Modulation of neuronal and glial cell function by adenosine and neuroprotection in vascular dementia

Abstract

Dementia is one of the major medical challenges in the industrialized countries. An increasing number of demented patients shows ischemic brain lesions. One strategy to treat dementia could be the reinforcement of the multifarious neuroprotective actions of the endogenous cell modulator adenosine. This involves the modulation of neuronal and glial cell functions. Adenosine appears to raise the threshold for the initiation of the pathophysiological cascade of ischemic neuronal death by counteracting ischemic membrane depolarization and the successive disturbance of intracellular Ca2+ homeostasis. When this threshold is overcome, adenosine seems to stimulate astrocyte differentiation and reinforce important protective astrocyte functions, e.g., synthesis and release of neurotrophic factors such as NGF and the clearance of abnormal neurotoxic levels of K+ and glutamate from the extracellular space. Propentofylline, a combined inhibitor of adenosine reuptake and cAMP phosphodiesterases, reinforces the actions of endogenous adenosine and cAMP. One important action of propentofylline is the inhibition of potentially neurotoxic functions of activated microglia (free radical formation and transformation into brain macrophages). Such drugs may help to inhibit the progressive neurodegenerative process in dementia.