Isobolographic Analysis of Synergistic Interactions between Neurosteroids and Tiagabine for Tonic Inhibition and Anticonvulsant Activity
Abstract number :
2.027
Submission category :
1. Translational Research: 1A. Mechanisms / 1A4. Mechanisms of Therapeutic Interventions
Year :
2017
Submission ID :
349400
Source :
www.aesnet.org
Presentation date :
12/3/2017 3:07:12 PM
Published date :
Nov 20, 2017, 11:02 AM
Authors :
Shu-Hui Chuang, Texas A&M University Health Science Center; K. Bakshi, Texas A&M University Health Science Center; B Clossen, Texas A&M University Health Science Center; and Doodipala Samba. Reddy, Texas A&M University Health Science Center
Rationale: Epilepsy is a neurological disorder characterized by recurrent, unprovoked seizures. Recent advancements utilizing neurosteroids for treatment of epilepsy have shown therapeutic potential, but little is known regarding their interactions with other antiepileptic drugs. Here we investigated the combination effects of the neurosteroid allopregnanolone (AP) and its synthetic analog ganaxolone (GX) with tiagabine (TG) on extrasynaptic tonic inhibition in murine dentate gyrus granule cells (DGGCs) and seizure protection in mice. Methods: Adult mice were used for electrophysiology and seizure studies. Isobolographic analysis was used to test for the presence and extent of synergistic interactions. Tonic currents were recorded from brain slices using whole-cell voltage-clamp recording. Anticonvulsant effects of drug combinations were evaluated in the 6-Hz seizure test. Results: Isobolographic analysis indicated that all combinations between GX and TG, or AP and TG at three fixed ratios (1:1, 3:1 and 1:3) displayed strong synergistic interactions for tonic inhibition in DGGCs. In seizure protection studies, GX, AP, and TG produced clear anticonvulsant effects in mice. The combination of GX and TG at the fixed-ratio of 1:1 exerted the greatest synergism (combination index, CI = 0.53), whereas CI’s for the combinations of GX and TG at 3:1 and 1:3 combinations were 0.94 and 0.96, respectively, indicating synergistic/ additive interactions. Similarly, combinations of AP and TG showed robust synergistic protection in 6-Hz test. Conclusions: These results demonstrate a synergistic effect of neurosteroids and TG in potentiating tonic inhibition and protecting against seizures. This effect is likely due to a greater allosteric agonism at extrasynaptic GABA-A receptors from TG-induced increase in GABA levels. These findings provide a mechanistic rationale for clinical potential of neurosteroids with TG for epilepsy therapy, possibly with better efficacy and reduced side effect outcomes. **Supported by NIH CounterACT Grant #U01-NS083460** Funding: **Supported by NIH CounterACT Grant #U01-NS083460**
Translational Research