Nicotine Activating α4β2 Nicotinic Acetylcholine Receptors to Suppress Neuroinflammation via JAK2-STAT3 Signaling Pathway in Ischemic Rats and Inflammatory Cells

Mol Neurobiol. 2022 May;59(5):3280-3293. doi: 10.1007/s12035-022-02797-4. Epub 2022 Mar 17.


Nicotine plays a role in inhibiting inflammatory factors, which contributes to improving cognitive impairment by activating α4β2 nAChRs in ischemic rats, but the underlying mechanism has not been fully elucidated. Janus tyrosine kinase 2-signal transducer and activator of transcription 3 (JAK2-STAT3) signaling pathway is involved in cognitive improvement, and there seems to be a relationship between nAChRs and JAK2-STAT3 as well. The aim of this study is to explore the role of JAK2-STAT3 signaling pathway in nicotine-mediated anti-inflammatory effect. Nicotine, DHβE (the strongest competitive antagonist of α4β2 nAChRs), and AG490 (a specific JAK2-STAT3 blocker) were used to intervene and treat ischemic rats and HEK-293 T-hα4β2 cells. The Morris water maze (MWM) test and 2-[18F]-A-85380 PET imaging were performed to detect the cognitive function and α4β2 nAChRs density in ischemic rats. The results demonstrated that nicotine intervention increased the density of α4β2 nAChRs and improved cognitive impairment, but this effect was blocked by AG490, and the receptors were still upregulated. Essentially, when the JAK2-STAT3 signaling pathway was blocked, nicotine could only upregulate the expression of α4β2 nAChRs, but not improve the cognitive function. PCR and Western blot analysis further confirmed these results. The cell experiments also showed that nicotine could reduce inflammatory factors stimulated by LPS and upregulate the expression of pJAK2 and pSTAT3 in HEK-293 T-hα4β2 cells, while AG490 and DHβE reversed the effect of nicotine. To sum up, our work indicated that JAK2-STAT3 signaling pathway played an important role in nicotine-induced cognitive improvement by upregulating α4β2 nAChRs in ischemic rats.

Keywords: Cognitive impairment; JAK2-STAT3; Neuroinflammation; Nicotine; α4β2 nicotinic acetylcholine receptor.

MeSH terms

  • Animals
  • HEK293 Cells
  • Humans
  • Ischemia
  • Janus Kinase 2 / metabolism
  • Neuroinflammatory Diseases
  • Nicotine* / pharmacology
  • Rats
  • Receptors, Nicotinic* / metabolism
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • TYK2 Kinase / metabolism
  • TYK2 Kinase / pharmacology
  • Tyrosine


  • Receptors, Nicotinic
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Tyrosine
  • Nicotine
  • JAK2 protein, human
  • Jak2 protein, rat
  • Janus Kinase 2
  • TYK2 Kinase