Ethosuximide: From Bench to Bedside

Abstract

Ethosuximide, 2-ethyl-2-methylsuccinimide, has been used extensively for "petit mal" seizures and it is a valuable agent in studies of absence epilepsy. In the treatment of epilepsy, ethosuximide has a narrow therapeutic profile. It is the drug of choice in the monotherapy or combination therapy of children with generalized absence (petit mal) epilepsy. Commonly observed side effects of ethosuximide are dose dependent and involve the gastrointestinal tract and central nervous system. Ethosuximide has been associated with a wide variety of idiosyncratic reactions and with hematopoietic adverse effects. Typical absence seizures are generated as a result of complex interactions between the thalamus and the cerebral cortex. This thalamocortical circuitry is under the control of several specific inhibitory and excitatory systems arising from the forebrain and brainstem. Corticothalamic rhythms are believed to be involved in the generation of spike-and-wave discharges that are the characteristic electroencephalographic signs of absence seizures. The spontaneous pacemaker oscillatory activity of thalamocortical circuitry involves low threshold T-type Ca2+ currents in the thalamus, and ethosuximide is presumed to reduce these low threshold T-type Ca2+ currents in thalamic neurons. Ethosuximide also decreases the persistent Na+ and Ca2+ -activated K+ currents in thalamic and layer V cortical pyramidal neurons. In addition, there is evidence that in a genetic absence epilepsy rat model ethosuximide reduces cortical gamma-aminobutyric acid (GABA) levels. Also, elevated glutamate levels in the primary motor cortex of rats with absence epilepsy (but not in normal animals) are reduced by ethosuximide.

T-Type Calcium Channel as a New Therapeutic Target for Tremor

“…On the other hand, mibefradil [37,39], lomerizine [39], and amiloride [39] failed to show antitremor effects. Both ethosuximide and zonisamide are antiepileptic drugs that are effective for absence seizure [20,40]. ECN is a neuroactive steroid [41].…”

Generalized seizures in a neural field model with bursting dynamics

“…However, the full mechanisms of action for antiseizure medication are more complicated than presented here and will require further analysis. For example, ethosuximide's main action in the neural field model is to decrease g X , but it also affects the GABA/Glutamate neurotransmitter systems (Gören and Onat 2007). More specifically, ethosuximide is known to block gamma-hydroxybutyrate (GHB) binding.…”

Ethosuximide Induces Hippocampal Neurogenesis and Reverses Cognitive Deficits in an Amyloid-β Toxin-induced Alzheimer Rat Model via the Phosphatidylinositol 3-Kinase (PI3K)/Akt/Wnt/β-Catenin Pathway

“…ETH is an AED that is selectively used in the treatment of absence epilepsy (51). It is of potential therapeutic value in other neuropsychiatric disorders (25,52).…”