Avtor/Urednik		Witkin, Jeffrey M.; Li, Guanguan; Golani, Lalit K.; Xiong, Wenhui; Smith, Jodi L.; Ping, Xingjie; Rashid, Farjana; Jahan, Rajwana; Černe, Rok; Cook, James M.; Jin, Xiaoming
Naslov		The positive allosteric modulator of [alpha]2/3-containing GABAA receptors, KRM-II-81, is active in pharmaco-resistant models of epilepsy and reduces hyperexcitability after traumatic brain injury
Tip		članek
Vol. in št.		Letnik 372, št. 1
Leto izdaje		2020
Obseg		str. 83-94
ISSN		0022-3565 - The Journal of pharmacology and experimental therapeutics
Jezik		eng
Abstrakt		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 [alpha]2/3-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 [alpha]1[beta]3[gamma]2L 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 [alpha]1His102, providing a structural rationale for its low affinity for [alpha]1-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.
Proste vsebinske oznake		travmatična poškodba možganov GABA-A receptorji epilepsija traumatic brain injury GABA-A receptors epilepsy