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Purinergic modulation of cytokine production in the central nervous system and its role in fever induced by systemic inflammation and ischemia/reperfusion brain injury

Ziel

Extracellular purines, adenosine (Ado) and adenosine 5-triphosphate (ATP), acting via G protein-coupled Ado receptors (A1, A2A, A2B, A3) and via ATP-gated non-selective action ionotropic P2X receptors, respectively, may play an important role in inflammation and ischemia/reperfusion brain injury, as ATP is considered to have a pro-inflammatory, and Ado - an anti-inflammatory and neuroprotective actions. Preliminary data clearly indicate that both ATP and Ado indeed play an important role in the development of the febrile response. Since various cytokines play important role in regulation of inflammatory responses and ischemic brain injury, current project will use animal and in vitro models to test the following hypothesis: Extracellular purines ATP and adenosine are involved in regulation of the febrile response and neuroprotection during brain ischemia/reperfusion via regulation the production of cytokines in the brain.
The project is dedicated to strengthen collaboration between Belarus and Russian laboratories and that of scientists in Germany and the United Kingdom aiming to dissect functional interactions between brain extracellular ATP, Ado and cytokines and to determine their role in the development of the febrile response and neuroprotection in ischemia/reperfusion brain injury. This interdisciplinary study will exploit various methods of neurophysiology, biochemistry and cytokine research to investigate the following tasks: 1) to determine in real time using enzymatic biosensors whether extracellular concentration of ATP and Ado in the brain increases during the development of fever induced by systemic inflammation in vivo or during brain ischemia/reperfusion; 2) to determine the effects of P2 and Ado receptor activation and blockade in the brain on body temperature during fever induced by systemic inflammation in vivo; 3) to investigate the effects of P2 and Ado receptor activation and blockade on cytokines (IL-1b, IL-6, IL-8 and TNFa) expression in the brain during fever induced by systemic inflammation in vivo and brain ischemia/reperfusion; 4) to determine using immunocytochemistry whether P2X7 and Ado receptors are co-expressed with cytokines IL-1b, IL-6, IL-8 and TNFa in neurons and/or in glial cells in the brain; 5) to investigate the effects of P2X7 and Ado receptor activation and blockade on cytokines (IL-1b, IL-6, IL-8 and TNFa) expression in brain slices, in primary hypothalamic neuroglial cultures, neuroblastoma cell lines and leukocyte fractions. Experimental testing the hypothesis will help to understand the roles played by ATP and Ado in modulation of cytokine expression in the brain during systemic inflammation and ischemia/reperfusion, and to determine the role of these purines in the development of the febrile response and neuroprotection against ischemia and may be significant in view of expected perspective of possible therapeutical applications of purines in the treatment of inflammatory diseases and stroke.

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University of Gießen, School of Veterinary Sciences
EU-Beitrag
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Frankfurter Straße 100
35392 Gießen
Deutschland

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Beteiligte (4)