Ranolazine Reduces Neuronal Excitability by Interacting with Inactivated States of Brain Sodium Channels

Abstract

Ranolazine is an approved drug for chronic stable angina that acts by suppressing a noninactivating current conducted by the cardiac sodium channel [persistent sodium ion current (I Na )]. Ranolazine has also been shown to inhibit the increased persistent I Na carried by Na V 1.1 channels encoding epilepsy-and migraine-associated mutations. Here, we investigate the antiepileptic properties of ranolazine exhibited through the reduction of hippocampal neuronal excitability. At therapeutically relevant concentrations, ranolazine reduced action potential firing frequency of hippocampal neurons in response to repetitive depolarizing current injections. Similarly, using a single current injection paradigm, ranolazine required a long depolarization (4 seconds) to produce significant inhibition of excitability, which was similar to that observed for the anticonvulsants phenytoin (slowly binds to the fast-inactivated state) and lacosamide (binds to the slow-inactivated state). Ranolazine enhanced the development of fast and slow inactivation assessed with conditioning prepulses of 100, 1000, or 10,000 milliseconds. Recovery of channels from inactivated states was also slowed in the presence of ranolazine. Interestingly, the use-dependent inhibition of hippocampal neurons was dependent on the duration of the voltage step, suggesting ranolazine does not selectively affect the open state and may also interact with inactivated states. NEURON (Yale University, New Haven, CT) computational simulations predict equal inhibition of action potential generation for binding to either fast-inactivated or slow-inactivated states. Binding of ranolazine to either preopen or open states did not affect the excitability of the simulation. Ranolazine was able to significantly reduce the epileptiform activity of the neuronal cultures, suggesting possible antiepileptic activity.

Pharmacogenomics in epilepsy

“…For example, ranolazine, a U.S. Food and Drug Administration (FDA)-approved drug for chronic angina treatment, was first identified as a selective blocker of persistent currents in mutant Na V 1.1 channels expressed in one of these models [76] . In follow-up studies in cultured rat hippocampal neurons, ranolazine was found to reduce neuronal excitability and suppress epileptiform activity evoked by NMDA receptor activation [77] . A more recent study showed that ranolazine does not inhibit the persistent Na+ current more strongly than phenytoin in central neurons, but is a better use-dependent blocker of transient Na+ current than phenytoin [78] .…”

10.2174/1381612823666170809115827

“…For example, ranolazine, a U.S. Food and Drug Administration (FDA)-approved drug for chronic angina treatment, was first identified as a selective blocker of persistent currents in mutant NaV1.1 channels expressed in one of these models [284]. In follow-up studies in cultured rat hippocampal neurons, ranolazine was found to reduce neuronal excitability and suppress epileptiform activity evoked by NMDA receptor activation [285]. A more recent study showed that ranolazine does not inhibit the persistent Na+ current more strongly than phenytoin in central neurons, but is a better use-dependent blocker of transient Na+ current than phenytoin [286].…”

Antiepileptic activity of preferential inhibitors of persistent sodium current

“…We previously reported that ranolazine can suppress persistent current generated by several human Na V 1.1 mutations associated with genetic epilepsies or familial hemiplegic migraine . In addition, ranolazine has been shown to reduce action potential firing and epileptiform activity in cultured neurons . Whether preferential suppression of persistent sodium current would be antiepileptic in vivo is unknown.…”

“…6 In addition, ranolazine has been shown to reduce action potential firing and epileptiform activity in cultured neurons. 7 Whether preferential suppression of persistent sodium current would be antiepileptic in vivo is unknown.…”