d.p.f. (n = 5) |
Transgenic model aldh7a1 | •Light induces rapid “whirlpool-like” swimming (stage 2) and body convulsions (stage 3) when exposed to aldh7a1 mutants at 10/11 d.p.f. •High number of bursts of abnormal electrical discharge with long duration and high amplitude was observed in the tested mutants •Pyridoxine treatment prevents seizure-like behavior |
Pena et al., 2017 | ||
| •Adult, laboratory strain WIK •(9–14 months) |
PTZ (15 mM) | •PTZ induces seizures within zebrafish •Eugenol at high concentration prolongs seizure latency •Visual appearance of seizure tracings was observed and can be differentiated into baseline, pre-seizure, seizure and post-seizure |
Pineda et al., 2011 | ||
| •Adult, Female laboratory strain WIK •(9–14 months) |
PTZ (15 mM) | •Hindbrain stimulation in •the locus coerulus region promotes seizure resistance •Higher PTZ concentration causes higher stimulation rate |
Pineda et al., 2013 | ||
| Adult, wild-type strain | PTZ (7.5 mM) | •PTZ induces behavioral changes in zebrafish (Stage I, II, and III seizures) •Increased latency to clonus-like convulsions are due to pretreatments PHT, GBP, and VPA •PTZ has no effect on ATP, ADP, and AMP hydrolysis but increases ecto-ADA and soluble-ADA activities |
Siebel et al., 2013 | ||
| Adult, AB strain (6–9 months) | Kainic acid (6 mg/kg) | •KA induces behavioral changes in zebrafish, followed by dose-dependent seizures •DHA supplemented groups showed an increase in latency at time of seizure onset |
Sierra et al., 2012 | ||
| •Larvae, wild-type strain (n = 6) •Larvae, Scn1a mutant (n = 6) |
Transgenic model with Scn1a mutation | •FA reduces epileptiform brain activity •σ1-agonist, 5-HT1D–or 5-HT2C-antagonist can prevent FA's effect on locomotor activity •66% decrease in monoamines due to FA treatment |
Sourbron et al., 2017 | ||
| Larvae, AB wild-type | PTZ (1–25 mM) | •Stage II seizures were evoked in larvae •DA treatment reduces time in seizure latency •The DA cohort travel 5 times more than another other PTZ groups •DA treatment increases mobility of larvae |
Tiedeken and Ramsdell, 2007 | ||
| Larvae, Tg (elavl3:GCamP6s), 4 d.p.f | PTZ (1–15 mM) | •Tetrodotoxin suppressed neuronal seizure activity caused by PTZ •GCaMP measurements can monitor basal activity and dynamics due to drug induced seizures •Valproate reduced larva motility and fluorescence |
Turrini et al., 2017 | ||
| Larvae, AB wild-type | PTZ (1–16 mM) Picrotoxin, PTX (1–625 micrometer) | PTX-treated group has a higher maximum and lower minimum locomotor activity as compared with PTZ-treated group in dark conditions | Yang et al., 2017 |
PTZ, Pentylenetetrazol; GEFS+, Generalized epilepsy with febrile seizures plus; GABA, γ-Aminobutyric acid; BS, Bang Sensitive; LEV, Levetiracetam; SLA, Seizure Like Activity; PTX, Picrotoxin; PHT, Phenytoin; VPA, Valproic Acid; Eas, Easily Shocked; Bss, Bang Sensless; Tko, Technical Knockout; Sda, Slam Dance; NMDA, N-Methyl-D-aspartic acid; PLSA, Planarian Seizure Like Activity; TPR, Topiramate; LTG, Lamotrigine; VHC, Vehicle Control; AED, Anti-Epileptic Drugs; MTC, Maximum Tolerated Concentration; GBP, Gabapentin; OXC, Oxcarbazepin; RSV, Rivastigmine; DZP, Diazepam; D.p.f, Days Post Fertilization; WT, Wild Type; ADA, Adenosine deaminase; KA, Kainic Acid; DHA, Docosahexaenoic acid; FA, Fenfluramine; DA, Domoic Acid.