Inhibition of Mammalian Target of Rapamycin Attenuates Recurrent Seizures Associated Cardiac Damage in a Zebrafish Kindling Model of Chronic Epilepsy

AbstractSudden Unexpected Death in Epilepsy (SUDEP) is primarily linked with the cardiac irregularities that occur due to recurrent seizures. Our previous studies found a role of mTOR pathway activation in seizures-linked cardiac damage in a rat model. In continuation to the earlier work, the present study was devised to explore the role of rapamycin (mTOR inhibitor and clinically used immunosuppressive agent) in a zebrafish kindling model and associated cardiac damage. Adult zebrafish were incubated with increasing concentrations of rapamycin (1, 2 and, 4 μM), followed by pentylenetetrazole (PTZ) exposure to record seizure latency and severity. In another experiment, zebrafish were subjected to a standardized PTZ kindling protocol. The kindled fish were treated daily with rapamycin for up to 25 days, along with PTZ to record seizure severity. At the end, zebrafish heart was excised for carbonylation assay, gene expression, and protein quantification studies. In the acute PTZ convulsion test, treatment with rapamycin showed a significant increase in seizure latency and decreased seizure severity without any change in seizure incidence. Treatmen t with rapamycin also reduced the severity of seizures in kindled fish. The cardiac expressions ofgpx, nppb,kcnh2, scn5a,mapk8,stat3,rps6 andddit were decreased, whereas the levels oftrxr2 andbeclin 1 were increased following rapamycin treatment in kindled fish. Furthermore, rapamycin treatment also decreased p-mTOR expression and pro...
Source: Journal of NeuroImmune Pharmacology - Category: Drugs & Pharmacology Source Type: research