3,4-Dimethoxyacetophenone ameliorates epileptogenesis by suppressing BDNF, c-fos, and JAK-2/ STAT-3 expression in a pentylenetetrazole-induced kindling model of epilepsy.
Abstract
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.