Hippocampal Proteomic Analysis in Male Mice Following Aggressive Behavior Induced by Long-Term Administration of Perampanel

Abstract

Antiepileptic drugs have been shown to be associated with inducing or exacerbating adverse psychotropic reaction, including aggressive behavior. Perampanel, the first pharmacological compound approved by the FDA in 2012, is an effective antiepileptic drug for intractable epilepsy but induces severe aggression. So far, the underlying molecular mechanisms of aggression induced by perampanel remain incompletely understood. In the present study, a model of aggressive behavior based on the clinical use of perampanel was established and resident–intruder test and open field test were performed. Changes in hippocampal protein profiles were detected by tandem mass tag (TMT) proteomics. The behavioral results indicated that long-term use of perampanel increased the aggressive behavior of C57BL/6J mice. Proteomic analysis revealed that 93 proteins were significantly altered in the hippocampus of the perampanel-treated group (corrected p < 0.05), which were divided into multiple functional groups, mainly related to synaptic function, synaptogenesis, postsynaptic density protein, neurite outgrowth, AMPA-type glutamate receptor immobilization, and others. Bioinformatic analysis showed that differentially expressed proteins were involved in synaptic plasticity and the Ras signaling pathway. Furthermore, validation results by western blot demonstrated that glutamate receptor 1 (GluA1) and phosphorylation of mitogen-activated protein kinase (ERK1/2) were notably up-regulated, and synaptophysin ( Syn ) and postsynaptic density 95 (PSD95) were down-regulated in perampanel-treated mice. Therefore, our results provide valuable insight into the molecular mechanisms of aggressive behavior induced by perampanel, as well as potential options for safety treatment of perampanel in the future.

Effects of the AMPAr antagonist, Perampanel, on Cognitive Function in Rats Exposed to Neonatal Iron Overload

“…Consistent with the above, several studies have shown that increased gene expression of the GluA1 subunit, as well as the relatively higher GluA1:GluA2 ratio [45] found in the present study, results in the synaptic insertion of a greater number of CP-AMPARs (Ca2 + ion-permeable AMPA receptors) [47], demonstrating a unique relationship between receptor expression, tra cking, and insertion in a variety of animal models of neurodegenerative disease [48].…”

“…In addition to changes in the synthesis of the various proteins and structures that regulate the insertion and function of AMPA receptors, during the process of neuronal toxicity, neuroin ammation and neurodegeneration, the expression of the receptor subunits may be regulated by the administration of PER, as shown by Yang et al [45], who demonstrated that the chronic use of PER can positively regulate the GluA2 subunit. However, in the present study, PER decreased, although not signi cantly, the expression of the gene encoding GluA2 and especially GluA1 in the groups exposed to iron overload.…”