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Cotinine: a potential new therapeutic agent against Alzheimer's disease.¡¡¥³¥Á¥Ë¥ó¡Ê¥Ë¥³¥Á¥ó¤ÎÀ¸À®Êª¡Ë¡§¥¢¥ë¥Ä¥Ï¥¤¥Þ¡¼É¤ËÂФ¹¤ëÀøºßŪ¤Ê¿·¤·¤¤¼£ÎÅÌô¡£

CNS Neurosci Ther¡£ 2012 Jul; 18
ÊÆ¹ñ¹ñΩ°å³Ø¿Þ½ñ´Û National Institutes of Health
Author information¡¡Echeverria V1, Zeitlin R.
Abstract
Tobacco smoking has been correlated with a lower incidence of Alzheimer's disease (AD). This negative correlation has been attributed to nicotine's properties. 

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In this review, we discuss evidence showing that cotinine, the main metabolite of nicotine, has many of the beneficial effects but none of the negative side-effects of its precursor. 

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Cotinine has been shown to be neuroprotective, to improve memory in primates as well as to prevent memory loss, and to lower amyloid-beta (A¦Â)) burden in AD mice. 

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In AD, cotinine's positive effect on memory is associated with the inhibition of A¦Â aggregation, the stimulation of pro-survival factors such as Akt, and the inhibition of pro-apoptotic factors such as glycogen synthase kinase 3 beta (GSK3¦Â). 

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Because stimulation of the ¦Á7 nicotinic acetylcholine receptors (¦Á7nAChRs) positively modulates these factors and memory, the involvement of these receptors in cotinine's effects are discussed. 

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Because of its beneficial effects on brain function, good safety profile, and nonaddictive properties, cotinine may represent a new therapeutic agent against AD.
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Beneficial effects of nicotine, cotinine and its metabolites as potential agents for Parkinson's disease
Front Aging Neurosci ¡¡Á°ÊýÏ·²½¿À·Ð³Ø ¡£
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George E. Barreto 

Parkinson's disease (PD) is a progressive neurodegenerative disorder, which is characterized by neuroinflammation, dopaminergic neuronal cell death and motor dysfunction, and for which there are no proven effective treatments.The negative correlation between tobacco consumption and PD suggests that tobacco-derived compounds can be beneficial against PD.Nicotine, the more studied alkaloid derived from tobacco, is considered to be responsible for the beneficial behavioral and neurological effects of tobacco use in PD.¡ÊÃæÎ¬¡ËCurrent evidence shows that nicotine, and some of its derivatives diminish oxidative stress and neuroinflammation in the brain and improve synaptic plasticity and neuronal survival of dopaminergic neurons.In vivo these effects resulted in improvements in mood, motor skills and memory in subjects suffering from PD pathology.In this review, we discuss the potential benefits of nicotine and its derivatives for treating PD.

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Introduction
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Parkinson's disease (PD) is the second most common neurodegenerative illness after Alzheimer's disease (AD), and reaches a prevalence of 3% after 65 years of age .Parkinson's disease is characterized by the presence of Lewy bodies, mainly composed of alpha-synuclein fibrils, a depletion of dopamine (DA)-generating neurons in substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) regions of the brain , that results in a decrease of DA levels in the striatum and frontal cortex regions of the brain (Thompson et al., 2005 The cause of death of dopaminergic neurons is still a mystery;however, actual evidence is consistent with the idea that oxidative stress, mitochondrial dysfunction and neuroinflammation are the main factors involved in the etiology of PD ¡¡It has been proposed that various genetic and environmental factors causing mitochondrial dysfunction result in abnormal accumulation of miscoded proteins and the generation of oxidative stress in the brain of subjects with PD 

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Nicotine and its derivatives as therapeutic agents against Parkinson's disease
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In spite of over almost 200 years passed from its discovery, there are no drugs available to slow down or stop the progression of PD (Connolly and Lang, 2014 ).Motor symptoms in PD can be improved by N-methyl-NMDA blockers as well as using dopaminergic and anticholinergic compounds.However, the cognitive deficits are not substantially improved by the current therapeutic interventions (Lorenz et al., 2014 ).Furthermore, the most used anti-PD drug, levodopa, produces severe toxic effects such as restlessness, mental impairment, mood changes, and after prolonged use (3–5 years), dyskinesia (Simuni and Sethi, 2008 ).For this reason, the development of potential new therapeutic approaches is imperative¡ÊÃæÎ¬¡Ë.

