The Positive Allosteric Modulator of α2/3-Containing GABAA Receptors, KRM-II-81, Is Active in Pharmaco-Resistant Models of Epilepsy and Reduces Hyperexcitability after Traumatic Brain Injury
dc.contributor.author | Witkin, Jeffrey M. | |
dc.contributor.author | Li, Guanguan | |
dc.contributor.author | Golani, Lalit K. | |
dc.contributor.author | Xiong, Wenhui | |
dc.contributor.author | Smith, Jodi L. | |
dc.contributor.author | Ping, Xingjie | |
dc.contributor.author | Rashid, Farjana | |
dc.contributor.author | Jahan, Rajwana | |
dc.contributor.author | Cerne, Rok | |
dc.contributor.author | Cook, James M. | |
dc.contributor.author | Jin, Xiaoming | |
dc.contributor.department | Neurological Surgery, School of Medicine | en_US |
dc.date.accessioned | 2022-05-10T17:32:52Z | |
dc.date.available | 2022-05-10T17:32:52Z | |
dc.date.issued | 2020-01 | |
dc.description.abstract | The imidizodiazepine, 5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole (KRM-II-81), is selective for α2/3-containing GABAA receptors. KRM-II-81 dampens seizure activity in rodent models with enhanced efficacy and reduced motor-impairment compared with diazepam. In the present study, KRM-II-81 was studied in assays designed to detect antiepileptics with improved chances of impacting pharmaco-resistant epilepsies. The potential for reducing neural hyperactivity weeks after traumatic brain injury was also studied. KRM-II-81 suppressed convulsions in corneal-kindled mice. Mice with kainate-induced mesial temporal lobe seizures exhibited spontaneous recurrent hippocampal paroxysmal discharges that were significantly reduced by KRM-II-81 (15 mg/kg, orally). KRM-II-81 also decreased convulsions in rats undergoing amygdala kindling in the presence of lamotrigine (lamotrigine-insensitive model) (ED50 = 19 mg/kg, i.p.). KRM-II-81 reduced focal and generalized seizures in a kainate-induced chronic epilepsy model in rats (20 mg/kg, i.p., three times per day). In mice with damage to the left cerebral cortex by controlled-cortical impact, enduring neuronal hyperactivity was dampened by KRM-II-81 (10 mg/kg, i.p.) as observed through in vivo two-photon imaging of layer II/III pyramidal neurons in GCaMP6-expressing transgenic mice. No notable side effects emerged up to doses of 300 mg/kg KRM-II-81. Molecular modeling studies were conducted: docking in the binding site of the α1β3γ2L GABAA receptor showed that replacing the C8 chlorine atom of alprazolam with the acetylene of KRM-II-81 led to loss of the key interaction with α1His102, providing a structural rationale for its low affinity for α1-containing GABAA receptors compared with benzodiazepines such as alprazolam. Overall, these findings predict that KRM-II-81 has improved therapeutic potential for epilepsy and post-traumatic epilepsy. SIGNIFICANCE STATEMENT: We describe the effects of a relatively new orally bioavailable small molecule in rodent models of pharmaco-resistant epilepsy and traumatic brain injury. KRM-II-81 is more potent and generally more efficacious than standard-of-care antiepileptics. In silico docking experiments begin to describe the structural basis for the relative lack of motor impairment induced by KRM-II-81. KRM-II-81 has unique structural and anticonvulsant effects, predicting its potential as an improved antiepileptic drug and novel therapy for post-traumatic epilepsy. | en_US |
dc.eprint.version | Final published version | en_US |
dc.identifier.citation | Witkin JM, Li G, Golani LK, et al. The Positive Allosteric Modulator of α2/3-Containing GABAA Receptors, KRM-II-81, Is Active in Pharmaco-Resistant Models of Epilepsy and Reduces Hyperexcitability after Traumatic Brain Injury. J Pharmacol Exp Ther. 2020;372(1):83-94. doi:10.1124/jpet.119.260968 | en_US |
dc.identifier.uri | https://hdl.handle.net/1805/28936 | |
dc.language.iso | en_US | en_US |
dc.publisher | American Society for Pharmacology and Experimental Therapeutics | en_US |
dc.relation.isversionof | 10.1124/jpet.119.260968 | en_US |
dc.relation.journal | The Journal of Pharmacology and Experimental Therapeutics | en_US |
dc.rights | Publisher Policy | en_US |
dc.source | PMC | en_US |
dc.subject | Anticonvulsants | en_US |
dc.subject | Drug Resistant Epilepsy | en_US |
dc.subject | GABA Agents | en_US |
dc.subject | Oxazoles | en_US |
dc.title | The Positive Allosteric Modulator of α2/3-Containing GABAA Receptors, KRM-II-81, Is Active in Pharmaco-Resistant Models of Epilepsy and Reduces Hyperexcitability after Traumatic Brain Injury | en_US |
dc.type | Article | en_US |
ul.alternative.fulltext | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927408/ | en_US |