Proteomic profiling of the rat hippocampus from the kindling and pilocarpine models of epilepsy: potential targets in calcium regulatory network

Leila Sadeghi,Babak Khorsand,Bahareh Dabirmanesh,Ilnur Ildusovich Salafutdinov,Javad Zahiri,Yaghoub Fathollahi,Amir Shojaei,Mohammad Sayyah,Khosro Khajeh,Javad Mirnajafi-Zadeh,Albert Anatolyevich Rizvanov

doi:10.1038/s41598-021-87555-7

Abstract

Herein proteomic profiling of the rat hippocampus from the kindling and pilocarpine models of epilepsy was performed to achieve new potential targets for treating epileptic seizures. A total of 144 differently expressed proteins in both left and right hippocampi by two-dimensional electrophoresis coupled to matrix-assisted laser desorption-mass spectrometry were identified across the rat models of epilepsy. Based on network analysis, the majority of differentially expressed proteins were associated with Ca2+ homeostasis. Changes in ADP-ribosyl cyclase (ADPRC), lysophosphatidic acid receptor 3 (LPAR3), calreticulin, ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), synaptosomal nerve-associated protein 25 (SNAP 25) and transgelin 3 proteins were probed by Western blot analysis and validated using immunohistochemistry. Inhibition of calcium influx by 8-Bromo-cADP-Ribose (8-Br-cADPR) and 2-Aminoethyl diphenylborinate (2-APB) which act via the ADPRC and LPAR3, respectively, attenuated epileptic seizures. Considering a wide range of molecular events and effective role of calcium homeostasis in epilepsy, polypharmacy with multiple realistic targets should be further explored to reach the most effective treatments.

Highlights

Proteomic profiling of the rat hippocampus from the kindling and pilocarpine models of epilepsy was performed to achieve new potential targets for treating epileptic seizures
Proteomic profiling of the rat hippocampus from the kindling and pilocarpine models of epilepsy could yield a sophisticated insight into pathophysiology of epileptic seizures which is critical to identify epilepsy biomarkers and its therapeutic targets
The present study demonstrated how groups of proteins work in concert with each other to keep the brain hyperexcitable following seizure induction

Summary

Introduction

Proteomic profiling of the rat hippocampus from the kindling and pilocarpine models of epilepsy was performed to achieve new potential targets for treating epileptic seizures. Inhibition of calcium influx by 8-Bromo-cADP-Ribose (8-Br-cADPR) and 2-Aminoethyl diphenylborinate (2-APB) which act via the ADPRC and LPAR3, respectively, attenuated epileptic seizures. Kindling is caused by repetitive administration of convulsant agents (pentylenetetrazol or electrical stimuli) to reduce seizure threshold in animals, similar to the process that take place in human TLE5. These models may provide useful insights into the activity of epileptic circuits and future treatment strategies for e pilepsy[5, 6]. Changes in ADPRC and LPAR3 proteins across the 3 rat models of epilepsy were probed by Western blot analysis and validated using immunohistochemistry. 8-Bromo-cADP-Ribose (8-Br-cADPR) and 2-Aminoethyl diphenylborinate (2-APB) were used to assess epileptic seizures via inhibiting ADPRC and LPAR3 pathways, respectively

Results

Discussion

Conclusion