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Beneficial Effects of Nicotine, Cotinine and Its Metabolites As Potential REVIEW ARTICLE published: 09 January 2015 AGING NEUROSCIENCE doi: 10.3389/fnagi.2014.00340 Beneficial effects of nicotine, cotinine and its metabolites as potential agents for Parkinson’s disease George E. Barreto 1*, Alexander Iarkov 2,3 and Valentina Echeverria Moran 2,3,4,5* 1 Department of Nutrition and Biochemistry, Pontificia Universidad Javeriana, Bogotá, D.C., Colombia 2 Center of Research in Biomedical Sciences, Universidad Autónoma de Chile, Santiago, Chile 3 Research & Development Service, Bay Pines VA Healthcare System, Bay Pines, FL, USA 4 Research Service, James A Haley Veterans’ Hospital, Tampa, FL, USA 5 Department of Molecular Medicine, Morsani College of Medicine, University of South, Tampa, FL, USA Edited by: Parkinson’s disease (PD) is a progressive neurodegenerative disorder, which is P.Hemachandra Reddy, Texas Tech characterized by neuroinflammation, dopaminergic neuronal cell death and motor University, USA dysfunction, and for which there are no proven effective treatments. The negative Reviewed by: Hui Wang, Children’s National correlation between tobacco consumption and PD suggests that tobacco-derived Medical Center, USA compounds can be beneficial against PD. Nicotine, the more studied alkaloid derived from Stefano Delli Pizzi, University “G. tobacco, is considered to be responsible for the beneficial behavioral and neurological d’Annunzio” of Chieti-Pescara, Italy effects of tobacco use in PD. However, several metabolites of nicotine, such as cotinine, *Correspondence: also increase in the brain after nicotine administration. The effect of nicotine and some George E. Barreto, Department of Nutrition and Biochemistry, of its derivatives on dopaminergic neurons viability, neuroinflammation, and motor and Pontificia Universidad Javeriana, memory functions, have been investigated using cellular and rodent models of PD. Current Carrera 7 No. 40-62, Bogotá, evidence shows that nicotine, and some of its derivatives diminish oxidative stress and D. C., Colombia neuroinflammation in the brain and improve synaptic plasticity and neuronal survival of e-mail: [email protected]; Valentina Echeverria Moran, dopaminergic neurons. In vivo these effects resulted in improvements in mood, motor Research & Development Service, skills and memory in subjects suffering from PD pathology. In this review, we discuss the Bay Pines VA Healthcare System, potential benefits of nicotine and its derivatives for treating PD. 10,000 Bay Pines Blvd., Bay Pines, FL 33744, USA Keywords: Akt (PKB), synucleinopathies, beta-amyloid, cotinine, nicotine, Parkinson disease e-mail: echeverria.valentina@ gmail.com INTRODUCTION (Thompson et al., 2005). Parkinson’s disease affects cognitive and Parkinson’s disease (PD) is the second most common neurode- motor abilities (Riedel et al., 2014), and progressively impairs generative illness after Alzheimer’s disease (AD), and reaches sleep (Dos Santos et al., 2014), attention, and short-term memory, a prevalence of 3% after 65 years of age (Jellinger, 2003). as well as visuospatial and executive functions (Liu et al., 2012; Parkinson’s disease is predominantly sporadic, and rarely familial. Conte et al., 2013; Rottschy et al., 2013; Zokaei et al., 2014). The The familial form of the disease can develop due to single genetic dopaminergic deficit observed in PD patients seems to underlie mutations (Dexter and Jenner, 2013). Parkinson’s disease is char- the motor impairment symptoms such as hypokinesia, tremor acterized by the presence of Lewy bodies, mainly composed of and rigidity (Murer and Moratalla, 2011). alpha-synuclein fibrils, a depletion of dopamine (DA)-generating The cause of death of dopaminergic neurons is still a mystery; neurons in substantia nigra pars compacta (SNc) and ventral however, actual evidence is consistent with the idea that oxida- tegmental area (VTA) regions of the brain (Wirths and Bayer, tive stress, mitochondrial dysfunction and neuroinflammation 2003; Dexter and Jenner, 2013), that results in a decrease of DA are the main factors involved in the etiology of PD (Büeler, levels in the striatum and frontal cortex regions of the brain 2010; Zuo and Motherwell, 2013; Camilleri and Vassallo, 2014; Celardo et al., 2014). It has been proposed that various genetic Abbreviations: Ab, beta-amyloid; AChE, acetylcholinesterase; AD, and environmental factors causing mitochondrial dysfunction Alzheimer’s disease; Akt (PKB), protein kinase B; DA, Dopamine; DMXBA, result in abnormal accumulation of miscoded proteins and the 3-(2,4-dimethoxy) benzylidene-anabaseine dihydrochloride; FPD, familial generation of oxidative stress in the brain of subjects with PD PD; GSK3b, glycogen synthase kinase 3b; FS, forced swim; iNOS, the (Bové and