Anyone may engage in aggressive behavior under the influence of stress. Animal models have been used to elucidate the mechanisms underlying aggression. Herein, we studied aggressive behavior in chronically isolation-reared male and female mice using an Aggressive Response Meter (ARM) device. The ARM device induces aggressive biting behavior (ABB) in mice toward inanimate objects, and measures its intensity and frequency, hereafter referred to as ABB intensity and ABB frequency, respectively. We characterized ABB intensity and frequency compared with open field test (OFT), social interaction test, and elevated plus maze (EPM). ABB intensity and frequency were increased and the time in the center zone in OFT was decreased in isolation-reared male and female mice compared with group-reared counterparts. No statistically significant correlation was detected between ABB intensity and other behavioral features in OFT, social interaction test, and EPM, indicating that ABB intensity reflects behavioral characteristics not fully explained by these behavioral characteristics. As the effects of GABA-targeting agents are poorly characterized, we examined the effect of diazepam on ABB. At higher doses (4 mg/kg), diazepam effectively reduced ABB levels in both males and females, with males showing higher sensitivity than females at lower doses (2 mg/kg). The number of c-Fos-expressing cells in the dmVMH and dlPAG was high in mice with high ABB. We next analyzed KCC2, a K+-Cl− co-transporter that maintains inhibitory GABA transmission. Low KCC2 expression in the hypothalamus of female was detected using qPCR and immunoblotting. Testosterone supplementation enhanced female responsiveness to diazepam at lower doses.
Epilepsy is a neurological condition that affects approximately 50 million individuals worldwide. Current treatments mainly alleviate symptoms and have substantial adverse effects, with about 1/3 of patients not responding to existing medications. This underscores the urgent need for new drugs that can overcome these challenges. According to recent studies, the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway play an important role in epileptogenesis. Brain-derived neurotrophic factor (BDNF) and c-fos are also involved in neuronal excitability and seizure-induced neuronal changes. The purpose of the present study was to examine the anticonvulsant and antiepileptogenic activities of 3,4-dimethoxyacetophenone (3,4-DMA) in the acute seizure and pentylenetetrazole (PTZ)-induced kindling models of epilepsy and to elucidate related molecular changes of BDNF, c-fos, and JAK-2/STAT-3 signaling pathways. 3,4-DMA was first evaluated in an acute seizure model, followed by a kindling model of epilepsy in mice. The effects of 3,4-DMA on BDNF, c-fos, and JAK-2/STAT-3 were assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). The results showed that 3,4-DMA significantly reduced seizure scores in a PTZ-induced kindling model. BDNF, c-fos, and JAK-2/STAT-3 were significantly upregulated in both the cortical and hippocampal tissues in PTZ-control mice. Conversely, treatment with 3,4-DMA attenuated this overexpression in the cortex and hippocampus. In conclusion, 3,4-DMA has antiepileptogenic effect as evidenced by a reduction in the expression of BDNF, c-fos and the JAK-2/STAT-3 pathway components. So, it can be a promising therapeutic candidate in the treatment of epilepsy. However, future studies measuring p-JAK-2 and p-STAT-3 will be required to confirm pathway activation status.
