Metabotropic glutamate receptors as targets for antiepileptic drug therapy: A behavioral and electroencephalographic analysis.

摘要

Epilepsy is a relatively common neurological disorder that involves recurrent seizures thought to be caused by an imbalance in the excitatory and inhibitory systems in the brain, in favor of excitation. Unfortunately, some types of epilepsy have drug resistance rates of up to 40%. Classically, targets for antiepileptic drugs have included glutamatergic ion channels. However, interfering with excitatory signalling at these channels can alter normal neural communication and can have negative side effects, including cognitive dysfunction and fatigue, which are among the most common complaints from patients. Given the high rate of drug-resistant patients, and the high rate of deleterious side effects, there is an obvious need to develop novel drugs with novel targets and mechanisms of action. Compounds targeting metabotropic glutamate receptors (mGluRs; specifically mGlur2 and 3) have shown promise in other hyperexcitatory neural disorders, and some have shown efficacy in models of epilepsy as well. The goal of these studies was to demonstrate a conclusive behavioral effect of particular mGluR active compounds in reducing the severity of seizures associated with two models of epilepsy. Both models that were used are models of generalized seizure, although one is characterized by convulsive seizures (pilocarpine model) and the other is characterized by the lack of convulsive seizure, or an "absence" seizure (GBL model). Mice were given mGluR2/3 active drugs either before or after seizure onset and behavioral observations relating to seizure were measured. In some cases, the mice had been implanted with tethered EEG devices to record neural activity that coincided with behavioral observations and measures. It was demonstrated that in generalized models of seizure, mGluR2/3 active agonists had some efficacy at reducing seizure severity. The effect of modulators at mGluR2 was also investigated. One in particular, CBiPES had a modest but significant effect in reducing the behavioral severity of pilocarpine induced seizures, but not of GBL induced seizures. In conclusion, mGluR2/3 remains a valid target for antiepileptic drug development. The ideal compound would yield higher response rates for patients while boasting a minimal negative side effect profile.