Research Projects

Epilepsy is a heterogeneous neurological disorder characterized by spontaneous recurrent seizures with a global incidence of approximately 50–60 per 100,000 person-years. Despite the availability of anti-epileptic drugs, approximately one-third of epileptic patients do not respond to the current therapies. Additionally, there are no FDA approved drugs to halt epileptogenesis driving extensive research for novel targets. Recently, epigenetic regulation, particularly histone deacetylases (HDACs) has garnered attention in the context of epilepsy. Emerging evidence links dysregulated HDAC activity to epilepsy pathogenesis, with studies showing decreased histone acetylation and increased HDAC 1, HDAC 3 and HDAC 6 activity. Non-selective HDAC inhibitors, such as SAHA, Valproic acid, sodium butyrate, and trichostatin, have demonstrated anti-epileptic and neuroprotective effects. Importantly, vorinostat inhibited seizures in intractable epileptic model of zebra fish and is currently being evaluated in phase II clinical trials for drug resistance. However, these HDACi are limited by non-selectivity and toxicity due to broad range of actions, necessitating the development of isoform-selective HDAC inhibitors. In this context, we designed, synthesized and characterized two novel HDAC inhibitors, NMJ-2 and NMJ-3 selective to HDAC 1 and 6 isoforms (experimental data provided in the technical document), which are relatively more potent and less toxic compared to the available FDA approved HDACi, SAHA. Through selective HDAC inhibition assays, NMJ-2 was identified to have more potency towards HDAC 1, 6 and 8 compared to SAHA. Moreover, these 3 compounds showed no cardiotoxicity and hematological disturbances like SAHA. Our previous studies indicated that these compounds are also blood brain permeable and neuroprotective. Using the Lithium-Pilocarpine drug resistant model of epilepsy, the effect of these identified compounds (NMJ-2, NMJ-3) on seizure severity, frequency, and key epileptogenic processes, including neuroinflammation, aberrant neurogenesis, blood-brain barrier integrity, and neurodegeneration will be studied. Further, the effect of these drugs on multi-drug efflux transporters, p-glycoprotein expression will be studied. This investigation will offer novel novel HDACi with improved safety and efficacy profiles for preventing the development of epilepsy and therapy of drug resistance. Further, given the potential therapeutic benefit of HDACi in several other neurological disorders, these molecules may have broader clinical applications, offering hope for improved management.