Búsqueda de nuevos análogos sintéticos de flavonoides y nicotina que promuevan la dendritogénesis: Mecanismos de acción y relación estructura-actividad

Las neuronas tienen una alta capacidad de adaptarse en respuesta a cambios en el ambiente y la actividad neuronal. Parte de esta plasticidad esta mediada por las dendritas que son las estructuras que reciben y procesan los “inputs” neuronales. Durante el desarrollo las dendritas son altamente dinámicas y responden retrayéndose y expandiéndose en respuesta a señales extrínsecas y del ambiente.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/s41467-018-05871-5","ISSN":"2041-1723","abstract":"Highly motile dendritic protrusions are hallmarks of developing neurons. These exploratory filopodia sample the environment and initiate contacts with potential synaptic partners. To understand the role for dynamic filopodia in dendrite morphogenesis and experience-dependent structural plasticity, we analyzed dendrite dynamics, synapse formation, and dendrite volume expansion in developing ventral lateral neurons (LNvs) of the Drosophila larval visual circuit. Our findings reveal the temporal coordination between heightened dendrite dynamics with synaptogenesis in LNvs and illustrate the strong influence imposed by sensory experience on the prevalence of dendritic filopodia, which regulate the formation of synapses and the expansion of dendritic arbors. Using genetic analyses, we further identified Amphiphysin (Amph), a BAR (Bin/Amphiphysin/Rvs) domain-containing protein as a required component for tuning the dynamic state of LNv dendrites and promoting dendrite maturation. Taken together, our study establishes dynamic filopodia as the key cellular target for experience-dependent regulation of dendrite development.","author":[{"dropping-particle":"","family":"Sheng","given":"Chengyu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Javed","given":"Uzma","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gibbs","given":"Mary","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Long","given":"Caixia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yin","given":"Jun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Qin","given":"Bo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yuan","given":"Quan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nature communications","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2018","8","22"]]},"language":"eng","page":"3362","publisher":"Nature Publishing Group UK","title":"Experience-dependent structural plasticity targets dynamic filopodia in regulating dendrite maturation and synaptogenesis","type":"article-journal","volume":"9"},"uris":["http://www.mendeley.com/documents/?uuid=6c23c7b8-9190-41dc-81a7-d18c4b399c4e"]},{"id":"ITEM-2","itemData":{"DOI":"10.1242/dev.171397","abstract":"The formation of neuronal dendrite branches is fundamental for the wiring and function of the nervous system. Indeed, dendrite branching enhances the coverage of the neuron's receptive field and modulates the initial processing of incoming stimuli. Complex dendrite patterns are achieved in vivo through a dynamic process of de novo branch formation, branch extension and retraction. The first step towards branch formation is the generation of a dynamic filopodium-like branchlet. The mechanisms underlying the initiation of dendrite branchlets are therefore crucial to the shaping of dendrites. Through in vivo time-lapse imaging of the subcellular localization of actin during the process of branching of Drosophila larva sensory neurons, combined with genetic analysis and electron tomography, we have identified the Actin-related protein (Arp) 2/3 complex as the major actin nucleator involved in the initiation of dendrite branchlet formation, under the control of the activator WAVE and of the small GTPase Rac1. Transient recruitment of an Arp2/3 component marks the site of branchlet initiation in vivo. These data position the activation of Arp2/3 as an early hub for the initiation of branchlet formation.","author":[{"dropping-particle":"","family":"Stürner","given":"Tomke","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tatarnikova","given":"Anastasia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mueller","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schaffran","given":"Barbara","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cuntz","given":"Hermann","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Yun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nemethova","given":"Maria","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bogdan","given":"Sven","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Small","given":"Vic","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tavosanis","given":"Gaia","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Development","id":"ITEM-2","issue":"7","issued":{"date-parts":[["2019","4","1"]]},"page":"dev171397","title":"Transient localization of the Arp2/3 complex initiates neuronal dendrite branching in vivo","type":"article-journal","volume":"146"},"uris":["http://www.mendeley.com/documents/?uuid=45762905-68c7-481c-a9d6-8ef653e98d1e"]}],"mendeley":{"formattedCitation":"1,2","plainTextFormattedCitation":"1,2","previouslyFormattedCitation":"1,2"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}1,2 En contraste, en el cerebro adulto las dendritas son estables y tienden a cambiar muy poco durante periodos prolongados de tiempo, fenómeno que ha sido asociado a la estabilidad que necesita el cerebro adulto para funcionar.