Nicotine induced neurocognitive protection and anti-inflammation effect by activating α4β2 nAChRs in ischemic rats.
To explore the mechanism of nicotine improving cognitive impairments in ischemic rats. 20 adult male Sprague-Dawley (SD) rats underwent ischemic model surgery by injecting ET-1 into the left thalamus, which were classified into four different groups with different intervention: nicotine (1.5mg/kg/d), DHβE (3mg/kg/d), nicotine (1.5mg/kg/d)+ DHβE (3mg/kg/d), or saline, after ischemic model surgery. Another 5 male SD rats also underwent same surgery, while not injecting ET-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, microPET imaging with 2-[18F]-A-85380, and mRNA test of α4 nAChR, β2 nAChR, TNF-α, IL-1β and IL-6. The MWM test showed the rats given nicotine showing better memory than ischemic rats (p<0.05), while the rats given DHβE or both nicotine and DHβE did not show any statistical difference from the ischemic rats(p>0.05). MicroPET 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 α4 nAChR and β2 nAChR in rats given nicotine increased significantly compared with ischemic rats, and decreased TNF-α, IL-1β and IL-6 mRNA (all p<0.05). By activating α4β2 nAChRs, nicotine plays a role in inhibiting the inflammatory factors, which contributes to improving cognitive impairment in ischemic rats. It is well acknowledged that vascular cognitive impairment (VCI) is the second most common cause of dementia after Alzheimer's disease (AD). 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 of VCI and inflammation. This study showed that nicotine had anti-inflammatory potency, which is most likely due to the activation of the nicotinic acetylcholine receptors (nAChRs). By activating α4β2 nAChRs, nicotine played a role in inhibiting the inflammatory factors, which contribute to improving cognitive impairment in ischemic rats.