Changes in the Blood-Brain Barrier Function Are Associated With Hippocampal Neuron Death in a Kainic Acid Mouse Model of Epilepsy

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.

Neuronal kinase SGK1.1 protects against brain damage after status epilepticus

“…As shown in Figure 1B (left panels), significant levels of neuronal damage were observed in B6.WT mice, reflected as a significant number of FJC-stained cells ( Figure 1C). This result was comparable to previous reports using similar experimental conditions (Hopkins et al, 2000;Yan et al, 2018). In contrast, activation of SGK1.1 in B6.Tg.sgk1 neurons conferred a remarkable level of protection against neuronal death in all brain areas studied, including hippocampus, somatosensorial auditive and piriform-entorhinal cortex ( Figure 1B, right panels, and Figure 1C).…”

Claudin-5: gatekeeper of neurological function

“…Following cerebroventricular injection of kainic acid (a glutamate receptor agonist that induces seizures), increased levels of claudin-5 and ZO-1 were observed in the hippocampus. This may result from the increased density of blood vessels associated with this model [127]. Another study found reduced levels of claudin-5 within 12 h of kainic acid injection with increased levels observed after 3 days.…”

Differential Expression of CD31 and Von Willebrand Factor on Endothelial Cells in Different Regions of the Human Brain: Potential Implications for Cerebral Malaria Pathogenesis

“…This is buttressed by the fact that CD31 is predominantly expressed at interendothelial junctions [46]. The expression of CD31 could increase in response to stimuli such as inflammation [47]. For example, the BBB dysfunction was associated with an increase in the expression of CD31 in the brain endothelium of cerebral malaria patients.…”