MRS-4203: a novel small molecule adenosine kinase inhibitor prevents epileptogenesis in mice
Abstract number :
3.403
Submission category :
2. Translational Research / 2E. Other
Year :
2021
Submission ID :
1886504
Source :
www.aesnet.org
Presentation date :
12/6/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:56 AM
Authors :
Madhuvika Murugan, PhD - Rutgers University; Detlev Boison, PhD - Professor, Neurosurgery, Rutgers University; Kenneth Jacobson, PhD - National Institutes of Health; Kiran Toti, PhD - National Institutes of Health
Rationale: The development of disease modifying therapies that prevent epilepsy or its progression remains the Holy Grail for epilepsy research and therapy development. We previously demonstrated that therapeutic adenosine augmentation affects the epileptogenic process through an epigenetic mechanism linked to an isoform of the adenosine metabolizing enzyme adenosine kinase, expressed in the cell nucleus (ADK-L). Targeting ADK-L with a small molecule inhibitor would be a rational approach for epilepsy prevention. To this end we developed a small molecule inhibitor, MRS-4203, designed to selectively target ADK-L.
Methods: The antiepileptogenic therapeutic efficacy of MRS-4203 was evaluated in the mouse intrahippocampal kainic acid model of temporal lobe epilepsy. Three days after priming epileptogenesis with an intrahippocampal injection of kainic acid, MRS-4203 (3.1 mg/day) or vehicle, was administered systemically for a transient time span of only 7 days through osmotic mini-pumps implanted into the intraperitoneal cavity. Development of epilepsy was evaluated 20 days after drug washout by continuous video-EEG monitoring.
Results: 28 days after KA injection control mice (n= 5) had developed a robust epileptic phenotype characterized by 11.4±9.4 seizures per hour and spent an average time of 228±56 minutes per day in seizures. By contrast, MRS-4203 treated mice (n=4) had a significantly reduced epilepsy phenotype experiencing only 2.0±1.6 seizures per hour and an average of 53±35 minutes per day spent in seizures. Overall we found >90% seizure reduction in 75% of all MRS-4203 treated mice. We also noted a significant reduction in histopathological hallmarks of epileptogenesis such as reduced granule cell dispersion in MRS-4203 treated mice compared to vehicle treated controls.
Conclusions: We conclude that MRS-4203, designed to target ADK-L, is a novel approach for antiepileptogenic therapy. Investigations on the epigenetic mechanisms underlying the antiepileptogenic effects of targeting ADK-L are underway.
Funding: Please list any funding that was received in support of this abstract.: National Institutes of Health (DB, R01 NS065957, R01 NS103740), Citizens United for Research in Epilepsy (DB, CURE Catalyst Award).
Translational Research