In view of the increasing evidence that a pathological glial activation plays a significant role in the development of neurodegenerative diseases, we investigated the underlying molecular signaling as a possible target for the pharmacological therapy. Here, we are particularly focusing on the endogenous modulation of the CA2+ and cyclic nucleotide-dependent signaling by the nucleoside adenosine and its reinforcement by the xanthine derivative propentofylline (PPF). As an experimental model, we used cultured rat microglial cells and astrocytes that are immature, show a high proliferation rate, and resemble in several aspects pathologically activated glial cells. A prolonged increase of the cellular cAMP level favored the differentiation of cultured astrocytes and associated properties required for the physiological nerve cell function. On the other hand a strengthening of the cyclic nucleotide-dependent signaling inhibited potentially neurotoxic properties of cultured microglial cells. Similar effects were obtained by treatment with propentofylline, which mimicked modulatory adenosine effects and increased the intracellular level of cAMP and cGMP. Such a pharmacological glial cell conditioning, obtained by modifying the strength and the timing of these second messengers, may provide a therapy of neurodegenerative diseases in which a pathological activation of microglial cells and astrocytes is discussed to playa pathogenic role.

Adenosine↗

PubMedDate not supplied

Modulation of nerve and glial function by adenosine--role in the development of ischemic damage.

Adenosine is released during brain ischemia and provides neuroprotection by actions on nerve and glial cells. Activation of the adenosine A1 receptor enhances the K+ and Cl- conductance in neurons, leading to membrane hyperpolarization and postsynaptic reduction of neuronal Ca2+ influx through voltage- and NMDA receptor-dependent channels. In addition adenosine A1 receptor activation decreases excitatory amino acid release, possibly via inhibition of N- and P-type Ca2+ channels. The A1 and A2 receptors, coupled to Gi/G(o) and Gs proteins respectively, often co-exist and interact with the phospholipase C-dependent activation of the protein kinase C and the adenylyl cyclase. Activation of the A1 receptor may mimic metabotropic receptor stimulation in activating intracellular Ca2+ mobilization and PKC. A2 receptor mediated cAMP formation is depressed by high intracellular Ca2+ but enhanced by PKC activation. By modulating these metabolic signaling events, adenosine may influence acute cell functions, gene transcription and sustained changes of nerve and glial cells relevant for the development of ischemic damage. The neuroprotective adenosine effect seems to be amplified by treatment with propentofylline, which enhances adenosine release, influences the balance between A1 and A2 receptor mediated actions, depresses the free radical formation in activated microglia and influences astrocyte reactions.

Adenosine↗

PubMedDate not supplied

Modulatory effects of adenosine upon the transmitter release in the hippocampal slice preparation of rats.

In the hippocampal slice preparation of rats, preloaded with 3H-glutamate a local perfusion technique was used in order to measure the labelled transmitter output. The electrical receptive stimulation of the Schaffer collateral-commissural projections resulted in a detectable 3H-glutamate release which was significantly increased in the presence of 4-aminopyridine (4-AP). Exogenous adenosine and its analogue L-PIA induced a slight unsignificant reduction of the release while in the presence of 4-AP the release was almost completely blocked. Adding adenosine deaminase (ADA) did not change the normal transmitter release while in the presence of 4-AP the elimination of the endogenous adenosine brought about a significantly higher 3H-glutamate output. It is concluded that the adenosine-induced presynaptic inhibition of the transmitter release could be a significant mechanism under conditions in which the synaptic activity is abnormally high. This effect seems to be mediated via the A1 adenosine receptor since the D-PIA isomer application has no significant inhibitory effects.

4-Aminopyridine↗