Effects of topiramate on the ultrastructure of synaptic endings in the hippocampal CA1 and CA3 sectors in the rat experimental model of febrile seizures: the first electron microscopy report

Abstract

The present study aimed at exploring a potentially neuroprotective effect of topiramate (TPM), one of the most commonly used newer-generation, broad-spectrum, antiepileptic drugs against ultrastructural damage of hippocampal synaptic endings in the experimental model of febrile seizures (FS). The study used male young Wistar rats aged 22-30 days, divided into three experimental groups and the control group. Brain maturity in such animals corresponds to that of 1-or 2-year-old children. Hyperthermic stress was evoked by placing animals in a 45°C water bath for four consecutive days. TPM at a dose of 80 mg/kg b.m. was administered with an intragastric tube before and immediately after FS. Specimens (1 mm 3) collected from the hippocampal CA1 and CA3 sectors, fixed via transcardial perfusion with a solution of paraformaldehyde and glutaraldehyde, were routinely processed for transmission-electron microscopic analysis. Advanced ultrastructural changes induced by hyperthermic stress were manifested by distinct swelling of hippocampal pre-and post-synaptic axodendritic and axospinal endings, including their vacuolization and disintegration. The axoplasm of the presynaptic boutons contained a markedly decreased number of synaptic vesicles and their abnormal accumulation in the active synaptic region. The synaptic junctions showed a dilated synaptic cleft and a decreased synaptic active zone. TPM used directly after FS was ineffective in the prevention of hyperthermia-induced injury of synaptic endings in hippocampal CA1 and CA3 sectors. However, "prophylactic" administration of TPM, prior to FS induction, demonstrated a neuroprotective effect against synaptic damage in approximately 25% of the synaptic endings in the hippocampal sectors, more frequently located in perivascular zones. It was manifested by smaller oedema of both presynaptic and postsynaptic parts, containing well-preserved mitochondria, increased number and regular distribution of synaptic vesicles within the axoplasm, and increased synaptic active zone. Our current and previous findings suggest that TPM administered "prophylactically", before FS, could exert a favourable effect on some synapses, indirectly, via the vascular factor, i.e. protecting blood-brain barrier components and through better blood supply of the hippocampal CA1 and CA3 sectors, which may have practical implications.

Influence of Topiramate on the Synaptic Endings of the Temporal Lobe Neocortex in an Experimental Model of Hyperthermia-Induced Seizures: An Ultrastructural Study

“…However, TPM administered “prophylactically”, i.e., prior to HS (TPM + HS group), such as in the hippocampal CA1 and CA3 sectors in the analogous model of seizures [ 34 ], demonstrated a neuroprotective effect against hyperthermia-induced synaptic damage in the neocortex in approximately 1/4 of these structures, causing distinct improvement in the morphologic synaptic parameters. The neuroprotective effect of topiramate on the ultrastructural picture of the synapses was demonstrated mainly by less substantial swelling of the synaptic endings.…”

“…Worthy of note is that TPM administered immediately after the induction of hypethermic stress had no beneficial effect on the structure of the synaptic endings, similarly to those in the ammonal cortex [ 34 ], which is reflected in the analyzed quantitative results.…”

“…Interestingly, in the current submicroscopic research, the neuroprotective effect of topiramate used as a “prophylaxis” was mainly found in the synaptic endings located directly in the perivascular zone of well-preserved capillaries or in the vicinity of such zones, which may indicate a crucial effect of the vascular factor in the morphogenesis of the neuroprotective action of this drug. This is in line with our previous ultrastructural studies on the morphological picture of the structural components of the BBB in the ammonal cortex in an analogous experimental model, in which TPM administered prior to FS at the same dose, i.e., 80 mb/kg b.m., caused distinct normalization of the morphological picture in over half of the capillaries of the CA1 and CA3 sectors [ 35 ], as well as a beneficial effect on the synaptic endings adhering in these sectors to well-preserved capillaries [ 34 ]. The protective effect of topiramate on the BBB components, mainly on the endothelial lining of capillaries, has been confirmed by electron microscopic studies of other authors who also observed a beneficial influence of TPM-pretreatment on the ultrastructural condition of the BBB components in experimental hyperthermic convulsions in rats [ 53 ].…”

“…The current work is a continuation of our histological, morphometric, and electron microscopic studies on the effects of this antiepileptic drug on the selected structural CNS components, mainly the ammonal cortex, specifically the blood-brain barrier (BBB), pyramidal neurons, and astrocytes in the HS model, as well as a continuation of our recent research into the synaptic endings of the hippocampal CA1 and CA3 sectors [13,[34][35][36][37].…”

Changes of serum metabolomics and gut microbiota reveal specific characteristics of children with febrile seizures

“…Febrile seizures (FS) are seizures or convulsions associated with fever in an infant or child at the age of 6 months to 6 years [1]. FS is the most common neurological disease emergency in pediatrics [2,3]. FS are commonly divided into two types, ‘‘simple’’ and ‘‘complex’’ [4].…”