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Koleske","given":"Anthony J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nature Reviews Neuroscience","id":"ITEM-1","issued":{"date-parts":[["2013","7","10"]]},"page":"536","publisher":"Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.","title":"Molecular mechanisms of dendrite stability","type":"article-journal","volume":"14"},"uris":["http://www.mendeley.com/documents/?uuid=04247693-3a43-4fc5-bd3a-0835dddcd7fb"]}],"mendeley":{"formattedCitation":"3","plainTextFormattedCitation":"3","previouslyFormattedCitation":"3"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}3 Sin embargo, en epilepsia,ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/j.1528-1167.2012.03482.x","abstract":"Summary Childhood epilepsy can be severe and even catastrophic. In these instances, cognition can be impaired—leading to long-term intellectual disabilities. One factor that could potentially cause cognitive deficits is the frequent seizures that characterize intractable epilepsy. However, it has been difficult to separate the effects seizures may have from those of preexisting neuropathologies and/or the effects of ongoing anticonvulsant therapies. Therefore, important questions are: Do early life seizures produce the learning deficits? And if they do, how do they do it? Results from recent animal models studies reviewed here show that recurrent seizures in infancy stop the growth of CA1 hippocampal dendrites. We speculate that the molecular mechanisms responsible for seizure-induced growth suppression are homeostatic/neuroprotective, used by the developing nervous system in an attempt to limit neuronal and network excitability and prevent the continued generation of seizures. However, by preventing the normal growth of dendrites, there is a reduction in CA1 glutamatergic synapses that supports long-lasting forms of synaptic plasticity thought to be the cellular basis of learning and memory. Therefore, dendrite growth suppression would reduce the neuroanatomic substrates for learning and memory, and in so doing could contribute in important ways to spatial learning and memory deficits that may be relevant to the cognitive deficits associated with childhood epilepsy.","author":[{"dropping-particle":"","family":"Casanova","given":"Jose R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nishimura","given":"Masataka","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Owens","given":"James W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Swann","given":"John W","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Epilepsia","id":"ITEM-1","issue":"s1","issued":{"date-parts":[["2012"]]},"page":"116-124","title":"Impact of seizures on developing dendrites: Implications for intellectual developmental disabilities","type":"article-journal","volume":"53"},"uris":["http://www.mendeley.com/documents/?uuid=cb549409-b7de-4f98-b4c4-55c461aca73e"]}],"mendeley":{"formattedCitation":"4","plainTextFormattedCitation":"4","previouslyFormattedCitation":"4"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}4 isquemiaADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.neuroscience.2006.01.039","ISSN":"03064522","abstract":"Dendrites and spines undergo dynamic changes in physiological conditions, such as learning and memory, and in pathological conditions, such as Alzheimer's disease and epilepsy. Long-term dendritic plasticity has also been reported after ischemia/hypoxia, which might be compensatory effects of surviving neurons for the functional recovery after the insults. However, the dendritic changes shortly after ischemia, which might be associated with the pathogenesis of ischemic cell death, remain largely unknown. To reveal the morphological changes of ischemia-vulnerable neurons after ischemia, the present study investigated the alteration of dendritic arborization of CA1 pyramidal neurons in rats after transient cerebral ischemia using intracellular staining technique in vivo. The general appearance of dendritic arborization of CA1 neurons within 48 h after ischemia was similar to that of control neurons. However, a dramatic increase of dendritic disorientation was observed after ischemia with many basal dendrites coursed into the territory of apical dendrites and apical dendrites branched into the region of basal dendrites. In addition, a significant increase of apical dendritic length was found 24 h after ischemia. The increase of dendritic length after ischemia was mainly due to the dendritic sprouting rather than the extension of individual dendrites, which mainly occurred in the middle segment of the apical dendrites. These results reveal a plasticity change in dendritic arborization of CA1 neurons shortly after cerebral ischemia. © 2006 IBRO.","author":[{"dropping-particle":"","family":"Ruan","given":"Y. W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zou","given":"B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fan","given":"Y.