Targeting neuroinflammatory pathways in epilepsy: a combined network-pharmacology and in vivo study of dapagliflozin and ticagrelor.

objectivesEpilepsy is a common neurological disorder that imposes a substantial socioeconomic burden. Today, drug repurposing has gained attention, allowing researchers to find new targets for existing therapies. Therefore, the present study aimed to evaluate the anticonvulsant actions of dapagliflozin and ticagrelor in maximal electroshock-induced convulsions in mice model of epilepsy.

methodsThe current study used two approaches, a computational and an experimental approach. The computational approach was used to identify the common targets between test drugs and epilepsy, to perform pathway enrichment analysis, and to find the binding efficiency between drugs and targets. Furthermore, experimental approach involves induction of seizures using a maximal electroshock (MES) convulsometer. Swiss albino mice were pre-treated with dapagliflozin (2.5 mg/kg & 5 mg/kg) and ticagrelor (50 mg/kg & 100 mg/kg) for 14 days. On day 15th, all the animals received maximum electroshock of 50 mA for 0.2 s via trans-auricular electrodes, and latency to generalised tonic-clonic seizures was observed. After 24 h, animals were euthanised, hippocampal region was isolated, and various molecular parameters, such as analysis of GABA content and GAD1 expression, immunohistochemistry of GFAP, and protein expression analysis of p- ERK1/2, p-TLR4, and p65 subunit of NF-κB, were performed.

resultsThe results of the computational approach suggested that MAPK, mainly ERK1/2, a possible target for dapagliflozin and ticagrelor, has been highly involved in the pathogenesis of epilepsy. These outcomes were further validated by an experimental approach, where MES-induced convulsions significantly raised the protein expression of p-ERK1/2, which impaired the GABA/GAD1 ratios. Furthermore, heightened p-ERK1/2 expression promotes the neuroinflammatory cascade, as evidenced by higher p-TLR4 and p65 subunit of NF-κB protein expression. The higher co-localisation of GFAP in hippocampal tissues indicated astrogliosis. However, dapagliflozin and ticagrelor significantly ameliorated these alterations, indicating both drugs possess anticonvulsant activity.