The mGlu7 receptor provides protective effects against epileptogenesis and epileptic seizures

Neurobiol Dis. 2019 Sep;129:13-28. doi: 10.1016/j.nbd.2019.04.016. Epub 2019 Apr 30.

Abstract

Finding new targets to control or reduce seizure activity is essential to improve the management of epileptic patients. We hypothesized that activation of the pre-synaptic and inhibitory metabotropic glutamate receptor type 7 (mGlu7) reduces spontaneous seizures. We tested LSP2-9166, a recently developed mGlu7/4 agonist with unprecedented potency on mGlu7 receptors, in two paradigms of epileptogenesis. In a model of chemically induced epileptogenesis (pentylenetetrazole systemic injection), LSP2-9166 induces an anti-epileptogenic effect rarely observed in preclinical studies. In particular, we found a bidirectional modulation of seizure progression by mGlu4 and mGlu7 receptors, the latter preventing kindling. In the intra-hippocampal injection of kainic acid mouse model that mimics the human mesial temporal lobe epilepsy, we found that LSP2-9166 reduces seizure frequency and hippocampal sclerosis. LSP2-9166 also acts as an anti-seizure drug on established seizures in both models tested. Specific modulation of the mGlu7 receptor could represent a novel approach to reduce pathological network remodeling.

Keywords: Animal models; Epilepsy; Metabotropic glutamate receptor; Neuropharmacology; Seizures.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminobutyrates / pharmacology*
  • Animals
  • Anticonvulsants / pharmacology*
  • Epilepsy / metabolism
  • Excitatory Amino Acid Agonists / pharmacology
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Kindling, Neurologic / drug effects
  • Mice
  • Mice, Mutant Strains
  • Receptors, Metabotropic Glutamate / agonists*
  • Seizures / metabolism*

Substances

  • Aminobutyrates
  • Anticonvulsants
  • Excitatory Amino Acid Agonists
  • LSP2-9166
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 7