AG490 protects cerebral ischemia/reperfusion injury via inhibiting the JAK2/3 signaling pathway

Abstract

Background Cerebral ischemia/reperfusion injury is a severe problem in patients with brain ischemia. Brain injury caused by the immune response is important in the pathogenesis of cerebral ischemia/reperfusion injury and immune pathways. It is important to investigate potential targets for the treatment of cerebral ischemia/reperfusion injury. Methods In this experiment, we evaluated the effect of an exogenous JAK antagonist AG490 in the cerebral ischemia/reperfusion injury model, which was established by middle cerebral artery occlusion (MCAO). Histology study, TUNEL staining, Western blot, and RT‐PCR were employed to examine the effects of AG490 in cerebral ischemia/reperfusion injury. Results In the brain tissue of MCAO mice, JAK2 was highly expressed. AG490 is an inhibitor of JAK2, which reduced the phosphorylation level of JAK2. AG490 downregulated the phosphorylated activation of JAK3 and their downstream STAT3. The antiapoptotic activity of AG490 on cerebral ischemia/reperfusion injury mice was consistent with in vitro data. It reduced the phosphorylation of JAK2/JAK3/STAT3 and the apoptosis rate in cultured neurons upon apoptosis induction. Besides, we also observed the neuroprotective effects of AG490 on cerebral ischemia/reperfusion injury. Administration of AG490 could further enhance the expression of neurotrophins including BNDF, NT3, and the neurotrophin receptor TrkB. Conclusion Therefore, AG490 is pluripotent for cerebral ischemia/reperfusion injury through both antiapoptosis and neuroprotective activities. The antiapoptosis effect is dependent on its regulation of the JAK‐STAT pathway.

Effect of lipoxin A4 methyl ester from arachidonic acid on JAK2/STAT3 pathway after cerebral ischemia-reperfusion injury

“…The above results indicated that AG490 partially blocked or reduced intracellular signal transduction of inflammatory cytokines by inhibiting JAK2 phosphorylation and STAT3 tyrosine phosphorylation. Our results agreed with the results of international researchers (Yang et al, 2017;Fan & Zhou, 2021b;Liang et al, 2016).…”

“…Satriotomo et al (2006) reported a close connection between STAT3 phosphorylation and neuronal death in cerebral ischemia. Downregulation of JAK2/STAT3 activation improves nerve function and achieves neuroprotective effects in focal cerebral ischemia (Fan & Zhou, 2021b). Neuroprotective effect against CIRI can be activated by the JAK/STAT3 inhibitors like AG490 (Yang et al, 2017;Liang et al, 2016).…”

Jak2 Inhibitor AG490 Improved Poststroke Central and Peripheral Inflammation and Metabolic Abnormalities in a Rat Model of Ischemic Stroke

“…Cerebral ischemia causes activation of the Jak2 signaling pathway, which is closely related to the occurrence of poststroke brain injury. Inhibiting activation of the Jak2 signaling pathway can inhibit neuronal apoptosis, thereby alleviating brain injury [ 28 , 29 , 30 , 31 , 32 ]. Conversely, the activation of the Jak2 signaling pathway is also pivotal in the cerebral ischemia neuroprotective actions of melatonin, resveratrol, leptin, and erythropoietin derivatives [ 53 , 54 , 55 , 56 ].…”

“…Furthermore, either with the reduction of IL-6 levels through anti-inflammatory treatments or the intravenous injection of IL-6 neutralizing antibodies, cerebral ischemic damage can be alleviated [ 24 , 25 , 26 , 27 ]. Besides this, the inhibition of the Jak2/Stat3 pathway that can be activated with excess IL-6 during the acute phase of cerebral ischemia confers neuroprotection in ischemic stroke [ 28 , 29 , 30 , 31 , 32 , 33 ]. Taken altogether, these findings indicated the deleterious effects of IL-6 on neuronal injury after cerebral ischemia.…”

Exercise preconditioning attenuates cerebral ischemia‐induced neuronal apoptosis, Th17/Treg imbalance, and inflammation in rats by inhibiting the JAK2/STAT3 pathway

“…Additionally, a study on autism found that resveratrol could compete with neuroimmune dysfunction by downregulating proinflammatory cytokines, such as IL‐6, and the JAK1/STAT3 pathway in BTBR mice (Ahmad, Ansari, et al., 2018). Moreover, inhibition of the JAK2/STAT3 pathway is essential in neuroprotection after CIRI (Fan & Zhou, 2021). The JAK2/STAT3 pathway plays a critical role in the inflammatory reaction, which is necessary for the function of cytokines, the differentiation of T lymphocytes, and the activation of adaptive immunity (O'Shea et al., 2015).…”