Upregulation of adenosine A2A receptor and downregulation of GLT1 is associated with neuronal cell death in Rasmussen's encephalitis

Abstract

Rasmussen encephalitis (RE) is a severe pediatric inflammatory brain disease characterized by unilateral inflammation and atrophy of the cerebral cortex, drug‐resistant focal epilepsy and progressive neurological and cognitive deterioration. The etiology and pathogenesis of RE remain unclear. Our previous results demonstrated that the adenosine A1 receptor (A1R) and the major adenosine‐removing enzyme adenosine kinase play an important role in the etiology of RE. Because the downstream pathways of inhibitory A1R signaling are modulated by stimulatory A2AR signaling, which by itself controls neuro‐inflammation, glial activation and glial glutamate homeostasis through interaction with glutamate transporter GLT‐1, we hypothesized that maladaptive changes in adenosine A2A receptor (A2AR) expression are associated with RE. We used immunohistochemistry and Western blot analysis to examine the expression of A2ARs, glutamate transporter‐I (GLT‐1) and the apoptotic marker Bcl‐2 in surgically resected cortical specimens from RE patients (n = 18) in comparison with control cortical tissue. In lesions of the RE specimen we found upregulation of A2ARs, downregulation of GLT‐1 and increased apoptosis of both neurons and astroglia. Double staining revealed colocalization of A2ARs and Bcl‐2 in RE lesions. These results suggest that maladaptive changes in A2AR expression are associated with a decrease in GLT‐I expression as a possible precipitator for apoptotic cell loss in RE. Because A2AR antagonists are already under clinical evaluation for Parkinson's disease, the A2AR might likewise be a tractable target for the treatment of RE.

Rasmussen’s encephalitis: mechanisms update and potential therapy target

“…78 Furthermore, our study demonstrated that upregulated A2AR led to downregulation of glutamate transporter GLT-1, and that neuron apoptosis was finally induced. 79 The above results proved that dysfunction of the adenosine system plays a significant role in the pathogenesis of RE, in particular in neuronal damage.…”

Adenosine kinase and adenosine receptors A1R and A2AR in temporal lobe epilepsy and hippocampal sclerosis and association with risk factors for SUDEP

“…Epilepsy is associated with altered cellular distribution of adenosine receptors and ADK that may occur as primary or secondary adaptive phenomena 1,2 . Earlier studies utilizing human tissues found enhanced neuronal expression of A 1 R 21 and upregulation of A 2A R in Rasmussen's encephalitis, with A 2A R expression in lesional astrocytes, endothelium, as well as neurons 5 . In TLE, A 2A R expression was primarily co‐localized with hippocampal GFAP‐positive astrocytes but not neuronal markers, showing increased receptor expression compared with postmortem controls 4 .…”

“…Alteration in adenosine receptors densities and their cellular distribution has been shown in animal models of epilepsy1,2 and human tissues 4‐6 . An imbalance between the inhibitory and excitatory effects of adenosine through differential activation of A 1 R and A 2A R receptors may contribute to temporal lobe epilepsy (TLE) 4 .…”

Adenosine A2A Receptors as Biomarkers of Brain Diseases

“…The A 2A R overactivation associated with brain dysfunction and disease is not only sustained by an increased bioavailability of the trigger of A 2A R-ATP-derived extracellular adenosine-but also involves an up-regulation of A 2A R in the afflicted brain areas (reviewed in Cunha, 2016). Indeed, an increased density of cortical A 2A R has been reported in animal models of epilepsy (Rebola et al, 2005;Cognato et al, 2010;Canas et al, 2018;Crespo et al, 2018), Rasmussen's encephalopathy (He et al, 2020), TBI (Zhao et al, 2017), AD (Espinosa et al, 2013;Viana da Silva et al, 2016;Silva et al, 2018), Lyme neuroborreliosis (Smith et al, 2014), ALS (Seven et al, 2020), or chronic stress/depression (Kaster et al, 2015;Machado et al, 2017), as well as in the diseased human brain (Albasanz et al, 2008;Temido-Ferreira et al, 2020). Likewise, A 2A R levels are also increased in the cerebellum of Machado-Joseph's ataxic mice (Gonçalves et al, 2013) and in the amygdala or fear-conditioned mice (Simões et al, 2016).…”