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

Journal of Neuroinflammation

Lorenz Hirt²  Christian Pasquali¹  Anne Vaslin¹  Corinne Benakis² 

[1] Department of Clinical Neuroscience, University Hospital of Lausanne, Xigen SA, Epalinges 1066, Switzerland;Department of Clinical Neuroscience, University Hospital of Lausanne, (CHUV), BH 07, Lausanne 1011, Switzerland

关键词: Neuroprotection;    Middle cerebral artery occlusion;    Keratinocyte-derived chemokine;    Interleukin-6;    Inflammation;    c-Jun N-terminal kinase;   

Others  :  1212662
DOI  :  10.1186/1742-2094-9-76

 received in 2011-09-18, accepted in 2012-04-25,  发布年份 2012

【 摘 要 】

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.

Findings

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.

【 授权许可】

   
2012 Benakis et al.; licensee BioMed Central Ltd.

【 图 表 】

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