Endothelial prostaglandin E2 regulates neuronal injury after seizure via activation of astrocytes

Abstract

Astrocytes interact closely with neurons via glutamate; this astrocyteneuron circuit may play a pivotal role in synaptic transmission. In addition, astrocytes contact vascular endothelial cells (ECs) with their end-feet; therefore, ECs may have some role in regulating neuronal activity via astrocytes in the brain. In our studies, we found that kainic acid (KA) microinjection induced the expression of microsomal prostaglandin E synthase-1 (mPGES-1) in venous ECs and the expression of the prostaglandin E 2 (PGE 2 ) receptor EP3 on astrocytes. Moreover, endothelial mPGES-1 exacerbated KA-induced neuronal injury in the mouse brain. In in vitro experiments, mPGES-1 produced PGE 2 , which increased astrocytic Ca 2+ levels and Ca 2+ -dependent glutamate release, thus aggravating neuronal injury. We found ECs had a role under pathological conditions and brain ECs are not merely a physiological barrier between the blood and brain; instead, they may also act as a signal transducer or amplifier. Moreover, the endotheliumastrocyte-neuron signaling pathway may be crucial for driving neuronal injury elicited by repetitive seizures and may be a new therapeutic target for epilepsy.

Possible interplay between the theories of pharmacoresistant epilepsy

“…Generation of COX‐2 knockout mice did not exhibit any glutamate‐induced increase in PGP levels (Hartz et al., 2009), further highlighting the role of NMDA receptors in PGP expression levels. Elevated levels of prostaglandin E2 also stimulate prostaglandin EP 3 receptors on astrocytes, which mobilizes several associated G proteins and eventually leads to the activation of phospholipase C (Putney & Tomita, 2012; Takemiya, 2017). This enzyme is responsible for generating inositol trisphosphate (IP 3 ) and diacylglycerol (DAG) from cellular phosphatidylinositol 4,5‐bisphosphate.…”

“…If these levels should fall, additional Ca 2+ is taken into the cell via the activation of store‐operated channels in a Ca 2+ ‐release‐activated Ca 2+ manner (Putney & Tomita, 2012). This ensures elevated intracellular Ca 2+ levels inside astrocytes prompting the generation of a Ca 2+ wave among neighboring astrocytes, thus modulating them and causing a further release of glutamate which subsequently increases the activation levels of NMDA and AMPA receptors (Sanzgiri et al., 1999; Shimada et al., 2014; Takemiya, 2017).…”