JAK2 and STAT3 activation contributes to neuronal damage following transient focal cerebral ischemia

J Neurochem. 2006 Sep;98(5):1353-68. doi: 10.1111/j.1471-4159.2006.04051.x.


Increased levels of interleukin-6 (IL-6) play a role in post-ischemic cerebral inflammation. IL-6 binding to its receptors induces phosphorylation of the receptor associated janus kinases (JAKs), and the down-stream signal transducer and activator of transcription (STAT) family of transcription factors, which amplify the IL-6 signal transduction. We evaluated the functional significance of JAK2 and STAT3 activation in focal ischemia-induced neuronal damage. Transient middle cerebral artery occlusion in adult rats led to increased JAK2 and STAT3 phosphorylation in the ipsilateral cortex and striatum after 6-72 h of reperfusion. Fluorescent immunohistochemistry with cell specific markers (NeuN for neurons, glial fibrillary acidic protein for reactive astrocytes and ED1/OX42 for activated macrophages/microglia) showed that both pJAK2 and pSTAT3 staining is predominantly localized in the macrophages/microglia in the post-ischemic brain. Intracerebroventricular infusion of rats with AG490 (a JAK2 phosphorylation inhibitor) prevented the post-ischemic JAK2 and STAT3 phosphorylation and significantly decreased the infarct volume, number of apoptotic cells and neurological deficits, compared to vehicle control. Furthermore, intracerebral injection of siRNA specific for STAT3 led to curtailed STAT3 mRNA expression and phosphorylation, decreased infarct volume, fewer apoptotic cells and improved neurological function following transient middle cerebral artery occlusion. These studies show that JAK2-STAT3 activation plays a role in post-ischemic brain damage.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Blotting, Western / methods
  • Cell Death / drug effects
  • Cell Death / physiology
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Enzyme Inhibitors / pharmacology
  • Immunohistochemistry / methods
  • In Situ Nick-End Labeling / methods
  • Ischemic Attack, Transient / pathology*
  • Janus Kinase 2
  • Nerve Tissue Proteins / metabolism
  • Neurologic Examination / methods
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neurons / pathology
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / pharmacology
  • Rats
  • Reperfusion / methods
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Time Factors
  • Tyrphostins / pharmacology


  • Enzyme Inhibitors
  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • STAT3 Transcription Factor
  • Tyrphostins
  • alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
  • Protein-Tyrosine Kinases
  • Jak2 protein, rat
  • Janus Kinase 2