Drug resistance and hippocampal damage after delayed treatment of pilocarpine-induced epilepsy in the rat

Abstract

Temporal lobe epilepsy (TLE) is the most common and pharmacoresistant form of epilepsy. Problems that cause pharmacoresistance may include delayed therapy due to late consultation, especially in developing countries. Our study aimed at unraveling consequences of delayed drug treatment using a rat model of TLE. Following pilocarpine-induced status epilepticus interrupted after 4 h, rats were continuously videorecorded for onset and recurrence of spontaneous convulsive seizures. The animals were then treated for 50 days with carbamazepine (CBZ; first-line drug in TLE and effective also in rats), starting at seizure onset (27.22 ± 3.38 days after status epilepticus) or 50 days later, and compared with epileptic untreated rats and non-epileptic CBZ-treated ones. Convulsive seizure frequency and duration, and hippocampal cell changes were evaluated. In particular, parvalbumin-containing hippocampal interneurons, astrocytes and microglia were characterized with immunohistochemistry and quantitative analyses. Prompt administration of CBZ suppressed seizures; delayed treatment only decreased frequency of convulsive seizures, which were also relatively prolonged. In hippocampal regions, histopathological damage, parvalbumin immunoreactivity loss, and glial activation were very marked after delayed treatment, and were reduced only slightly compared to untreated epilepsy, but enhanced compared to early treatment. The data on high frequency and duration of convulsive seizures in late-therapy rats indicate that delayed CBZ administration caused a high degree of drug resistance. This condition was subserved by severe damage in the hippocampus, presumably consequent to long-term seizure recurrence. Overall the data indicate that the paradigm of delayed treatment of limbic epilepsy could provide a model of drug-refractory TLE with hippocampal sclerosis.