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Li","given":"Y.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lin","given":"N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zeng","given":"Y. S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gao","given":"T. M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yao","given":"Z.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Xu","given":"Z. C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Neuroscience","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2006"]]},"page":"191-201","title":"Dendritic plasticity of CA1 pyramidal neurons after transient global ischemia","type":"article-journal","volume":"140"},"uris":["http://www.mendeley.com/documents/?uuid=0f8f2c38-e3db-4c4f-b2c0-09b46d1b4fb6"]}],"mendeley":{"formattedCitation":"5","plainTextFormattedCitation":"5","previouslyFormattedCitation":"5"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}5 y algunas enfermedades neurodegenerativasADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.5483/BMBRep.2017.50.1.131","ISSN":"1976670X","abstract":"One of the characteristics of the neurons that distinguishes them from other cells is their complex and polarized structure consisting of dendrites, cell body, and axon. The complexity and diversity of dendrites are particularly well recognized, and accumulating evidences suggest that the alterations in the dendrite structure are associated with many neurodegenerative diseases. Given the importance of the proper dendritic structures for neuronal functions, the dendrite pathology appears to have crucial contribution to the pathogenesis of neurodegenerative diseases. Nonetheless, the cellular and molecular basis of dendritic changes in the neurodegenerative diseases remains largely elusive. Previous studies in normal condition have revealed that several cellular components, such as local cytoskeletal structures and organelles located locally in dendrites, play crucial roles in dendrite growth. By reviewing what has been unveiled to date regarding dendrite growth in terms of these local cellular components, we aim to provide an insight to categorize the potential cellular basis that can be applied to the dendrite pathology manifested in many neurodegenerative diseases. [BMB Reports 2017; 50(1): 5-11]","author":[{"dropping-particle":"","family":"Kweon","given":"Jung Hyun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Sunhong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Sung Bae","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"BMB Reports","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2017"]]},"page":"5-11","title":"The cellular basis of dendrite pathology in neurodegenerative diseases","type":"article-journal","volume":"50"},"uris":["http://www.mendeley.com/documents/?uuid=cd3dcdc3-0166-4842-aa03-fef525ddf120"]}],"mendeley":{"formattedCitation":"6","plainTextFormattedCitation":"6","previouslyFormattedCitation":"6"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}6 y mentalesADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Forrest","given":"Marc P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parnell","given":"Euan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Penzes","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nature Reviews Neuroscience","id":"ITEM-1","issued":{"date-parts":[["2018","3","16"]]},"page":"215","publisher":"Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.","title":"Dendritic structural plasticity and neuropsychiatric disease","type":"article-journal","volume":"19"},"uris":["http://www.mendeley.com/documents/?uuid=147ed6ce-7812-47ce-875d-0111ffd1557f"]}],"mendeley":{"formattedCitation":"7","plainTextFormattedCitation":"7","previouslyFormattedCitation":"7"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}7 hay un remodelamiento dendrítico anormal que lleva a una reducción de la complejidad del árbol dendrítico,pérdida de espinas e interrupción en la integración y generación de potenciales de acción. Estos cambios estructurales y funcionales ocurrenen las primeras etapas de estas enfermedades y por consiguiente se ha sugerido que intervenir las deficiencias dendritogénicas pueden tener potencial terapéutico en la prevención o tratamiento de estas enfermedades. Figura 1. Efecto de la rutina sobre la complejidad del árbol dendrítico de neuronas corticales tratadas por 6 y 24 horas. **P>0.01 & ***P>0.001.. Se ha demostrado que los flavonoides,metabolitos secundarios de las plantas, no solo tienen capacidad antioxidante, sino que también pueden activar vías de señalización involucradas en los procesos de dendritogénesis y espinogénesis (plasticidad estructural).ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/BF02968247","ISSN":"02536269","abstract":"In last couple of decades the use of natural compounds like flavonoids as chemopreventive agents has gained much attention. Our current study focuses on identifying chemopreventive flavonoids and their mechanism of action on human prostate cancer cells. Human prostate cancer cells (PC3), stably transfected with activator protein 1 (AP-1) luciferase reporter gene were treated with four main classes of flavonoids namely flavonols, flavones, flavonones, and isoflavones. The maximum AP-1 luciferase induction of about 3 fold over control was observed with 20 ?M concentrations of quercetin, chrysin and genistein and 50 ?M concentration of kaempferol. At higher concentrations, most of the flavonoids demonstrated inhibition of AP-1 activity. The MTS assay for cell viability at 24 h showed that even at a very high concentration (500 ?M), cell death was minimal for most of the flavonoids. To determine the role of MAPK pathway in the induction of AP-1 by flavonoids, Western blot of phospho MAPK proteins was performed. Four out of the eight flavonoids namely kaempferol, apigenin, genistein and naringenin were used for the Western Blot analysis. Induction of phospho-JNK and phospho-ERK activity was observed after two hour incubation of PC3-AP1 cells with flavonoids. However no induction of phospho-p38 activity was observed. Furthermore, pretreating the cells with specific inhibitors of JNK reduced the AP-1 luciferase activity that was induced by genistein while pretreatment with MEK inhibitor reduced the AP-1 luciferase activity induced by kaempferol. The pharmacological inhibitors did not affect the AP-1 luciferase activity induced by apigenin and naringenin. These results suggest the possible involvement of JNK pathway in genistein induced AP-1 activity while the ERK pathway seems to play an important role in kaempferol induced AP-1 activity.","author":[{"dropping-particle":"","family":"Gopalakrishnan","given":"Avanthika","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Xu","given":"Chang Jiang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nair","given":"Sujit S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Chi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hebbar","given":"Vidya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kong","given":"Ah Ng Tony","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Archives of Pharmacal Research","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2006"]]},"page":"633-644","title":"Modulation of activator protein-1 (AP-1) and MAPK pathway by flavonoids in human prostate cancer PC3 cells","type":"article-journal","volume":"29"},"uris":["http://www.mendeley.com/documents/?uuid=10f5c185-339b-4e54-b570-0069894d874a"]},{"id":"ITEM-2","itemData":{"DOI":"10.1073/pnas.0607822103","ISSN":"0027-8424","abstract":"Small molecules that activate signaling pathways used by neurotrophic factors could be useful for treating CNS disorders. Here we show that the flavonoid fisetin activates ERK and induces cAMP response element-binding protein (CREB) phosphorylation in rat hippocampal slices, facilitates long-term potentiation in rat hippocampal slices, and enhances object recognition in mice. Together, these data demonstrate that the natural product fisetin can facilitate long-term memory, and therefore it may be useful for treating patients with memory disorders.","author":[{"dropping-particle":"","family":"Maher","given":"Pamela","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Akaishi","given":"Tatsuhiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Abe","given":"Kazuho","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Proceedings of the National Academy of Sciences","id":"ITEM-2","issue":"44","issued":{"date-parts":[["2006"]]},"page":"16568-16573","publisher":"National Academy of Sciences","title":"Flavonoid fisetin promotes ERK-dependent long-term potentiation and enhances memory","type":"article-journal","volume":"103"},"uris":["http://www.mendeley.com/documents/?uuid=0c801a74-7bdc-4c48-ad26-15d5b35e57ca"]},{"id":"ITEM-3","itemData":{"DOI":"10.1016/j.ejphar.2007.09.028","ISSN":"00142999","abstract":"Nobiletin isolated from citrus peels prevents bulbectomy- and amyloid-β protein-induced memory impairment in rodents. In the present study, using combined methods of biochemistry and electrophysiology, we examined the effects of nobiletin on phosphorylation of GluR1 receptor, the subunit of α-amino-3-hydroxy-5-methyl-d-aspartate (AMPA) receptors, and the receptor-mediated synaptic transmission in the hippocampus, a region implicated in memory formation, in culture and/or in slices. Western blot analysis showed that nobiletin-stimulated phosphorylation of multiple protein kinase A (PKA) substrates at 10 min following the treatment in cultured