JAK2/STAT3 Signaling Pathway Plays a Key Role in Nicotine Mediated Neuroinflammation Suppression in an Ischemic Rat Model

Abstract

BackgroundTo explore the mechanism of nicotine mediated improvement of cognitive impairment in an established ischemic rat model. MethodsEndothelin-1 (ET-1) was injected into the left thalamic region in adult male Sprague-Dawley (SD) rats to establish ischemia model. 6 groups of rats (6 rats in each group) were then treated with nicotine, nicotine+DHβE, DHβE, AG490, nicotine +AG490 and saline respectively via intraperitoneal injection for 9 days. Another sham operation group was treated with saline as above. Morris Water Maze (MWM) test was performed for 6 consecutive days starting on the 4th day after operation to detect the cognitive function of rats in each group. 2-[18F]-A-85380 microPET imaging was performed on day 10 to evaluate the changes of α4β2 nAChRs in different brain regions of rats. Real-time PCR and Western blot were used to detect the amount of α4β2 nAChRs, JAK2, STAT3 and inflammatory factors in thalamus of rats in each group. ResultsThe results of MWM test showed the spatial learning and memory abilities of rats in the nicotine and sham operation groups were significantly better than the saline treating group in this ischemic rat model (p<0.05). There was no significant difference in other groups (p>0.05). MicroPET imaging showed more uptake of 2-[18F]-A-85380 in the nicotine, nicotine+AG490 and sham operation groups than in saline treating group, while there was no significant difference found in other groups (p>0.05). The expression of α4- and β2-nAChR in nicotine, nicotine+AG490 and sham operation groups was significantly higher than the saline treating group (p<0.05). In the nicotine group, the expression of p-JAK2 and p-STAT3 in left thalamus of rats was significantly higher than the saline treating group (p<0.05), and the expression of IL-1β and IL-6 protein was found to be lower than the saline treating group (p<0.05). While the expression of p-JAK2, p-STAT3 and inflammatory factors was not significantly different in all the other groups (p>0.05). ConclusionThe study suggests nicotine inhibits the expression of inflammatory factors by activating α4β2 nAChRs through the activation of JAK2-STAT3 signaling pathway to improve cognitive impairment in ischemic rats.