The role of adenosine and interleukin-6 in neuroprotection
08 / 2000 - 09 / 2004
Under pathological conditions like ischaemia and seizures, the energy supply to the brain decreases. ATP, the energy source of cells, is metabolised in adenosine, which is subsequently transported out of the cells. By stimulating adenosine receptors present throughout the brain adenosine has neuroprotective effects, that counteract the processes resulting from the shortage of energy. Some neuroprotective effects mediated by adenosine A1 receptors present on neurons are: presynaptical inhibition of excitatory neurotransmitters like glutamate, postsynaptical hyperpolarization of the membrane potential and a reduction of Ca2+-influx. Glial cells, like astrocytes and microglia also express adenosine receptors. Research has shown that stimulation of adenosine receptors on astrocytes induces the synthesis of neurotrophins like NGF and interleukin-6. The proinflammatory cytokine interleukin-6 (IL-6) is also released under pathological conditions like adenosine and is known to have neuroprotective properties. However, so far nothing is known regarding the mechanism of IL-6 mediated neuroprotection. Recent findings have provided evidence that IL-6 stimulation leads to an upregulation of adenosine A1 receptor expression in cultured astrocytes. This effect might be an explanation for the neuroprotective function of IL-6. The aim of this PhD project is to shed some light on the interactions between the adenosinergic system and IL-6. Using IL-6 knock-out mice we would like to investigate the relationship between IL-6 release in the brain and the expression of adenosine receptors in CNS pathologies like seizures or stroke. We are also interested in possible other mechanisms by which adenosine can exert neurotrophic effects. Are there other substances that glial cells release after adenosine receptor stimulation, which might be neuroprotective? However, not much is known about the mouse adenosine receptors, since most research is done in rats. Therefore in the first part of this project the expression pattern of the different types of adenosine receptors has been studied as well as their pharmacology. Furthermore cultured glial cell will be stimulated with adenosine receptor agonists to investigate the effect on mRNA expression and protein release of a number of substances like IL-6 and neurotrophins. Before starting the in-vivo experiments it will be checked if the effects found in rat as also found in mouse.