Introduction The main objective of this study was to explore the mechanism of nicotine improving cognitive impairments in ischemic rats. Methods Twenty adult male Sprague–Dawley (SD) rats underwent ischemic model surgery by injecting endothelin-1 into the left thalamus, which were classified into four different groups with different intervention: nicotine (1.5 mg/kg/d), dihydro-β-erythroidine (DHβE; 3 mg/kg/d), nicotine (1.5 mg/kg/d) + DHβE (3 mg/kg/d), or saline, after ischemic model surgery. Another five male SD rats also underwent same surgery, while not injecting endothelin-1 but saline, as the control group. Morris water maze (MWM) test was adopted to assess the cognition. All the rats underwent the MWM test, micro positron emission tomography imaging with 2-[18F]-A-85380, and messenger RNA (mRNA) test of α 4 nicotinic acetylcholine receptor (nAChR), β 2 nAChR, tumor necrosis factor-alpha (TNF-α), IL-1β, and IL-6. Results The MWM test showed the rats given nicotine showing better memory than ischemic rats (p < .05), whereas the rats given DHβE or both nicotine and DHβE did not show any statistical difference from the ischemic rats (p > .05). Micro positron emission tomography imaging showed higher uptake of tracer in the left thalamus and whole brain in rats given nicotine than in ischemic rats, but the rats given DHβE or both nicotine and DHβE did not. By real-time PCR test, the mRNA of α 4 nAChR and β 2 nAChR in rats given nicotine increased significantly compared with ischemic rats and decreased TNF-α, IL-1β, and IL-6 mRNA (all ps < .05). Conclusions By activating α 4β 2 nAChRs, nicotine plays a role in inhibiting the inflammatory factors, which contributes to improving cognitive impairment in ischemic rats. Implications It is well acknowledged that vascular cognitive impairment (VCI) is the second most common cause of dementia after Alzheimer’s disease. Cholinergic agents have potential for the symptomatic treatment of the cognitive symptoms of dementia, but the exact mechanism still remains unclear. There are potential complex associations and interactions between VCI and inflammation. This study showed that nicotine had anti-inflammatory potency, which is most likely because of the activation of the nAChRs. By activating α4β2 nAChRs, nicotine played a role in inhibiting the inflammatory factors, which contribute to improving cognitive impairment in ischemic rats.

Nicotine plays a role in inhibiting the in ammatory factors, which contributes to improving cognitive impairment by activating α 4 β 2 nAChRs in ischemic rats, but the underling 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 a relationship between nAChRs and JAK2-STAT3 as well. This study was designed to investigate the role of JAK2-STAT3 signaling pathway in nicotine-mediated anti-in ammation effect. Nicotine, DHβE (the most potent competitive antagonist of α 4 β 2 nAChRs) and AG490 (a speci c JAK2-STAT3 blocker) were adopted for intervention treatment in ischemic rats and HEK-293T-hα 4 β 2 cells. Morris Water Maze (MWM) test and 2-[18F]-A-85380 PET imaging were performed to detect the cognition and α 4 β 2 nAChRs in ischemic rats. The results demonstrated that nicotine intervention increased the density of α 4 β 2 nAChRs and improved cognitive impairment, but this effect would be blocked by AG490, while receptors were still upregulated.Essentially, when JAK2-STAT3 signaling pathway was blocked, nicotine could only upregulate the expression of α 4 β 2 nAChRs, but not improve the cognitive function. The results were further con rmed by PCR and Western blot analysis. The cell experiments also showed that nicotine could reduce in ammatory factors stimulated by LPS and upregulate the expression of pJAK2 and pSTAT3 in HEK-293T-hα 4 β 2 cells, while AG490 and DHβE reversed nicotine's effect. In summary, our work indicated that JAK2-STAT3 signaling pathway played an important role in nicotine-induced cognitive improvement by up-regulating α 4 β 2 nAChRs in ischemic rats.

Nicotine plays a role in inhibiting the inflammatory factors, which contributes to improving cognitive impairment by activating α4β2 nAChRs in ischemic rats, but the underling 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 a relationship between nAChRs and JAK2-STAT3 as well. This study was designed to investigate the role of JAK2-STAT3 signaling pathway in nicotine-mediated anti-inflammation effect. Nicotine, DHβE (the most potent competitive antagonist of α4β2 nAChRs) and AG490 (a specific JAK2-STAT3 blocker) were adopted for intervention treatment in ischemic rats and HEK-293T-hα4β2 cells. Morris Water Maze (MWM) test and 2-[18F]-A-85380 PET imaging were performed to detect the cognition and α4β2 nAChRs in ischemic rats. The results demonstrated that nicotine intervention increased the density of α4β2 nAChRs and improved cognitive impairment, but this effect would be blocked by AG490, while receptors were still upregulated. Essentially, when JAK2-STAT3 signaling pathway was blocked, nicotine could only upregulate the expression of α4β2 nAChRs, but not improve the cognitive function. The results were further confirmed by PCR and Western blot analysis. The cell experiments also showed that nicotine could reduce inflammatory factors stimulated by LPS and upregulate the expression of pJAK2 and pSTAT3 in HEK-293T-hα4β2 cells, while AG490 and DHβE reversed nicotine’s effect. In summary, our work indicated that JAK2-STAT3 signaling pathway played an important role in nicotine-induced cognitive improvement by up-regulating α4β2 nAChRs in ischemic rats.