Adenosine A2A receptor and ecto-5′-nucleotidase/CD73 are upregulated in hippocampal astrocytes of human patients with mesial temporal lobe epilepsy (MTLE)

Abstract

Refractoriness to existing medications of up to 80 % of the patients with mesial temporal lobe epilepsy (MTLE) prompts for finding new antiepileptic drug targets. The adenosine A 2A receptor emerges as an interesting pharmacological target since its excitatory nature partially counteracts the dominant antiepileptic role of endogenous adenosine acting via inhibitory A 1 receptors. Gain of function of the excitatory A 2A receptor has been implicated in a significant number of brain pathologies commonly characterized by neuronal excitotoxicity. Here, we investigated changes in the expression and cellular localization of the A 2A receptor and of the adenosine-generating enzyme, ecto-5′-nucleotidase/ CD73, in the hippocampus of control individuals and MTLE human patients. Western blot analysis indicates that the A 2A receptor is more abundant in the hippocampus of MTLE patients compared to control individuals. Immunoreactivity against the A 2A receptor predominates in astrocytes staining positively for the glial fibrillary acidic protein (GFAP). No colocalization was observed between the A 2A receptor and neuronal cell markers, like synaptotagmin 1/2 (nerve terminals) and neurofilament 200 (axon fibers). Hippocampal astrogliosis observed in MTLE patients was accompanied by a proportionate increase in A 2A receptor and ecto-5′-nucleotidase/CD73 immunoreactivities. Given our data, we hypothesize that selective blockade of excessive activation of astrocytic A 2A receptors and/or inhibition of surplus adenosine formation by membrane-bound ecto-5′-nucleotidase/CD73 may reduce neuronal excitability, thus providing a novel therapeutic target for drug-refractory seizures in MTLE patients. • Ecto-5′-nucleotidase/CD73 localizes in close proximity with adenosine A 2A receptors in astrocytes of the human hippocampus. Keywords Mesial temporal lobe epilepsy (MTLE• Up-regulation of A 2A receptors and ecto-5′-nucleotidase/CD73 associates with astrogliosis of the hippocampus of MTLE patients.• Targeting astrocytic A 2A activation and/or adenosine formation via ecto-5′-nucleotidase/CD73 may control neuronal excitability.• Inhibitors of astrocytic A 2A receptors and ecto-5′-nucleotidase/CD73 may be a novel therapeutic strategy to control drug-refractory MTLE.

Enhanced ATP release and CD73‐mediated adenosine formation sustain adenosine A2A receptor over‐activation in a rat model of Parkinson's disease

“…Additionally, the present study is the first to report an up‐regulation and an increased activity of CD73 in an animal model of PD, which occurs in parallel to the changes in A 2A receptors. A similar parallel up‐regulation of A 2A receptors and CD73 was also observed in the limbic cortex of both animal models of epilepsy (see Bonan et al, ; Rebola et al, , ), and in patients with temporal lobe epilepsy (Barros‐Barbosa et al, ). The same changes occur in the hippocampus upon brain ischaemia (Braun, Zhu, Krieglstein, Culmsee, & Zimmermann, ; Ye et al, ), repeated stress (Cunha et al, ; Fontella et al, ), or aging (Cunha, Almeida, & Ribeiro, ).…”

A2AR‐induced transcriptional deregulation in astrocytes: An in vitro study

“…Previous studies emphasized that astrocytic A 2A R might control cognition in physiological and pathological situations (Barros-Barbosa et al, 2016;Orr et al, 2015;Matos et al, 2015). Astrocytic A 2A Rs were shown to control glutamate uptake through the control of Na + -K + -ATPase (Matos et al, 2012;Matos et al, 2013), gliotransmitter release (Cervetto et al, 2017), proliferation via Nfk-B (Ke et al, 2009), and the production of nitric oxide (Brodie et al, 1998).…”

“…In physiological conditions, A 2A Rs play an important role in fine synaptic tuning (Cunha, 2016): neuronal A 2A Rs regulated NMDA receptors to control synaptic plasticity processes (Rebola et al, 2008;Temido-Ferreira et al, 2018) while astrocytic A 2A Rs control glutamate and GABA uptakes (Lopes et al, 2002;Matos et al, 2012Matos et al, , 2013Cristovao-Ferreira et al, 2013), regulating the excitatory/inhibitory balance. Interestingly, reactive astrocytes have been shown to exhibit adenosine A 2A R upregulation in different neuropathological conditions such as AD, epilepsy, Sandhoff disease, and also in animal models of AD and PD (Orr et al, 2015(Orr et al, , 2018Barros-Barbosa et al, 2016;Zhao et al, 2017;Faivre et al, 2018;Lee et al, 2018;Yu et al, 2008;Hu et al, 2016;Ogawa et al, 2018). However, the pathophysiological impact of such astrocytic A 2A R upsurge remains unclear.…”

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

“…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 .…”

“…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 . In addition to seizure termination, postictal depression, refractoriness, and respiratory depression are considered manifestations of overactivation of A 1 R coupled with underactivation of A 2A R. This has led to the “adenosine hypothesis of SUDEP” (sudden unexpected death in epilepsy) as common clinical phenomena, respiratory depression, and impaired arousal 7 could be mediated through overstimulation of these receptors in autonomic and brainstem centers in the postictal period 8‐12 …”