Combinatorial Regimen of Carbamazepine and Imipramine Exhibits Synergism against Grandmal Epilepsy in Rats: Inhibition of Pro-Inflammatory Cytokines and PI3K/Akt/mTOR Signaling Pathway

Abstract

Epilepsy is a neurodegenerative disorder that causes recurring seizures. Thirty-five percent of patients remain refractory, with a higher prevalence of depression. We investigated the anticonvulsant efficacy of carbamazepine (CBZ; 20 and 50 mg/kg), imipramine (IMI; 10 and 20 mg/kg) alone, and as a low dose combination. This preclinical investigation included dosing of rats for 14 days followed by elicitation of electroshock on the last day of treatment. Along with behavioral monitoring, the rat hippocampus was processed for quantification of mTOR, IL-1β, IL-6 and TNF-α levels. The histopathological analysis of rat hippocampus was performed to ascertain neuroprotection. In vitro studies and in silico studies were also conducted. We found that the low dose combinatorial therapy of CBZ (20 mg/kg) + IMI (10 mg/kg) exhibits synergism (p < 0.001) in abrogation of maximal electroshock (MES) induced convulsions/tonic hind limb extension (THLE), by reducing levels of pro-inflammatory cytokines, and weakening of the PI3K/Akt/mTOR signal. The combination also exhibits cooperative binding at the Akt. As far as neuroprotection is concerned, the said combination increased cell viability by 166.37% compared to Pentylenetetrazol (PTZ) treated HEK-293 cells. Thus, the combination of CBZ (20 mg/kg) + IMI (10 mg/kg) is a fruitful combination therapy to elevate seizure threshold and provide neuroprotection.

Identification of miRNAs in extracellular vesicles as potential diagnostic markers for pediatric epilepsy and drug-resistant epilepsy via bioinformatics analysis

“…Three miRNA target gene prediction databases were incorporated for the prediction of the potential target genes of these four miRNAs and their potential functions. KEGG enrichment analysis of the target genes revealed their main involvement in the PI3K-Akt signaling pathway, MAPK signaling pathway, and cell cycle, all of which have been confirmed to be involved in epileptogenesis by several studies (54)(55)(56)(57)(58). Approximately 1/3 of patients with epilepsy eventually develop DRE (59).…”

Molecular Basic of Pharmacotherapy of Cytokine Imbalance as a Component of Intervertebral Disc Degeneration Treatment

“…Carbamazepine reduces the expression of TNF-α and IL -1β induced by lipopolysaccharide in the rat hippocampus [342]. Carbamazepine alleviates neuronal hyperinflammation by reducing levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), especially when carbamazepine is combined with imipramine [343]. However, the effect of carbamazepine on cytokine status in patients with IDD is not well understood.…”

Neuroprotective Effects and Therapeutic Potential of Dichloroacetate: Targeting Metabolic Disorders in Nervous System Diseases

“…[2][3][4][5] Currently, many neuroprotective drugs have shown an extraordinary ability to prevent neuronal damage by mechanisms such as limiting mitochondrial dysfunction, oxidative stress, neuroinflammation, apoptosis, excitotoxicity, and protein misfolding, which are leading therapeutic strategies for these diseases. [6][7][8] Dichloroacetate (DCA) inhibits all four pyruvate dehydrogenase kinase (PDK) isoforms found in vivo. 9,10 PDK phosphorylates three serine residues (Ser293, Ser300, and Ser232) of the α-subunit of pyruvate dehydrogenase (PDH) to cause a decrease in PDH activity.…”