Effect of trans 4-butylcyclohexane carboxylic acid (4-BCCA) upon neurodegeneration, oxidative stress related to epileptogenesis in pilocarpine-induced status epilepticus

Abstract

Objective

4-butylcyclohexane carboxylic acid (4-BCCA), a low-affinity inhibitor of AMPA receptors at the trans-membrane domain have been suggested as potential therapeutic option for epilepsy, but its potential impact on status epilepticus and disease-modification and neurodegeneration following status epilepticus have not been investigated.

Methods

This study established the effect of 4-BCCA along with standard antiseizure medications (ASMs) [valproate (VPA) and perampanel (PER)] in Li-pilocarpine induced status epilepticus rat model. We first established the effective dose of 4-BCCA in status epilepticus followed by an acute and long-term effect study. Assessments of neurobehaviour (by elevated plus maze and passive avoidance), neurodegeneration [by transmission electron microscopy (TEM) and immunohistochemistry in hippocampal slices], total antioxidant capacity (TAC) and neuronal loss [by neuron specific enolase (NSE) in cerebral tissue] were performed.

Results

4-BCCA at 200 mg/kg. i.p. was found to be an effective dose and in comparison, to other ASMs it showed better seizure control in terms of latency and number of stage 3/4 seizures. PER group and 4-BCCA+PER showed better memory retention but without significant difference among the drug-treated groups. In TEM, 4-BCCA+PER and 4-BCCA+VPA group showed less nucleus and cytoplasmic changes. In immunohistochemistry 4-BCCA, PER and combination groups showed better neuronal viability. 4-BCCA+ PER showed higher TAC and lower NSE level.

Significance

4-BCCA alone and its combination with ASMs especially perampanel in status epilepticus model in rats showed better seizure control and neuroprotection.