Table 4.
Experimental drugs tested in models of DEE
| Drug | Mechanism | Model/Species | Treatment Protocol | Effect | Reference |
|---|---|---|---|---|---|
| ES models | |||||
| CGP35348 | GABABR antagonism | Mouse, Down/GBL | Pretreatment | Shortens EDRs | (183) |
| Baclofen | GABABR agonist | Mouse, Down/GBL | Pretreatment | Prolongs EDRs | (183) |
| 5-OH-tryptophan | Serotonin increase | Mouse, Down/GBL | Pre-treatment | Prolongs EDRs | (183) |
| GIRK2 knockout | Deletion of GABABR associated inward-rectifying potassium channel | GIRK2 KO mouse, Down/GBL | GIRK2 knockout mice | GIRK2 knockout confers resistance to GBL-induced spasms | (187) |
| Rapamycin | mTOR inhibitor | Rat, prenatal betamethasone/postnatal NMDA | Pretreatment | No effect, no evidence of target relevance | (182) |
| Ganaxolone | Allosteric activator of GABAAR, synaptic and extrasynaptic | Rat, prenatal betamethasone/postnatal NMDA | Pretreatment | Reduces number, delays onset of NMDA spasms | (585) |
| Acton prolongatum® | Synthetic ACTH based on porcine ACTH | Rat, prenatal betamethasone/postnatal NMDA | Pretreatment | Reduces number, delays onset of NMDA spasms after 2 doses but not after single dose | (586) |
| AQB-565 | ACTH1–24 linked to melanocyte stimulating hormone, acts on MC3, MC4 melanocortin receptors | Rat, prenatal betamethasone/postnatal NMDA | Pretreatment | Reduces number of NMDA spasms after 8 doses | (183) |
| Estradiol, diethylstilbestrol | Gonadal hormone, estrogen analogue | Rat, prenatal betamethasone/postnatal NMDA | Pretreatment (PN3–10) | No effect on spasms; increased GAD67 cells in neocortex | (184) |
| β-OH-butyrate | Ketoacid | Rat, prenatal betamethasone/postnatal NMDA | Pretreatment | Reduces spasms and delays latency to NMDA spasms after repeat but not single dose administration | (177) |
| β-OH-butyrate | Ketoacid | Rat, Prenatal betamethasone / postnatal NMDA | Pretreatment (200 mg/kg ip) | No effect | (587) |
| 2-Deoxyglucose | Metabolic inhibition of glycolysis | Rat, prenatal betamethasone/postnatal NMDA | Pretreatment | No effect | (587) |
| ISS models | |||||
| Rapamycin, pulse | mTOR inhibitor | Rat, multiple hit | Treatment after spasm onset, 3 days | Decreases spasms within 2 h; stops spasms with repeat dosing; improves spatial learning; prevents adult epilepsy; reverses mTOR dysregulation | (157, 163) |
| CPP-115 | High-affinity vigabatrin analog | Rat, multiple hit | Treatment after spasm onset, repeated (PN4–12) | Reduces spasms from the first hour and for up to 3 days; better efficacy and tolerability than vigabatrin | (158) |
| Carisbamate | Unknown; effect on spasms not due to sodium channel blockade | Rat, multiple hit | Treatment after spasms onset, single dose (PN4 or PN6–7) | Reduces spasms within the first hour | (162) |
| NAX-5055 | Galanin receptor 1 (GalR1) agonist | Rat, multiple hit | Treatment after spasms onset, single dose (PN4 or PN6–7) | No effect; low expression of GalR1 in pups | (160) |
| VX-765 | Caspase 1 inhibitor | Rat, multiple hit | Treatment after spasms onset, single dose (PN4) | No effect | (159) |
| CGP 35348 | GABABR antagonism | Rat, multiple hit | Treatment after spasms onset, single dose (PN4) | No effect | (159) |
| 17β-Estradiol | Gonadal hormone | Rat, multiple hit | Treatment started after induction (PN3–10) | No effect | (159) |
| 17β-Estradiol | Gonadal hormone | Mouse, Arx KI [Arx (GCG10+7)] | Pretreatment (PN3–10) | Prevents spasms and other seizures, restores interneuronopathy | (152) |
| 17β-estradiol | Gonadal hormone | Mouse, Arx with PA1 or PA2 expansion | Pre-treatment (PN3-10) | Reduces seizures but not the abnormal behavior | (195) |
| Dravet syndrome models | |||||
| Soticlestat | Cholesterol 24-hydroxylase inhibitor | Mouse, Scn1atm1Kea with exon 1 deletion | Treatment after hyperthermia priming | Reduced seizures, protected against hyperthermia seizures, prevented SUDEP | (588) |
