When Drugs Do Not Work: Alternatives to Antiseizure Medications.

PURPOSE OF REVIEW: Despite the increase in the number of novel antiseizure medications over the past 20 years, approximately one-third of patients will not have adequate seizure control on medications. For these patients, additional options need to be considered, including dietary, device, and surgical treatments. In addition, many complementary therapies can be considered as adjunctive treatment, with the intent of improving quality of life for persons with epilepsy and potentially allowing for improvement in seizure control. RECENT FINDINGS: This review outlines established and developing treatments for drug-resistant epilepsy. Surgical treatments, including resective surgery and vagus nerve stimulation, have been routine care for several decades. In the last several years, new neurostimulation options have been approved (responsive neurostimulation and deep brain stimulation) or are under development (continuous subthreshold cortical stimulation). For patients with lesion or well-defined seizure-onset zones, less invasive options including laser ablation and ultrasound therapy provide the potential for faster recovery times and less morbidity. Not all therapies are in the pharmacological or surgical arenas. This review also explores the evidence for complementary treatments, including relaxation and meditation techniques, and art and music therapy. Despite the range of antiseizure medications available, they still provide inadequate for a large number of patients with epilepsy, either due to ongoing seizures or intolerable side effects. Complementary therapies, including diet, meditation techniques, and music therapy, provide compelling treatment options to improve quality of life while potentially improving seizure control. In appropriate patients, stimulation devices or surgical resection can offer options for significant seizure reduction or even cure. The full range of therapeutics should be considered for each patient with epilepsy when they are struggling with inadequate seizure control or side effects with traditional pharmacological treatment.

Implementation of a fluorescence-based screening assay identifies histamine H3 receptor antagonists clobenpropit and iodophenpropit as subunit-selective N-methyl-D-aspartate receptor antagonists.

N-Methyl-D-aspartate (NMDA) receptors are ligand-gated ion channels that mediate a slow, Ca(2+)-permeable component of excitatory synaptic transmission in the central nervous system and play a pivotal role in synaptic plasticity, neuronal development, and several neurological diseases. We describe a fluorescence-based assay that measures NMDA receptor-mediated changes in intracellular calcium in a BHK-21 cell line stably expressing NMDA receptor NR2D with NR1 under the control of a tetracycline-inducible promoter (Tet-On). The assay selectively identifies allosteric modulators by using supramaximal concentrations of glutamate and glycine to minimize detection of competitive antagonists. The assay is validated by successfully identifying known noncompetitive, but not competitive NMDA receptor antagonists among 1800 screened compounds from two small focused libraries, including the commercially available library of pharmacologically active compounds. Hits from the primary screen are validated through a secondary screen that used two-electrode voltage-clamp recordings on recombinant NMDA receptors expressed in Xenopus laevis oocytes. This strategy identified several novel modulators of NMDA receptor function, including the histamine H3 receptor antagonists clobenpropit and iodophenpropit, as well as the vanilloid receptor transient receptor potential cation channel, subfamily V, member 1 (TRPV1) antagonist capsazepine. These compounds are noncompetitive antagonists and the histamine H3 receptor ligand showed submicromolar potency at NR1/NR2B NMDA receptors, which raises the possibility that compounds can be developed that act with high potency on both glutamate and histamine receptor systems simultaneously. Furthermore, it is possible that some actions attributed to histamine H3 receptor inhibition in vivo may also involve NMDA receptor antagonism.