Riluzole and novel naphthalenyl substituted aminothiazole derivatives prevent acute neural excitotoxic injury in a rat model of temporal lobe epilepsy

• Published in: Neuropharmacology Vol. 224; p. 109349
• Main Authors: Kyllo, Thomas, Singh, Vikrant, Shim, Heesung, Latika, Singh, Nguyen, Hai M., Chen, Yi-Je, Terry, Ellen, Wulff, Heike, Erickson, Jeffrey D.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15.02.2023
• Subjects: Animals; Disease Models, Animal; Epilepsy, Temporal Lobe - chemically induced; Epilepsy, Temporal Lobe - drug therapy; Glutamate/glutamine cycle; Hippocampus; Kainic Acid - toxicity; Kainic acid/excitotoxin; Kinetics; Neuroprotection/neurodegeneration; Rats; Riluzole - pharmacology; Riluzole/benzothiazole/aminothiazole/antiepileptic drugs; Seizures - chemically induced; Seizures - drug therapy; Seizures - prevention & control; Status Epilepticus; Status epilepticus/epileptogenic seizure; Temporal lobe epilepsy/epileptic disease; Glutamate/glutamine cycle; Riluzole/benzothiazole/aminothiazole/antiepileptic drugs; Neuroprotection/neurodegeneration; Status epilepticus/epileptogenic seizure; Kainic acid/excitotoxin; Temporal lobe epilepsy/epileptic disease
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2022.109349

Epileptogenic seizures, or status epilepticus (SE), leads to excitotoxic injury in hippocampal and limbic neurons in the kainic acid (KA) animal model of temporal lobe epilepsy (TLE). Here, we have further characterized neural activity regulated methylaminoisobutryic acid (MeAIB)/glutamine transport activity in mature rat hippocampal neurons in vitro that is inhibited by riluzole (IC50 = 1 μM), an anti-convulsant benzothiazole agent. We screened a library of riluzole derivatives and identified SKA-41 followed by a second screen and synthesized several novel chlorinated aminothiazoles (SKA-377, SKA-378, SKA-379) that are also potent MeAIB transport inhibitors in vitro, and brain penetrant following systemic administration. When administered before KA, SKA-378 did not prevent seizures but still protected the hippocampus and several other limbic areas against SE-induced neurodegeneration at 3d. When SKA-377 - 379, (30 mg/kg) were administered after KA-induced SE, acute neural injury in the CA3, CA1 and CA4/hilus was also largely attenuated. Riluzole (10 mg/kg) blocks acute neural injury. Kinetic analysis of SKA-378 and riluzoles’ blockade of Ca2+-regulated MeAIB transport in neurons in vitro indicates that inhibition occurs via a non-competitive, indirect mechanism. Sodium channel NaV1.6 antagonism blocks neural activity regulated MeAIB/Gln transport in vitro (IC50 = 60 nM) and SKA-378 is the most potent inhibitor of NaV1.6 (IC50 = 28 μM) compared to NaV1.2 (IC50 = 118 μM) in heterologous cells. However, pharmacokinetic analysis suggests that sodium channel blockade may not be the predominant mechanism of neuroprotection here. Riluzole and our novel aminothiazoles are agents that attenuate acute neural hippocampal injury following KA-induced SE and may help to understand mechanisms involved in the progression of epileptic disease. •Ca2+-regulated neural MeAIB/Gln transport is inhibited by aminothiazole derivatives of riluzole.•Riluzole and SKA-378 prevent acute hippocampal neural injury when administered after KA-induced SE.•SKA-378 does not prevent KA-induced SE events, is orally active, brain penetrant and is not sedative.•Riluzole and SKA-378 are tools to study the mechanisms to prevent neural injury after KA-induced SE.•Riluzole and SKA-378 could have therapeutic value as antiepileptic drugs for a potential new target.