title: Neuroprotection by inhibiting the c-Jun N-terminal kinase pathway after cerebral ischemia occurs independently of interleukin-6 and keratinocyte-derived chemokine (KC/CXCL1) secretion.
abstract: BACKGROUND
  Cerebral ischemia is associated with the activation of glial cells, infiltration of leukocytes and an increase in inflammatory mediators in the ischemic brain and systemic circulation. How this inflammatory response influences lesion size and neurological outcome remains unclear. D-JNKI1, an inhibitor of the c-Jun N-terminal kinase pathway, is strongly neuroprotective in animal models of stroke. Intriguingly, the protection mediated by D-JNKI1 is high even with intravenous administration at very low doses with undetectable drug levels in the brain, pointing to a systemic mode of action, perhaps on inflammation.
  
  
  RESULTS
  We evaluated whether D-JNKI1, administered intravenously 3 h after the onset of middle cerebral artery occlusion (MCAO), modulates secretion of the inflammatory mediators interleukin-6 and keratinocyte-derived chemokine in the plasma and from the spleen and brain at several time points after MCAO. We found an early release of both mediators in the systemic circulation followed by an increase in the brain and went on to show a later systemic increase in vehicle-treated mice. Release of interleukin-6 and keratinocyte-derived chemokine from the spleen of mice with MCAO was not significantly different from sham mice. Interestingly, the secretion of these inflammatory mediators was not altered in the systemic circulation or brain after successful neuroprotection with D-JNKI1.
  
  
  CONCLUSIONS
  We demonstrate that neuroprotection with D-JNKI1 after experimental cerebral ischemia is independent of systemic and brain release of interleukin-6 and keratinocyte-derived chemokine. Furthermore, our findings suggest that the early systemic release of interleukin-6 and keratinocyte-derived chemokine may not necessarily predict an unfavorable outcome in this model.
authors.affiliation: Department of Clinical Neuroscience, University Hospital of Lausanne-CHUV, BH 07 Lausanne 1011, Switzerland. corinne.benakis@unil.ch
authors.forename: Corinne
authors.initials: C
authors.lastname: Benakis
authors.forename: Anne
authors.initials: A
authors.lastname: Vaslin
authors.forename: Christian
authors.initials: C
authors.lastname: Pasquali
authors.forename: Lorenz
authors.initials: L
authors.lastname: Hirt
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control*; D054360:Chemokine CXCL1 / Q000378:metabolism*; D018925:Chemokines / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010455:Peptides / Q000627:therapeutic use*; D011237:Predictive Value of Tests; D011897:Random Allocation
chemical_list: D054360:Chemokine CXCL1; D018925:Chemokines; C475895:Cxcl1 protein, mouse; D015850:Interleukin-6; D018696:Neuroprotective Agents; D010455:Peptides; C074302:keratinocyte-derived chemokines; D048031:JNK Mitogen-Activated Protein Kinases; C478085:D-JNKI-1