Targeting metabotropic glutamate receptors in the treatment of epilepsy: rationale and current status

ABSTRACT

Introduction: Several drugs targeting the GABAergic system are used in the treatment of epilepsy, but only one drug targeting glutamate receptors is on the market. This is surprising because an imbalance between excitatory and inhibitory neurotransmission lies at the core of the pathophysiology of epilepsy. One possible explanation is that drug development has been directed towards the synthesis of molecules that inhibit the activity of ionotropic glutamate receptors. These receptors mediate fast excitatory synaptic transmission in the central nervous system (CNS) and their blockade may cause severe adverse effects such as sedation, cognitive impairment, and psychotomimetic effects. Metabotropic glutamate (mGlu) receptors are more promising drug targets because these receptors modulate synaptic transmission rather than mediate it.

Areas covered: We review the current evidence that links mGlu receptor subtypes to the pathophysiology and experimental treatment of convulsive and absence seizures.

Expert opinion: While mGlu₅ receptor negative allosteric modulators have the potential to be protective against convulsive seizures and hyperactivity-induced neurodegeneration, drugs that enhance mGlu₅ and mGlu₇ receptor function may have beneficial effects in the treatment of absence epilepsy. Evidence related to the other mGlu receptor subtypes is more fragmentary; further investigations are required for an improved understanding of their role in the generation and propagation of seizures.

KEYWORDS:

• Metabotropic glutamate receptors
• epilepsy
• convulsive seizures
• absence seizures

Article Highlights

• There is a need for new drugs for the treatment of epilepsy.

• Metabotropic glutamate receptors are candidate drug targets for the treatment of epilepsy because they modulate excitatory and inhibitory neurotransmission.

• Positive allosteric modulators of mGlu₅ and mGlu₇ receptors hold promise for the treatment of epileptic syndromes characterized by absence seizures.

• Drugs that activate mGlu₂ receptors or inhibit mGlu₅ receptors are potentially effective in the treatment of convulsive seizures.

• The study of mGlu receptors in the process of epileptogenesis is in its infancy.

This box summarizes the key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was funded by The Italian Ministry of Health.