STIMULATION OF REACTIVE ASTROGLIOSIS IN-VIVO BY EXTRACELLULAR ADENOSINE-DIPHOSPHATE OR AN ADENOSINE A(2) RECEPTOR AGONIST

Adenosine and its nucleotides adenosine triphosphate (ATP) and adenosi ne diphosphate (ADP) stimulate the proliferation of brain astrocytes i n vitro and augment the effects of other growth factors. Following bra in injury, hypoxia, or around solid tumors with necrotic centers, such as glioblastoma multiformes, high concentrations of adenine nucleotid es and adenosine are released into the extracellular space; extracellu lar adenosine concentrations can rise 30-100-fold to a concentration i n excess of 100 mu M. Increased concentrations of extracellular adenos ine and adenine nucleotides may contribute to reactive astrocytic prol iferation following brain injury. To test this hypothesis, adenosine, an adenosine analog 5'-(N-cyclopropyl)carboxamidoadenosine (CPCA), or ADP Was microinjected into rat cortex. The number of glial fibrillary acidic protein-immunopositive cells was compared between the treated a nd contralateral saline-injected hemispheres. Within 48 hr, astrocyte density around the CPCA (100 mu M) infusion site was almost double tha t around the control saline infusion site. In hemispheres into which C PCA was infused, there was an increase in astrocytes in the subpial re gion along fiber tracts and around blood vessels, characteristic of Sc herer's secondary structures found in association with malignant astro cytic brain tumors. The increased astrogliosis elicited by CPCA was ab olished by coinfusion of the adenosine A(2) receptor antagonist 1,3-di propyl-7-methylxanthine (DPMX). While microinjection of adenosine (1 m M) failed to stimulate astrogliosis, microinjection of ADP (500 mu M) also resulted in a significant reactive astrogliosis and accumulation of astrocytes similar to Scherer's secondary structures. These data in dicate that purine nucleosides and nucleotides may play a role in reac tive astrogliosis following injury and may also play a role in stimula ting the astrocyte migration responsible for Scherer's secondary struc tures around astrogliomas. (C) 1994 Wiley-Liss, Inc.