hippocampal neurons. In the cultured neurons, this natural compound also increased not only PKA activity, but also phosphorylation of GluR1 receptor at a PKA phosphorylation site, Ser 845, which has been demonstrated to be critical for synaptic plasticity, including enhancement of postsynaptic glutamate response, and important for spatial memory in vivo. The increased phosphorylation of GluR1 receptor at Ser 845 was abolished by H89 (N-(2-[p-bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide hydrochloride), the PKA inhibitor, but not U0126 (1,4-diamino-2,3-dicyano-1,4-bis (2-aminophenylthio) butadiene), the mitogen-activated protein kinase/ERK kinase (MEK) inhibitor, in the cultured neurons. An increment of the phosphorylation of GluR1 receptor at Ser 845 was induced by nobiletin in the hippocampal slices as well. Furthermore, our electrophysiological analysis showed that nobiletin potentiated the AMPA receptor-mediated synaptic transmission at Schaffer collateral-CA1 pyramidal cell synapses in the hippocampal slices. This potentiation induced by the natural compound was not accompanied by the changes in paired-pulse ratio, and partially occluded the long-term potentiation, indicating the possible involvement of the postsynaptic mechanism. These findings suggest that nobiletin probably up-regulates synaptic transmission via the postsynaptic AMPA receptors at least partially by stimulation of PKA-mediated phosphorylation of GluR1 receptor in the hippocampus. © 2007 Elsevier B.V. All rights reserved.","author":[{"dropping-particle":"","family":"Matsuzaki","given":"Kentaro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kenichi Miyazaki","given":"","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sakai","given":"Seiichiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yawo","given":"Hiromu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nakata","given":"Norihito","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moriguchi","given":"Shigeki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fukunaga","given":"Kohji","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yokosuka","given":"Akihito","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sashida","given":"Yutaka","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mimaki","given":"Yoshihiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yamakuni","given":"Tohru","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ohizumi","given":"Yasushi","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European Journal of Pharmacology","id":"ITEM-3","issue":"2-3","issued":{"date-parts":[["2008"]]},"page":"194-200","title":"Nobiletin, a citrus flavonoid with neurotrophic action, augments protein kinase A-mediated phosphorylation of the AMPA receptor subunit, GluR1, and the postsynaptic receptor response to glutamate in murine hippocampus","type":"article-journal","volume":"578"},"uris":["http://www.mendeley.com/documents/?uuid=6f531648-8cd8-49cb-9c52-21535359232d"]},{"id":"ITEM-4","itemData":{"DOI":"10.1155/2012/758097","ISSN":"1741-427X","abstract":" The flavonoid myricetin is found in several sedative herbs, for example, the St. John's Wort, but its influence on sedation and its possible mechanism of action are unknown. Using patch-clamp technique on a brain slice preparation, the present study found that myricetin promoted GABAergic activity in the neurons of hypothalamic paraventricular nucleus (PVN) by increasing the decay time and frequency of the inhibitory currents mediated by GABAA receptor. This effect of myricetin was not blocked by the GABAA receptor benzodiazepine- (BZ-) binding site antagonist flumazenil, but by KN-62, a specific inhibitor of the Ca 2+ /calmodulin-stimulated protein kinase II (CaMK-II). Patch clamp and live Ca 2+ imaging studies found that myricetin could increase Ca 2+ current and intracellular Ca 2+ concentration, respectively, via T- and L-type Ca 2+ channels in rat PVN neurons and hypothalamic primary culture neurons. Immunofluorescence staining showed increased phosphorylation of CaMK-II after myricetin incubation in primary culture of rat hypothalamic neurons, and the myricetin-induced CaMK-II phosphorylation was further confirmed by Western blotting in PC-12 cells. The present results suggest that myricetin enhances GABAA receptor activity via calcium channel/CaMK-II dependent mechanism, which is distinctively different from that of most existing BZ-binding site agonists of GABAA receptor. ","author":[{"dropping-particle":"","family":"Zhang","given":"Xiao Hu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ma","given":"Ze Gang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rowlands","given":"Dewi Kenneth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gou","given":"Yu Lin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fok","given":"Kin Lam","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wong","given":"Hau Yan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yu","given":"Mei