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Nicotinic acetylcholine receptors regulate synaptic transmission and synaptic plasticity, in several regions of the brain including the midbrain DA centers.These receptors are ligand-gated Ca 2+ , Na + and K + channels, whose activation causes membrane depolarization and the increase of both intraneuronal calcium levels and neurotransmitter release probability.At the postsynaptic sites the activation of the nAChRs also stimulates cell signaling pathways promoting the expression of synaptic proteins mediating, at cellular level, higher cognitive functions such as attention, learning and memory and other cognitive functions (McKay et al., 2007 ).Furthermore, it has been shown that nAChRs activation prevents neurodegeneration by mechanisms involving the activation of pro-survival signaling factors such as phosphatidylinositol 3-kinase (PI3K), Akt and Bcl proteins in the brain (Kawamata and Shimohama, 2011 ).¡ÊÃæÎ¬¡ËAcetylcholine by stimulating the ¦Á7nAChR inhibits the activity of the pro-inflammatory neurothrophic factor kappa B (NF¦ÊB) in human macrophages and consequently the expression and release of cytokines such as the tumor necrosis factor (TNF) by these immune cells (Balakumar and Kaur, 2009 ).¡ÊÃæÎ¬¡Ë

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Several epidemiological studies have shown that tobacco users have a lower incidence or severity of PD (Baron, 1996 ).A meta-analysis of four cohorts and 44 single-subject studies, showed a 40% decrease of risk of developing PD for smokers when compared to never smokers (Hernán et al., 2002 ).Together with smoking, other natural products such as caffeine have shown to be preventative against PD.In one of these studies (Hernán et al., 2002 ), the epidemiological evidence on the association between cigarette smoking, coffee drinking, and the odds of developing PD was reviewed.Results for smoking were calculated based on 44 case-control and four cohort studies, and for coffee on eight case-control and five cohort studies.Compared with never smokers, the relative risk of PD was 0.59 for ever smokers, 0.80 for past smokers, and 0.39 for current smokers.Compared with non-exposed to caffeine controls, relative risk of PD was 0.69 for coffee drinkers.This meta-analysis showed strong epidemiological evidence supporting that in addition to nicotine also caffeine decreased the risk of PD (Chen et al., 2010 ).These findings have been confirmed by several large prospective studies for either coffee or cigarette consumption.Interestingly, other caffeine-containing beverages, such as black tea and Japanese and Chinese teas also reduced PD risk.¡ÊÃæÎ¬¡ËA case-control study assessed the relationship between the ability to quit smoking and nicotine substitute use, in 1808 patients with PD and 1876 sex and age matched controls (Ritz et al., 2014 ).Data from this study revealed that PD patients quit smoking more easily than controls.The authors suggested that this finding was the result of a decreased sensitivity to nicotine in PD patients.Furthermore, they proposed that superior ability to quit smoking is an early sign of PD, similar to constipation, olfactory dysfunction, and sleep disorders.They also suggested that the positive effect of smoking revealed by epidemiologic studies was the result of reverse causation and not a protective effect of nicotine per se .Albeit an interesting observation, newly published evidence, in agreement with previous studies, strongly supports the view that smoking was neuroprotective against PD.The analysis of longitudinal data from 305,468 participants of the NIH-AARP Diet and Health cohort, of whom 1662 had a PD diagnosis, clearly showed that the number of cigarettes and years of smoking inversely and significantly correlated with diminished odds of developing PD.Compared with non-smokers, the odds ratios were 0.78 for past smokers and 0.56 for current smokers.Furthermore, the time of smoking was linked to a lower risk of developing PD.When compared with non-smokers, the odds ratio among past smokers decreased with the smoking duration.Thus, the odds ratio for those who smoked more than 20 cigarettes per day per 1–9, 10–19, 20–29 and 30 years were 0.96, 0.78, 0.64 and 0.59, respectively.These studies strongly suggest that caffeine and nicotine are neuroprotective.

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About the mechanism of neuroprotection, in addition to the mechanisms discussed, a new hypothesis proposes that both cigarette and coffee exert their effects by a completely different mechanism.The hypothesis states that tobacco and caffeine both exert their effects by changing the composition of the microbiota in the gut and consequently reducing intestinal inflammation since pro-inflammatory cytokines are also produced by enteric glial cells (EGC) in the gut (Derkinderen et al., 2014 ).According to this hypothesis, inflammation would promote ¦Á-synuclein aggregation within enteric neurons (EN).The aggregated protein thus may spread to the central nervous system via the vagal preganglionic innervation of the gut and the dorsal motor nucleus of the vagus (DMNV)After several years, the LC and the SN will become affected.Thus, the decrease of inflammation induced by nicotine and caffeine will decrease ¦Á-synuclein aggregation in enteric nerves, and its propagation to the brain.This effect will reduce neurodegeneration and reduce the risk of PD.

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The neuroprotective effect derived from a general reduction of systemic inflammation is an interesting idea that merit further investigation.Certainly, we consider reasonable to propose that the anti-inflammatory effects of nicotine and nicotine-derived compounds is a key contributor to their neuroprotective effects in the brain.The neuroprotective effect of tobacco has been mainly attributed to nicotine, a naturally occurring alkaloid from tobacco that consistently showed beneficial pro-cognitive effects in cellular and animal models of PD (Parain et al., 2003 ).The positive effect of nicotine on motor coordination and behavior has been attributed to its ability to increase DA availability and reduce the production of reactive oxygen species.Although, the detailed mechanism of neuroprotection is not well understood, the activation of nAChRs is considered the main mechanism of action of nicotine against PD (Budzianowski, 2013 ).¡ÊÃæÎ¬¡ËThese results are coherent with the idea that nicotine may prevent PD by stimulating the expression of neuroprotective signaling factors in the brain.

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