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.
Highlights
Epilepsy is a chronic neurological disease featuring escalated susceptibility to seizures [1,2,3]
Despite progress in the drug development for all neurodegenerative disorders, including epilepsy, 35% of epileptic patients remain refractory, which badly affects their quality of life (QoL) [10,11]
In agreement with most studies, we found that CBZ and IMI exhibit dose-dependent anticonvulsant effects, but the low dose combination therapy of CBZ (20 mg/kg) + IMI (10 mg/kg) exhibits synergism (p < 0.001) in abrogation of electroshock induced seizures in rats
Summary
Epilepsy is a chronic neurological disease featuring escalated susceptibility to seizures (hypersynchronous neuronal activity) [1,2,3]. Signs of neurologic impairment involving seizures were elevated in mice with overexpression of TNF-α, Pharmaceuticals 2021, 14, x FOR PEER REVIEW. Signs of neuro ofof19TNFlogic impairment involving seizures were elevated in mice with overexpression α, while in transgenic mice with TNF-α at low-moderate levels, a decrease in vulnerability to seizures was reported [31]. Exceswhile The in transgenic mice with TNF-αisat levels,network a decrease infunction vulnerability sive andwas sudden stimulation of extra-synaptic NMDA receptors is neurotoxic [32]. The said by neurodegeneration, leading to a decrease in the responsiveness to drugs) and intercept combination could be used in refractory patients of epilepsy and those with epilepsy the transformation of the brain from responsive to nonresponsive. Combination could be used in refractory patients of epilepsy and those with epilepsy comorbid with depression
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