MTEP, a Selective mGluR5 Antagonist, Had a Neuroprotective Effect but Did Not Prevent the Development of Spontaneous Recurrent Seizures and Behavioral Comorbidities in the Rat Lithium–Pilocarpine Model of Epilepsy

Alexandra V Dyomina,Alexandra V Griflyuk,Irina V Antonova,Aleksey V Zaitsev,Tatiana Yu Postnikova,Maria V Zakharova,Anna A Kovalenko,Ilya V Smolensky

doi:10.3390/ijms23010497

Abstract

Metabotropic glutamate receptors (mGluRs) are expressed predominantly on neurons and glial cells and are involved in the modulation of a wide range of signal transduction cascades. Therefore, different subtypes of mGluRs are considered a promising target for the treatment of various brain diseases. Previous studies have demonstrated the seizure-induced upregulation of mGluR5; however, its functional significance is still unclear. In the present study, we aimed to clarify the effect of treatment with the selective mGluR5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) on epileptogenesis and behavioral impairments in rats using the lithium–pilocarpine model. We found that the administration of MTEP during the latent phase of the model did not improve survival, prevent the development of epilepsy, or attenuate its manifestations in rats. However, MTEP treatment completely prevented neuronal loss and partially attenuated astrogliosis in the hippocampus. An increase in excitatory amino acid transporter 2 expression, which has been detected in treated rats, may prevent excitotoxicity and be a potential mechanism of neuroprotection. We also found that MTEP administration did not prevent the behavioral comorbidities such as depressive-like behavior, motor hyperactivity, reduction of exploratory behavior, and cognitive impairments typical in the lithium–pilocarpine model. Thus, despite the distinct neuroprotective effect, the MTEP treatment was ineffective in preventing epilepsy.

Highlights

Temporal lobe epilepsy (TLE) is a severe neurological disorder, which manifests with spontaneously recurrent seizures and, in many cases, is accompanied by psychiatric comorbidities, such as depression, anxiety, psychosis, and cognitive impairment [1,2,3]
The specific aim of the present study was to clarify the impact of MTEP treatment on epileptogenesis in the rat lithium–pilocarpine model
Rats without rearing after administration of 40 mg/kg pilocarpine were excluded from the experiment

Summary

Introduction

Temporal lobe epilepsy (TLE) is a severe neurological disorder, which manifests with spontaneously recurrent seizures and, in many cases, is accompanied by psychiatric comorbidities, such as depression, anxiety, psychosis, and cognitive impairment [1,2,3]. It is difficult to find a treatment for this type of epilepsy, and almost 30% of cases are resistant to drug therapy [4,5]. Since TLE is frequently the result of a primary brain injury, preventing TLE development following injury is considered an optimal therapeutic strategy for the acquired TLE [6,7]. A preventive treatment for epilepsy still does not exist [5]. Epileptogenesis refers to the sequence of events that converts the normal brain into one that can support a seizure. Seizures are thought to occur when the mechanisms that generally create a balance between excitation and inhibition are disturbed [8]

Objectives

Methods

Results