| Medium chain triglyceride diet (decanoic C10, octanoic acid C8 mix) | Ketogenic diet metabolite | Mouse, Scn1a KI, R1407X | 4-wk treatment prior to hyperthermia | C10/C8 (80:20) reduce both seizures and mortality; C10 reduces mortality | (589) |
| Gabra2 repair | GABRA2 expression restoration (increase) | Mouse, Scn1a+/− | Genetic repair of Gabra2 | Rescues epilepsy phenotype | (590) |
| Trpv1 receptor deletion | Trpv1 receptor deletion | Mouse, Scn1a+/− | Trpv1 receptor deletion | No effects on hyperthermia seizures, frequency of spontaneous seizures or survival | (591) |
| SB-705498 | Trpv1-selective antagonist | Mouse, Scn1a+/- | No effect on seizures or survival | (591) | |
| Cannabigerolic acid | Phytocannabinoid | Mouse, Scn1a+/- | Pretreatment | Potentiated clobazam effects on hyperthermia-induced and spontaneous seizures, anticonvulsant in MES, proconvulsant in 6-Hz test. | (592) |
| Cannabichromene, 5-fluoro- cannabichromene | Phytocannabinoid | Mouse, Scn1a+/− | Pretreatment | Anticonvulsant | (593) |
| Ketogenic diet | Ketogenic diet | Mouse, Scn1a KI, R1407X | Ketogenic diet, 14 days | Decreases SUDEP, protects against seizure-induced respiratory arrest | (594) |
| SCN1A transfer in the brain (adenoviral) | SCN1A expression in the brain | Mouse, SCN1A-A1783V KI | Adenovirus expressing SCN1A, intracerebral injection | Protected from death, attenuation of epilepsy; hyperactivity persisted; cognitive effects variable | (595) |
| Naltrexone | Opioid antagonist | Zebrafish, scn1Lab | Pretreatment, 30 min before PTZ | Anticonvulsant effects | (596) |
| Fenfluramine, Norflenfluramine enantiomers | Reuptake inhibitor of 5-OH-tryptamine | Zebrafish, scn1Lab-/- | Treatment exposure | Anticonvulsant effects | (217) |
| Fenfluramine | Reuptake inhibitor of 5-OH-tryptamine | Zebrafish, scn1Lab | Treatment exposure | Anticonvulsant effects | (597) |
| Dimethadione | Calcium channel blocker | Zebrafish, scn1Lab | Treatment exposure | Anticonvulsant effects | (597) |
| Clemizole | Serotoninergic | Zebrafish, scn1Lab | Treatment exposure | Anticonvulsant effects | (598) |
| PK11195 | Pck1 activator and translocator protein ligand | Zebrafish, scn1Lab | Treatment exposure | Anticonvulsant effects | (599) |
| GR-46611 | 5HT1D receptor agonist | Mouse, 129S-Scn1Atm1Kea/Mmjax | Pretreatment | Protects from hyperthermia seizures, decreases seizure severity, improves survival | (600) |
| ASO, increases Scn1a | ASO, increases Scn1a (TANGO method) | Mouse, F1:129S-Scn1a+/− Å∼ C57BL/6J | PN2 or 14, intracerebroventricular injection | Reduces seizures and SUDEP | (282) |
| CRISPR/dCas9-based Scn1a gene activation in inhibitory neurons | CRISPR/dCas9-based Scn1a gene activation in inhibitory neurons | Mouse, Scn1aRx/+, floxed dCas9-VPRVPR/+, Vgat-CreCre/+, | Intravenous AAV injection, 4 wk | Improved behavioral deficits, ameliorated febrile seizures | (601) |
| MV1369, MV1312 | NaV1.6 inhibitor | Zebrafish, Scn1Lab KO | Treatment | Reduced spontaneous burst movements and seizures | (602) |
| AA43279 | NaV1.1 activator | Zebrafish, Scn1Lab KO | Treatment | Reduced spontaneous burst movements and seizures | (602) |
AQB-565, ACTH1–24 linked to melanocyte stimulating hormone; ASO, antisense oligonucleotides; CPP-115, high-affinity GABA aminotransferase inhibitor; CRISPR, clustered regularly interspaced short palindromic repeats; EDRs, electrodecremental responses; GABRA2, GABAAR A2 subunit; CGP35348, GABAB receptor (GABABR) inhibitor; DEE, developmental and epileptic encephalopathy; ES, epileptic spasms; GalR, galanin receptor; GBL, gamma butyrolactone; GIRK, inward-rectifying potassium channel; 5-HT, serotonin; KI, knockin; MC, melanocortin receptor; mTOR, mechanistic target of rapamycin; Nav, sodium channel; NMDA, N-methyl-d-aspartate; PCK1, phosphoenolpyruvate carboxykinase 1; PN, postnatal; Scn1a, sodium channel 1; SUDEP, sudden death in epilepsy; Trpv1, transient receptor potential cation channel subfamily V member 1; vgat, vesicular GABA transporter.