Selective Inhibition of Janus Kinase 3 Has No Impact on Infarct Size or Neurobehavioral Outcomes in Permanent Ischemic Stroke in Mice

Abstract

Janus kinase 3 (JAK3) is associated with the common gamma chain of several interleukin (IL) receptors essential to inflammatory signaling. To study the potential role of JAK3 in stroke-induced neuroinflammation, we subjected mice to permanent middle cerebral artery occlusion and investigated the effects of JAK3 inhibition with decernotinib (VX-509) on infarct size, behavior, and levels of several inflammatory mediators. Results from our double immunofluorescence staining showed JAK3 expression on neurons, endothelial cells, and microglia/macrophages in the ischemic mouse brain (n = 3). We found for the first time that total and phosphorylated/activated JAK3 are dramatically increased after stroke in the ipsilateral hemisphere (**P < 0.01; n = 5–13/group) in addition to increased IL-21 expression after stroke (**P < 0.01; n = 5–7/group). However, inhibition of JAK3 confirmed by reduced phosphorylation of its activation loop at tyrosine residues 980/981 does not reduce infarct volume measured at 48 h after stroke (n = 6–10/group) nor does it alter behavioral outcomes sensitive to neurological deficits or stroke-induced neuroinflammatory response (n = 9–10/group). These results do not support a detrimental role for JAK3 in acute neuroinflammation following permanent focal cerebral ischemia. The functional role of increased JAK3 activation after stroke remains to be further investigated.

Neurovascular protection by adropin in experimental ischemic stroke through an endothelial nitric oxide synthase-dependent mechanism

“…After 24 h of incubation, brains were transferred to PBS and kept at 4 °C for less than one week until sectioned at 20 μm using a semi-automated vibrating microtome. Double immunostaining of adropin with different cell markers was performed following our previously described protocol [ 32 ]. Briefly, brain sections were mounted to a slide and dried at 50 °C for 30 min to ensure that tissue adhered tightly to the slide.…”

The role of JAK/STAT signaling pathway in cerebral ischemia-reperfusion injury and the therapeutic effect of traditional Chinese medicine: A narrative review

“…Notably, it has been noted that activation of JAK3 after cerebral ischemia has no effect on the neuroinflammatory response. [71] Instead of directly mediating neuroinflammation, the JAK/ STAT pathway mediates the inflammatory response by transforming the microglia toward the M1 cell phenotype. [72] There are many mechanisms of microglia recruitment in ischemically injured brain tissue.…”

“…Notably, it has been noted that activation of JAK3 after cerebral ischemia has no effect on the neuroinflammatory response. [71]…”

Adropin confers neuroprotection and promotes functional recovery from ischemic stroke

“…After 24 hours of incubation, brains were transferred to PBS and kept at 4°C for less than one week until sectioned at 20 µm using a semi-automated vibrating microtome. Double immunostaining of adropin with different cell markers was performed following our previously described protocol (70). Briefly, brain sections were mounted to a slide and dried at 50°C for 30 min to ensure that tissue adhered tightly to the slide.…”