Intercellular Signaling Pathway among Endothelia, Astrocytes and Neurons in Excitatory Neuronal Damage

Abstract

Neurons interact closely with astrocytes via glutamate; this neuron-glia circuit may play a pivotal role in synaptic transmission. On the other hand, astrocytes contact vascular endothelial cells with their end-feet. It is becoming obvious that non-neuronal cells play a critical role in regulating the neuronal activity in the brain. We find that kainic acid (KA) administration induces the expression of microsomal prostaglandin E synthase-1 (mPGES-1) in venous endothelial cells and the prostaglandin E2 (PGE2) receptor prostaglandin E receptor (EP)-3 on astrocytes. Endothelial mPGES-1 exacerbates KA-induced neuronal damage in in vivo experiments. In in vitro experiments, mPGES-1 produces PGE2, which enhances astrocytic Ca2+ levels via the EP3 receptor and increases Ca2+-dependent glutamate release, thus aggravating neuronal injury. This novel endothelium-astrocyte-neuron signaling pathway may be crucial for driving neuronal damage after repetitive seizures and could be a new therapeutic target for epilepsy and other brain disorders.

Montelukast potentiates the anticonvulsant effect of phenobarbital in mice: An isobolographic analysis

“…Most of the studies investigating the role of arachidonic acidderivatives on seizures have elected prostaglandins as the main target [4,9,26,27], for several reasons. Probably the most obvious one is because prostaglandins are the ultimate fever mediator, and there is a long known association between fever and seizures [18,28,29].…”

“…wakefulness) from basal and after treatment periods were identified in EEG recording and divided in 15 s segments and a 4 s epoch from each segment (without artifacts) was used to carry out the power analysis by the conversion into frequency domain by fast Fourier transformation (FFT) method. The resultant power values displayed for each frequency were grouped into 5 bands represented by delta (0.1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) and gamma . For power analysis of decomposed waves, the power sum from all frequencies (0.1-80 Hz) was considered as 100%.…”

Transient Oxygen/Glucose Deprivation Causes a Delayed Loss of Mitochondria and Increases Spontaneous Calcium Signaling in Astrocytic Processes

“…Although the mechanisms are not fully understood, astrocytic Ca 2ϩ signaling has been implicated in mediating neurovascular coupling Dunn et al, 2013;Otsu et al, 2015), which is not surprising given the positioning of astrocytes between synapses and the vasculature, and their reliance on Ca 2ϩ for propagating information (for review, see Parpura et al, 2012). In addition to altered neurovascular coupling, Ca 2ϩ -induced vesicular glutamate release from astrocytes has been shown to increase excitotoxic damage from seizure and stroke (Ding et al, 2007;Hines and Haydon, 2013;Takemiya and Yamagata, 2013). Increased astrocytic Ca 2ϩ signaling with a lower threshold for induction has been observed in in vitro and in vivo models of I/R (for review, see Ding, 2014).…”

Inhibition of prostaglandin E2 receptor EP3 mitigates thrombin-induced brain injury

“…2,3 For many years, investigators have been researching ways to either reduce PGE 2 production or regulate the four receptors to minimize progressive brain damage. [4][5][6] PGE 2 receptor EP3 (EP3R) is expressed mainly by neurons and activated glial cells in brain 7,8 and is associated with neuronal death. 8,9 Of the four G-proteincoupled PGE 2 receptors, EP3R is unique in its ability to bind to multiple G-proteins based on different spliced carboxy-terminal tail isoforms.…”