Perier, 2012; Cabezas et al., 2012, 2014; Perier and Vila, inducible nitric oxide synthase; MAOIs, monoamine oxidase inhibitors; MT, 2012; Dexter and Jenner, 2013; Trinh and Farrer, 2013; Zuo and metallothionein; NFkB, neurothrophic factor kappa B; nAChRs, nicotinic Motherwell, 2013; Figure 1). acetylcholine receptors; NMDA, N-methyl-D-aspartate; PAM, positive Mild cognitive impairment later progressing to dementia is allosteric modulator; PD, Parkinson’s disease; PI3K, phosphatidylinositol 3-kinase; PIB, Pittsburgh compound B; PSD95, postsynaptic density protein commonly found in patients with PD (Aarsland et al., 2010; Hu 95; SNc, substancia nigra pars compacta; TNF, tumor necrosis factor; VTA, et al., 2014). Dementia develops in approximately 80% of PD ventral tegmental area. patients after 20 years with the condition (Cummings, 1988a,b; Frontiers in Aging Neuroscience www.frontiersin.org January 2015 | Volume 6 | Article 340 | 1 Barreto et al. Nicotine and derivatives for Parkinson’s disease FIGURE 1 | Potential etiological factors of Parkinson’s disease. reduced ATP generation and increased levels of reactive oxygen Current evidence suggests that environmental factors and genetic risk species. Also, abnormal release of cytochrome C from damaged factors provoking oxidative stress, excitotoxicity and mitochondrial mitochondria can trigger the activation of the apoptotic signaling dysfunction in the brain can lead to the degeneration of the midbrain cascades and the release of caspases, resulting in neuronal cell death. dopaminergic system, resulting in PD. In PD, the generation of protein The generation of free radicals may then result in further damage to aggregates may disrupt the mitochondrial membrane potential and cellular macromolecules and organelles through nitrosylation, oxidation, 2 induce abnormal Ca + influx, impaired respiratory enzyme activities, and peroxidation, directly contributing to neuronal injury. Hughes et al., 2000). New evidence also suggests that the level (Cabezas et al., 2012). Also as mentioned above abnormal aggre- of alpha-synuclein in the cerebral spine fluid can predict the gation and/or mutation of proteins such as beta amyloid, DJ- progression of cognitive decline but not of motor dysfunction 1, PTEN-induced putative kinase 1, parkin, leucine-rich repeat in PD (Stewart et al., 2014). Dementia in PD is also associated kinase 2 and a-synuclein have been observed in PD (el-Agnaf with the accumulation in the central nervous system of pro- and Irvine, 2002; Nunomura et al., 2007; Alcalay et al., 2009). tein aggregates such as b-amyloid peptide (Ab) also present in Families with autosomal dominant early-onset of familial PD other neurological conditions such as AD (Mandal et al., 2006; (FPD) commonly present mutations in the a-synuclein gene Kalaitzakis et al., 2008). The analysis of 30 PD cases from the A53T, A30P and E46K that accelerate a-synuclein aggregation United kingdom PD’s society showed that Ab deposition in the (Corti et al., 2011; Roth, 2014). In addition to protein mutations, striatum strongly correlated with dementia in humans suggesting environmental factors such as pesticides, ethanol consumption, that this accumulation is a contributing factor for the devel- metals and the accumulation of somatic mitochondrial DNA opment of cognitive impairment and neurodegeneration in this mutations have been observed in the SNc during aging and PD condition (Mandal et al., 2006; Kalaitzakis et al., 2008). Subjects (Zuo and Motherwell, 2013) that may negatively affect brain with PD and dementia show degeneration of several subcortical homeostasis leading to neurodegeneration (Perez et al., 2010; nuclei, including the cholinergic nucleus basalis of Meynert, the Perfeito et al., 2013; Roth, 2014). Protein aggregation may dis- medial SN, and the noradrenergic locus coeruleus (LC; Shin et al., rupt the mitochondrial membrane potential, impair respiratory 2012). It has been postulated that the presence of secondary enzyme activities and result in reduced ATP generation, energy 2 neuropathologies may further increase oxidative stress, decrease deficits and increased levels of reactive oxygen species (O − brain energy and enhance the degenerative process in the brain and H2O2). In fact, energetic and antioxidant compounds are of subjects with PD (Sasaki et al., 1992; Kurosinski et al., 2002; considered to have beneficial effects against PD (Klein and Fer- Slawek et al., 2008). rante, 2007; Sutachan et al., 2012). In turn, oxidative stress can also affect protein degradation by deteriorating the ubiquitin- OXIDATIVE STRESS, NEUROINFLAMMATION, PROTEIN proteasome system (Díaz et al., 2010; Perfeito et al., 2013). AGGREGATION AND BRAIN ENERGY DEFICITS IN Furthermore, the release of cytochrome C from damaged mito- PARKINSON’S DISEASE
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