Nucleotide signaling in astrogliosis

Acute and chronic damage to the central nervous system (CNS) releases large quantities of ATP. Whereas the ATP concentration in the extracellular space is normally in the micromolar range, under these conditions it increases to millimolar levels. A number of ligand-gated cationic channels termed P2X receptors (7 mammalian subtypes), and G protein-coupled P2Y receptors (8 mammalian subtypes) are located at astrocytes, as confirmed by the measurement of the respective mRNA and protein. Activation of both the P2X7 and P2Y1,2 subtypes identified at astrocytes initiates astrogliosis isolating damaged brain areas from surrounding healthy cells and synthesizing neurotrophins and pleotrophins that participate in neuronal recovery. Astrocytes are considered as cells of high plasticity which may alter their properties in a culture medium. Therefore, recent work concentrates on investigating nucleotide effects at in situ (acute brain slices) and in vivo astrocytes. A wealth of data relates to the involvement of purinergic mechanisms in astrogliosis induced by acute CNS injury such as mechanical trauma and hypoxia/ischemia. The released ATP may act within minutes as an excitotoxic molecule; at a longer time-scale within days it causes neuroinflammation. These effects sum up as necrosis/apoptosis on the one hand and proliferation on the other. Although the role of nucleotides in chronic neurodegenerative illnesses is not quite clear, it appears that they aggravate the consequences of the primary disease. Epilepsy and neuropathic pain are also associated with the release of ATP and a pathologic glia-neuron interaction leading to astrogliosis and cell death. In view of these considerations, P2 receptor antagonists may open new therapeutic vistas in all forms of acute and chronic CNS damage.