In a recent article published in Nature Communications, Zheng et al. report that heightened stimulation of A2A receptors (A2ARs) located in epithelial cells of the chrorioid plexus (ChP) is responsible for the development of hydrocephalus (Zheng et al., Nat Commun 17:83, 2025). They show evidence in hydrocephalus patients and mice models of hydrocephalus that the cerebrospinal fluid (CSF) concentration of adenosine is raised to about threefold of the control value. Under pathological conditions, CSF adenosine levels may be increased in response to infection, hemorrhage, traumatic insults, and tumors, all of which are known to be the initiators of hydrocephalus. In careful experiments, performed mostly in mice models, established by the injection of autologous blood (imitation of hemorrhage) or kaolin (imitation of obstruction) to the cerebral ventricles, the production of CSF, the level of adenosine, and the expression of A2ARs was increased and in consequence the ventricles enlarged. The signaling mechanisms leading to increased production of CSF were then identified by the genetic knockdown of proteins that were assumed to be involved in this process. The A2AR-SPAK (SPS1-related proline/alanine-rich kinase)-PI3K (phosphoinositide 3 kinase)-Akt (protein kinase B)-NF-κB (a nuclear factor)-ATP1A2 (a Na+,K+-ATPase) pathway was suggested to be instrumental in hydrocephalus development. The clinically important conclusion deriving from this observation was that A2AR blockade by istradefylline, a Food and Drug Administration-approved drug could be introduced into the therapy of human hydrocephalus.
