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

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.

Ameliorative Potential of (-) Pseudosemiglabrin in Mice with Pilocarpine-Induced Epilepsy: Antioxidant, Anti-Inflammatory, Anti-Apoptotic, and Neurotransmission Modulation

“…As a result of these data, epilepsy can be induced by a disruption in GABAergic and glutamatergic neurotransmission. These findings are consistent with earlier findings [ 1 , 9 , 13 , 16 , 37 , 38 ].…”

“…Glutamate hyperactivation of NMDARs promotes neuronal excitotoxicity and degeneration via many pathways, including nitric oxide synthase activation, ROS, and RNS production [ 37 ]. The pathophysiology of pilocarpine-induced epilepsy is considered to include both oxidative and nitrosative stress, as persistent seizures cause an increase in mitochondrial oxidative and nitrosative stress, with subsequent cell damage [ 13 , 29 , 37 ].…”

“…The most common epilepsy, attributable to approximately 60% of all epileptic patients, is temporal lobe epilepsy, with nearly 30% of patients refractory to conventional pharmacological therapy [ 1 , 13 ]. Additionally, none of the anticonvulsants currently on the market work to resolve co-morbidities or the underlying pathophysiology of epilepsy; they merely treat the symptoms of epilepsy [ 14 , 15 , 16 ].…”

Changes in Metabotropic Glutamate Receptor Gene Expression in Rat Brain in a Lithium–Pilocarpine Model of Temporal Lobe Epilepsy

“…MPEP and MTEP, antagonists of group I mGluRs, provided a neuroprotective effect in models of epilepsy [ 42 , 43 ]. A study performed in our laboratory also showed the neuroprotective effect of MTEP, but administration of this antagonist did not prevent the development of epilepsy [ 44 ]. Simultaneously, activation of mGluR5 provided functional recovery after brain injury and reduced neuroinflammation in virus-induced epilepsy [ 45 , 46 ].…”

“…Then, the RNA was precipitated with LiCl. RNA concentration and purity were determined as described previously [ 44 ].…”