Interfering with the pathologic activation of microglial cells and astrocytes in dementia

Cascading glial cell activation is believed to play an essential pathogenic role in the development of dementia. Reactive microglia may contribute to neuronal damage by the generation of free oxygen radicals and nitric oxide (NO), which forms the particularly aggressive peroxynitrites, and by the re lease of potentially neurotoxic cytokines such as tumor necrosis factor-alp ha (TNF-alpha). The pathologically stimulated release of interleukin-1 beta (IL-1 beta) from microglial cells triggers secondary activation of astrocy tes, which are forced to proliferate and to give up their differentiated st ate. As a consequence, physiologically required astrocyte functions may be impaired, such as uptake of glutamate and K+ from the extracellular space a nd release of neurotrophic factors. At the same time, production of inflamm atory proteins which, for example, promote the formation of toxic beta-amyl oids, is reported to be stimulated in reactive astrocytes. Because the comp lex molecular signaling that controls glial cell activation is only beginni ng to be elaborated, we attempted to elucidate the role that has been adopt ed during evolution by the endogenous cell modulator adenosine. This nucleo side exerts a homeostatic effect on reactive glial cell functions by a soph isticated control of the second messenger interplay, counteracting a pathol ogically induced dysbalance of the Ca2+- and cAMP-dependent signaling. A st rengthening of the cAMP-dependent signaling chains was found to counteract the proliferation rate, the formation of free oxygen radicals, and the stim ulated release of TNF-alpha and IL-1 beta in cultivated microglia. It also helped proliferative astrocytes to regain their differentiated state and a mature ion channel pattern. The cAMP-linked homeostatic adenosine effects c ould be reinforced or mimicked by propentofylline, a pharmacon that raises the effective extracellular concentration of adenosine by inhibiting its ce llular reuptake and increases the cellular cyclic nucleotide content by sel ective phosphodiesterase inhibition. We conclude that a pharmacologically r einforced homeostatic control of the pathologically altered Ca2+/cAMP cross talk may prevent glia-related neuronal damage, providing a potential option for the treatment of dementia.