Neuroprotective effect of nicotine on dopaminergic neurons by anti‐inflammatory action

Abstract

Epidemiological studies have reported that smoking is associated with a lower incidence of Parkinson's disease (PD), leading to theories that smoking in general and nicotine in particular might be neuroprotective. Recent studies suggested cholinergic antiinflammatory pathway-regulating microglial activation through a7 nicotinic receptors. In the present study, we used lipopolysaccharide (LPS)-induced in vitro and in vivo inflammation models to investigate whether nicotine has a protective effect on the dopaminergic system through an anti-inflammatory mechanism. Nicotine pretreatment considerably decreased microglial activation with significant reduction of tumour necrosis factor (TNF)-a mRNA expression and TNF-a release induced by LPS stimulation. In co-cultures of microglia and mesencephalic neurons, nicotine pretreatment significantly decreased the loss of tyrosine hydroxylase-immunopositive (TH-ip) cells, approximately twice more than the LPS-only treatment. a-Bungarotoxin, an a7 nicotinic acetylcholine receptor subunit-selective blocker, considerably blocked the inhibitory effects of nicotine on microglial activation and TH-ip neuronal loss. Chronic nicotine pretreatment in rats showed that TH-ip neuronal loss induced by LPS stimulation in the substantia nigra was dramatically decreased, which was clearly accompanied by a reduction in the formation of TNF-a. The present study demonstrated that nicotine has a neuroprotective effect on dopaminergic neurons via an anti-inflammatory mechanism mediated by the modulation of microglial activation. Along with various neuroprotective effects of nicotine, the anti-inflammatory mechanism of nicotine could have a major therapeutic implication in the preventive treatment of PD.

Understanding the Bases of Function and Modulation of α7 Nicotinic Receptors: Implications for Drug Discovery

“…A brain cholinergic pathway also exists that regulates microglial activation through a7 (Shytle et al, 2004). This pathway is crucial for neuroprotection (Park et al, 2007) and is probably important in Parkinson disease (Stuckenholz et al, 2013), oxygen and glucose deprivation (Parada et al, 2013), and global ischemia (Guan et al, 2015). Therefore, a7 nAChR is emerging as an important drug target for the modulation of inflammation in different pathologic contexts, including sepsis, ischemia/reperfusion, rheumatoid arthritis, and pancreatitis.…”

Nicotinic Acetylcholine Receptor Signalling: Roles in Alzheimer's Disease and Amyloid Neuroprotection

“…tion of both with ␣-BTX does lead to neuroprotection, suggesting that TNF␣ and nicotine protect through antagonistic pathways (Carlson et al, 1998;Gahring et al, 2003). Nicotine may regulate the neuroprotective secretion of TNF␣ by microglia through enhancement of lowlevel TNF secretion and suppression of lipopolysaccharide-induced TNF␣ secretion (Suzuki et al, 2006;Park et al, 2007) via ␣7-dependent activation of JNK and MAPK pathways.…”

Idiopathic Parkinson's Disease, Vascular Risk Factors and Cognition: A Critical Review

“…Moreover, the study of Park et al (2007) with microglia cultures demonstrated that nicotine had a neuroprotective effect on DA neurons due to an anti-inflammatory action. Supporting the results of animal studies, Kelton et al (2000) reported improvements in reaction time, central processing speed and tracking in 15 non-demented PD patients after they received an acute administration of nicotine (phase I).…”