Abstract
Background: Nicotine is an agonist of alpha-7 nicotinic acetylcholine receptor (α7 nAChR). The association between the expression of α7 nAChR and neuroinflammation has been extensively reported. Herein, we assessed the efficacy of Nicotine in the management of spinal cord injury (SCI) complications and mediating mechanisms.Methods: In this study, 64 male rats were randomly allocated to 7 SCI and a sham-operated groups. SCI was induced through an aneurysmal clip at the T9/T10 level. The group list consists of a non-treated group as the control, four Nicotine-treated groups receiving 0.5, 1, 1.5, and 3 mg/kg of the drug, a Methyllycaconitine (MLA, 1.5 mg/kg)-treated group, a group of rodents receiving MLA plus the most effective dosage of Nicotine, and a sham one. Locomotion and mechanical allodynia were assessed during 28 days using the Basso, Beattie, Bresnahan (BBB) and von Frey methods, respectively. In the end, spinal cord samples were taken to assess cavity formation, the expression levels of M1 and M2 macrophages, pro-inflammatory and anti-inflammatory factors, as well as α7 nAChR and NF-κB gene levels.Results: Repeated measures analysis revealed significant effect of time-treatment interaction on locomotion [F (42, 336) = 120.2, p < 0.001] and mechanical sensitivity [F (35, 280) = 45.47, p < 0.001]. Behavioral response to Nicotine was dose-dependent, and 1 mg/kg of this reagent was the most efficient dosage. H&E staining represented lesser histopathological disruptions in Nicotine-treated animals. SCI increased the M1/M2 ratio (p < 0.001) via shifting macrophages polarization towards M1 subset and 1 mg/kg of Nicotine could attenuate this ratio (p < 0.001) through reversing the shift. Meanwhile, Nicotine administration resulted in a significant elevation of α7 nAChR and a reduction of NF-κB genes. Finally, in the Nicotine group, there were declines in the levels pro-inflammatory biomarkers, including TNF-α, IL-1β, and IL-6, while IL-10 was found higher than the control group (p values < 0.05). MLA-treated groups showed almost none of the aforementioned alterations. Conclusion: Single-dose therapy with Nicotine could improve locomotor and sensory complications of SCI. Nicotine possible mechanism of action is through increasing the α7 nAChR level, which alleviates neuro-inflammation by changing microglial phenotyping.
The Association Between Alpha-7 Nicotinic Acetylcholine Receptor and Microglial Polarization in Spinal Cord Injury: Nicotine as an Alternative Therapy for Neuroinflammation