Kuen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tsang","given":"Lai Ling","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mu","given":"Li","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Lei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yung","given":"Wing Ho","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chung","given":"Yiu Wa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Bei Lin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhao","given":"Hua","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chan","given":"Hsiao Chang","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Evidence-Based Complementary and Alternative Medicine","id":"ITEM-4","issued":{"date-parts":[["2012"]]},"page":"1-10","title":" Flavonoid Myricetin Modulates GABAA Receptor Activity through Activation of Ca2+ Channels and CaMK-II Pathway ","type":"article-journal","volume":"2012"},"uris":["http://www.mendeley.com/documents/?uuid=7b90fcd7-f226-4083-a8e3-9de295c6124d"]}],"mendeley":{"formattedCitation":"8–11","plainTextFormattedCitation":"8–11","previouslyFormattedCitation":"8–11"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}8–11 Adicionalmente, tienen baja toxicidad sobre células sanas y son capaces de atravesar la barrera hemato-encefálica,ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1046/j.1471-4159.2003.01652.x","ISSN":"00223042","abstract":"There is considerable current interest in the neuroprotective effects of flavonoids. This study focuses on the potential for dietary flavonoids, and their known physiologically relevant metabolites, to enter the brain endothelium and cross the blood-brain barrier (BBB) using well-established in vitro models (brain endothelial cell lines and ECV304 monolayers co-cultured with C6 glioma cells). We report that the citrus flavonoids, hesperetin, naringenin and their relevant in vivo metabolites, as well as the dietary anthocyanins and in vivo forms, cyanidin-3-rutinoside and pelargonidin-3-glucoside, are taken up by two brain endothelial cell lines from mouse (b.END5) and rat (RBE4). In both cell types, uptake of hesperetin and naringenin was greatest, increasing significantly with time and as a function of concentration. In support of these observations we report for the first time high apparent permeability (Papp) of the citrus flavonoids, hesperetin and naringenin, across the in vitro BBB model (apical to basolateral) relative to their more polar glucuronidated conjugates, as well as those of epicatechin and its in vivo metabolites, the dietary anthocyanins and to specific phenolic acids derived from colonic biotransformation of flavonoids. The results demonstrate that flavonoids and some metabolites are able to traverse the BBB, and that the potential for permeation is consistent with compound lipophilicity.","author":[{"dropping-particle":"","family":"Youdim","given":"Kuresh A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dobbie","given":"Michael S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kuhnle","given":"Gunter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Proteggente","given":"Anna R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Abbott","given":"N. Joan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rice-Evans","given":"Catherine","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Neurochemistry","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2003"]]},"page":"180-192","title":"Interaction between flavonoids and the blood-brain barrier: In vitro studies","type":"article-journal","volume":"85"},"uris":["http://www.mendeley.com/documents/?uuid=bbdf1f15-c587-4d6f-8639-f8180186f1ab"]}],"mendeley":{"formattedCitation":"12","plainTextFormattedCitation":"12","previouslyFormattedCitation":"12"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}12 lo que los hace candidatos promisorios en la prevención y tratamiento de enfermedades del sistema nervioso.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1021/jf204452y","ISSN":"00218561","abstract":"Recent attention has been given to the influence of dietary factors on health and mental well-being. Oxidative stress is associated with many diseases including neurodegenerative disorders. Dietary flavonoids exert cardioprotective, chemopreventive, and neuroprotective effects. The biological activities of flavonoids have been attributed to their antioxidant, anti-inflammatory, and signaling properties. A clear understanding of the mechanisms of action, as either antioxidants or signaling molecules, is crucial for the application of flavonoids as interventions in neurodegeneration and as brain foods. Citrus flavonoids exert little adverse effect and have low or no cytotoxicity to healthy, normal cells. The main citrus flavonoids can also traverse the blood-brain barrier; hence, they are promising candidates for intervention in neurodegeneration and as constituents in brain foods. In this review, we discuss the bioactivity, multiple neuroprotection mechanisms, and antioxidant and signaling properties of citrus