Abstract
The kainic acid (KA)-induced epilepsy experimental model is widely used to study the mechanisms underlying this disorder. Recently, the blood-brain barrier (BBB) has become an innovative alternative treatment target for epilepsy patients. KA causes neuronal injury and BBB damage in this experimental epilepsy model but the mechanisms underlying epilepsy-related neuronal injury, autophagy, and BBB damage remain unclear. Therefore, the present study investigated the relationships among neuronal injury, the expressions of autophagy-related proteins, and changes in BBB-related proteins during the acute phase of epilepsy to further understand the mechanisms and pharmacotherapy of epilepsy. NeuN immunohistochemistry and Fluoro-Jade B (FJ-B) staining in the hippocampal CA3 region revealed that neuronal death induced by intraventricular injections of 10 μg/kg KA was greater than that induced by 3 μg/kg KA. In addition, there were transient increases in the levels of microtubule-associated protein light chain 3-II (LC3I/II) and Beclin-1, which are autophagy-related proteins involved in neuronal death, in this region 24 h after the administration of 10 μg/kg KA. There were also morphological changes in BBB-related cells such as astrocytes, endothelial cells (ECs), and tight junctions (TJs). More specifically, there was a significant increase in the activation of astrocytes 72 h after the administration of 10 μg/kg KA as well as continuous increases in the expressions of platelet endothelial cell adhesion molecule-1 (PECAM-1) and BBB-related TJ proteins (Zonula occludens-1 and Claudin-5) until 72 h after KA treatment. These results suggest that the overexpression of autophagy-related proteins and astrocytes and transient increases in the expressions of BBB-related TJ proteins may be closely related to autophagic neuronal injury. These findings provide a basis for the identification of novel therapeutic targets for patients with epilepsy.
Highlights
Epilepsy is the sudden abnormal discharge of neurons that can lead to chronic occurrences of transient cerebral dysfunction [1]
Changes in autophagy-related proteins, blood-brain barrier (BBB)-associated tight junctions (TJs) proteins, astrocytes, and microglia were investigated in the acute phase of epilepsy because they may be closely related to the mechanisms underlying neuronal death
Some studies have shown that the neuronal injury caused by kainic acid (KA) injections in the acute phase are the most serious [42] autophagy has been induced in a variety of experimental epilepsy models, including KA- and pilocarpine-induced seizure models [43]
Summary
Epilepsy is the sudden abnormal discharge of neurons that can lead to chronic occurrences of transient cerebral dysfunction [1]. 70% of epileptic patients can control their symptoms with regular antiepileptic drug treatments but the remaining 30% do not respond to existing medications. This subset of patients is often diagnosed with temporal lobe epilepsy [2, 3], which is the most common type of epilepsy [4, 5]. The biochemical actions of autophagosomes include the accumulation of microtubule-associated protein light chain 3-II (LC3-II), which are intracellular double-membraned vesicles that encompass organelles and the cytoplasm [12]. It is thought that autophagy activation contributes to various neurodegenerative diseases [14]
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