The novel persistent sodium current inhibitor PRAX-562 has potent anticonvulsant activity with improved protective index relative to standard of care sodium channel blockers.

Objective: This study investigates the effects of PRAX-562 on sodium current (I _Na ), intrinsic neuronal excitability, and protection from evoked seizures to determine whether a preferential persistent I _Na inhibitor would exhibit improved preclinical efficacy and tolerability compared to two standard voltage-gated sodium channel (Na _V ) blockers.
Methods: Inhibition of I _Na  was characterized using patch clamp analysis. The effect on intrinsic excitability was measured using evoked action potentials recorded from hippocampal CA1 pyramidal neurons in mouse brain slices. Anticonvulsant activity was evaluated using the maximal electroshock seizure (MES) model, and tolerability was assessed by measuring spontaneous locomotor activity (sLMA).
Results: PRAX-562 potently and preferentially inhibited persistent I _Na induced by ATX-II or the SCN8A mutation N1768D (half-maximal inhibitory concentration [IC ₅₀ ] = 141 and 75 nmol·L ^-1 , respectively) relative to peak I _Na tonic/resting block (60× preference). PRAX-562 also exhibited potent use-dependent block (31× preference to tonic block). This profile is considerably different from standard Na _V blockers, including carbamazepine (CBZ; persistent I _Na IC ₅₀ = 77 500 nmol·L ^-1 , preference ratios of 30× [tonic block], less use-dependent block observed at various frequencies). In contrast to CBZ, PRAX-562 reduced neuronal intrinsic excitability with only a minor reduction in action potential amplitude. PRAX-562 (10 mg/kg po) completely prevented evoked seizures without affecting sLMA (MES unbound brain half-maximal efficacious concentration = 4.3 nmol·L ^-1 , sLMA half-maximal tolerated concentration = 69.7 nmol·L ^-1 , protective index [PI] = 16×). In contrast, CBZ and lamotrigine (LTG) had PIs of approximately 5.5×, with significant overlap between doses that were anticonvulsant and that reduced locomotor activity.
Significance: PRAX-562 demonstrated robust preclinical anticonvulsant activity similar to CBZ but improved compared to LTG. PRAX-562 exhibited significantly improved preclinical tolerability compared with standard Na _V blockers (CBZ and LTG), potentially due to the preference for persistent I _Na . Preferential targeting of persistent I _Na may represent a differentiated therapeutic option for diseases of hyperexcitability, where standard Na _V blockers have demonstrated efficacy but poor tolerability.
(© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)