The Experimental Autoimmune Encephalomyelitis Disease Course Is Modulated by Nicotine and Other Cigarette Smoke Components

Abstract

Epidemiological studies have reported that cigarette smoking increases the risk of developing multiple sclerosis (MS) and accelerates its progression. However, the molecular mechanisms underlying these effects remain unsettled. We have investigated here the effects of the nicotine and the non-nicotine components in cigarette smoke on MS using the experimental autoimmune encephalomyelitis (EAE) model, and have explored their underlying mechanism of action. Our results show that nicotine ameliorates the severity of EAE, as shown by reduced demyelination, increased body weight, and attenuated microglial activation. Nicotine administration after the development of EAE symptoms prevented further disease exacerbation, suggesting that it might be useful as an EAE/MS therapeutic. In contrast, the remaining components of cigarette smoke, delivered as cigarette smoke condensate (CSC), accelerated and increased adverse clinical symptoms during the early stages of EAE, and we identify a particular cigarette smoke compound, acrolein, as one of the potential mediators. We also show that the mechanisms underlying the opposing effects of nicotine and CSC on EAE are likely due to distinct effects on microglial viability, activation, and function.

Nicotine modulates neurogenesis in the central canal during experimental autoimmune encephalomyelitis

“…Clinical deficits consistent with EAE were evident at Day 7 after EAE onset, reached the peak around Day 21 with subsequent recovery (Gao et al, 2014). To assess how NSCs responded to EAE, nestin expression was examined in spinal cord samples collected at different timepoints (Day 0, Day 14, Day 21, Day 28) after EAE induction (Fig.…”

“…EAE was actively induced by subcutaneous injection of MOG35-55 peptide (MEVGWYRSPFSRVVHLYRNGK, Yale University Peptide Synthesis Facility) in 8 week-old female mice as previously described(Lu et al, 2002, Bhasin et al, 2007, Wu et al, 2012, Nissen et al, 2013, Gao et al, 2014). EAE clinical symptoms were scored on a scale of 0 to 5 with gradations of 0.5 for intermediate symptoms.…”

“…200mg/ml nicotine ditartrate in saline was loaded into mini-osmotic pumps (28-day, infusion rate of 0.25μL/h, Alzet)(Shi et al, 2009, Gao et al, 2014) and then implanted subcutaneously in the back of the mice. The serum cotinine levels were measured at 83.8ng/ml (14-day infusion) and 85.7ng/ml (28-day infusion), which is comparable to that found in heavy smokers (80–100ng/ml)(Paulson et al, 2010).…”

“…Experimental autoimmune encephalomyelitis (EAE) is the most commonly used animal model for MS (Gao and Tsirka, 2011). Previous studies from our lab demonstrated that nicotine, an agonist of nicotinic acetylcholine receptors (nAChRs), attenuated clinical symptoms of EAE mice (Gao et al, 2014). Nicotine-treated EAE mice presented reduced EAE clinical scores, decreased inflammation, and significantly less demyelination in the WM of spinal cord.…”

“…Nicotine-treated EAE mice presented reduced EAE clinical scores, decreased inflammation, and significantly less demyelination in the WM of spinal cord. The mechanism of nicotine’s effects involved inhibition of microglia activation and differentiation(Gao et al, 2014). However, results from recent studies suggested that protective roles of nicotine on MS/EAE might not only rely on suppressing microglia activity or inflammation.…”