Recent evidence obtained in cultured glial cells indicates that cGMP-mediated pathways regulate cytoskeleton dynamics, glial fibrillary acidic protein expression and motility in astrocytes, as well as inflammatory gene expression in microglia, suggesting a role in the regulation of the glial reactive phenotype. The aim of this work was to examine if cGMP regulates the glial inflammatory response in vivo following CNS damage caused by a focal cryolesion onto the cortex in rats. Results show that treatment with the cGMP phosphodiesterase inhibitor zaprinast (10 mg/kg i.p.) 2 h before and 24 and 48 h after the lesion results 3 days post-lesion in notably enhanced astrogliosis manifested by increased glial fibrillary acidic protein immunoreactivity and protein levels around the lesion. In contrast, zaprinast decreased the number of round/ameboid lectin-positive cells and the expression of the activated microglia/macrophage markers Iba-1 and CD11b indicating decreased recruitment and activation of these cells. This altered inflammatory response is accompanied by a decrease in protein oxidative stress, apoptotic cell death and neuronal degeneration. In addition, zaprinast enhanced angiogenesis in the lesioned cortex probably as a result of vascular endothelial growth factor expression in reactive astrocytes. These results suggest that regulation of the glial inflammatory response may contribute to the reported neuroprotective effects of cGMP-phosphodiesterase inhibitors in brain injury.