Stimulation of reactive astrogliosis in vivo by extracellular adenosine diphosphate or an adenosine A2 receptor agonist

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Abstract
Adenosine and its nucleotides adenosine triphosphate (ATP) and adenosine diphosphate (ADP) stimulate the proliferation of brain astrocytes in vitro and augment the effects of other growth factors. Following brain injury, hypoxia, or around solid tumors with necrotic centers, such as glioblastoma multiformes, high concentrations of adenine nucleotides and adenosine are released into the extracellular space; extracellular adenosine concentrations can rise 30–100-fold to a concentration in excess of 100 μM. Increased concentrations of extracellular adenosine and adenine nucleotides may contribute to reactive astrocytic proliferation 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 prtein-immunopositive cells was compared between the treated and contralateral saline-injected hemispheres. Within 48 hr, astrocyte density around the CPCA (100 μM) infusion site was almost double that around the control saline infusion site. In hemispheres into which CPCA was infused, there was an increase in astrocytes in the subpial region along fiber tracts and around blood vessels, characteristic of Scherer's secondary structures found in association with malignant astrocytic brain tumors. The increased astrogliosis elicited by CPCA was abolished by coinfusion of the adenosine A2 receptor antagonist 1,3-dipropyl-7-methylxanthine (DPMX). While microinjection of adenosine (1 mM) failed to stimulate astrogliosis, microinjection of ADP (500 μM) also resulted in a significant reactive astrogliosis and accumulation of astrocytes similar to Scherer's secondary structures. These data indicate that purine nucleosides and nucleotides may play a role in reactive astrogliosis following injury and may also play a role in stimulating the astrocyte migration responsible for Scherer's secondary structures around astrogliomas.