Editorial Adenosine: A Complex Role in Neurodegeneration David Blum, PhD A denosine is central to life. Not only as a part of the genetic code but it is also an ubiquitous signal, vir- tually produced by every cell, transducing through four G- protein coupled receptors, themselves expressed widely at the cellular level throughout the body. 1 Adenosine derives from ATP, through intracellular and extracellular path- ways, 2 ensuring a very unconventional autocrine/paracrine neuromodulatory role, if we referred to classical neuro- transmission. While adenosine is known to play a very important function in synaptic fine tuning, 3 our current knowledge is relatively limited. Not speaking about nonreceptor-dependent mechanisms, 4 how adenosine re- leased by neurons, glial, and endothelial cells couples synaptic neuroglial activity to neurovascular function, both spatially and temporally, remains largely unknown. How dyshomeostasis of both ligand and receptors en- countered in detrimental conditions such as neurological disorders 5–9 impacts on the interaction between neurons and glial cells remains also poorly understood, not taking into account the possible impact on adenosine catabolism known to produce neuroactive compounds such as inosine or urate. 10 Furthermore, how reconcile the apparent para- doxical effects of parenchymal rise of adenosine after equilibrative nucleoside transporter blocking and the out- come observed after specific adenosine receptor blockade or inhibition of CD73 ectonucleotidase? 11–13 On the top of that, how can we integrate this extremely complex scheme to the ability of adenosine receptors to dimerize with other G-protein coupled receptors and control their activities (Ferre and Ciruela, this issue)? At this stage, we must be humble and admit that we are far from understanding the precise impact of adenosine tone on brain function as well as the precise cell-dependent role of each released pool of adenosine and receptors in physiological and path- ological situations. The present issue aims at giving an update on some re- cent scientific focus in the field, which we hope will make you glimpse several aspects of this fascinating modula- tory system. The now large number of genetic association studies interested in correlating adenosine receptor vari- ants with human behavior and brain disorders is an ex- cellent example of the already mentioned homeostatic function of adenosine (Huin et al., this issue). Temido- Ferreira et al. (this issue) discuss the recent advances in- volving the adenosinergic transmission in hippocampal plasticity and its link to memory control. Xapelli et al. (this issue) address a still overlooked role of adenosine in the regulation of neurogenesis, discussing impact toward cognition and neurodegenerative conditions. Finally, sev- eral contributions illustrate the impact of adenosinergic regulation system in various neurodegenerative conditions (Sebastiao and Chern, this issue; Ferrante et al., this issue; Sanchez-Melgar et al., this issue; Aguiar et al., this issue) to provide some interesting clues about the thera- peutic potential to target adenosine receptors. We hope this series of articles will illustrate the complexity and the importance of the adenosine universe in the nervous system. We also expect these review series will enlighten new scientists to embark boldly where no man has gone before! References 1. Jacobson KA, Gao ZG. Adenosine receptors as therapeu- tic targets. Nat Rev Drug Discov. 2006;5:247–264. 2. Cellai L, Carvalho K, Faivre E, et al. The adenosiner- gic signaling: a complex but promising therapeutic target for Alzheimer’s disease. Front Neurosci. 2018; 12:520. 3. Cunha RA. How does adenosine control neuronal dys- function and neurodegeneration? J Neurochem. 2016; 139:1019–1055. 4. Williams-Karnesky RL, Sandau US, Lusardi TA, et al. Epigenetic changes induced by adenosine augmentation therapy prevent epileptogenesis. J Clin Invest. 2013; 123:3552–3563. University of Lille, Inserm, CHU Lille, UMR-S 1172- JPArc, LabEx DISTALZ, F-59000 Lille, France. JOURNAL OF CAFFEINE AND ADENOSINE RESEARCH Volume 9, Number 3, 2019 ª Mary Ann Liebert, Inc. DOI: 10.1089/caff.2019.29015.dbl 71 Downloaded by 18.206.13.133 from www.liebertpub.com at 05/26/20. For personal use only.