Microglial Adenosine Receptors: From Preconditioning to Modulating the M1/M2 Balance in Activated Cells

Neuronal survival depends on the glia, that is, on the astroglial and microglial support. Neurons die and microglia are activated not only in neurodegenerative diseases but also in physiological aging. Activated microglia, once considered harmful, express two main phenotypes: the pro-inflammatory or M1, and the neuroprotective or M2. When neuroinflammation, i.e., microglial activation occurs, it is important to achieve a good M1/M2 balance, i.e., at some point M1 microglia must be skewed into M2 cells to impede chronic inflammation and to afford neuronal survival. G protein-coupled receptors in general and adenosine receptors in particular are potential targets for increasing the number of M2 cells. This article describes the mechanisms underlying microglial activation and analyzes whether these cells exposed to a first damaging event may be ready to be preconditioned to better react to exposure to more damaging events. Adenosine receptors are relevant due to their participation in preconditioning. They can also be overexpressed in activated microglial cells. The potential of adenosine receptors and complexes formed by adenosine receptors and cannabinoids as therapeutic targets to provide microglia-mediated neuroprotection is here discussed.

Automated summary

Neuronal survival relies on glial support, with activated microglia showing either harmful pro-inflammatory (M1) or beneficial neuroprotective (M2) phenotypes; maintaining the M1/M2 balance is crucial in neuroinflammation. Adenosine receptors play a significant role in increasing M2 cell numbers and preconditioning for better resilience against damaging events. The potential therapeutic targeting of adenosine receptors and adenosine-cannabinoid complexes for microglia-mediated neuroprotection is discussed.