flavonoids. Receptor-mediated neuroprotective actions and parallel signaling pathways are also explored. Finally, the induction of cellular defense proteins against oxidative stress and neurotoxicity by hesperetin, a main and widespread citrus flavonoid, are also discussed. It is suggested that citrus fruits, which are rich in abundant sources of hesperetin and other flavonoids, are promising for the development of general food-based neuroprotection and brain foods. © 2012 American Chemical Society.","author":[{"dropping-particle":"","family":"Hwang","given":"Sam Long","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shih","given":"Ping Hsiao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yen","given":"Gow Chin","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Agricultural and Food Chemistry","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2012"]]},"page":"877-885","title":"Neuroprotective effects of citrus flavonoids","type":"article-journal","volume":"60"},"uris":["http://www.mendeley.com/documents/?uuid=90aac37c-74a6-4857-96b7-e953e0ad5ffb"]}],"mendeley":{"formattedCitation":"13","plainTextFormattedCitation":"13","previouslyFormattedCitation":"13"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}13 Estudios recientes de nuestros grupos han mostrado que el flavonol rutina tiene la capacidad de inducir un aumento del árbol dendrítico de neuronas corticales in vitro (Figura 1) a través de un mecanismo que involucra flujo de calcio extracelular, activación de la vía de las MAP quinasas y receptores AMPA. Similar a la rutina, otros flavonoides pueden activar vías similares de señalización, lo que permite realizar estudios de correlación entre estructura, actividad y mecanismos de acción. Por otra parte, también se conoce que la nicotina ejerce efectos benéficos en pacientes con enfermedades como Parkinson,ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1021/jacs.6b08856","ISBN":"0002-7863\\r1520-5126","ISSN":"15205126","PMID":"27631602","abstract":"This Perspective illustrates the defining characteristics of free radical chemistry beginning with its rich and storied history. Studies from our laboratory are discussed along with recent developments emanating from others in this burgeoning area. The practicality and chemoselectivity of radical reactions enables rapid access to molecules of relevance to drug discovery, agrochemistry, materials science, and other disciplines. Thus, these reactive intermediates possess inherent translational potential as they can be widely used to expedite scientific endeavors for the betterment of mankind.","author":[{"dropping-particle":"","family":"Yan","given":"Ming","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lo","given":"Julian C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Edwards","given":"Jacob T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Baran","given":"Phil S.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American Chemical Society","id":"ITEM-1","issue":"39","issued":{"date-parts":[["2016"]]},"page":"12692-12714","title":"Radicals: Reactive Intermediates with Translational Potential","type":"article-journal","volume":"138"},"uris":["http://www.mendeley.com/documents/?uuid=65808461-f687-4fb8-9636-e7172d0d7081"]},{"id":"ITEM-2","itemData":{"DOI":"https://doi.org/10.1016/j.bcp.2015.06.014","ISSN":"0006-2952","abstract":"Accumulating evidence suggests that CNS α7 nicotinic acetylcholine receptors (nAChRs) are important targets for the development of therapeutic approaches for Parkinson's disease. This progressive neurodegenerative disorder is characterized by debilitating motor deficits, as well as autonomic problems, cognitive declines, changes in affect and sleep disturbances. Currently l-dopa is the gold standard treatment for Parkinson's disease motor problems, particularly in the early disease stages. However, it does not improve the other symptoms, nor does it reduce the inevitable disease progression. Novel therapeutic strategies for Parkinson's disease are therefore critical. Extensive pre-clinical work using a wide variety of experimental models shows that nicotine and nAChR agonists protect against damage to nigrostriatal and other neuronal cells. This observation suggests that nicotine and/or nAChR agonists may be useful as disease modifying agents. Additionally, studies in several parkinsonian animal models including nonhuman primates show that nicotine reduces l-dopa-induced dyskinesias, a side effect of l-dopa therapy that may be as incapacitating as Parkinson's disease itself. Work with subtype selective nAChR agonists indicate that α7 nAChRs are involved in mediating both the neuroprotective and antidyskinetic effects, thus offering a targeted strategy with optimal beneficial effects and minimal adverse responses. Here, we review studies demonstrating a role for α7 nAChRs in protection against neurodegenerative effects and for the reduction of l-dopa-induced dyskinesias. Altogether, this work suggests that α7 nAChRs may be useful targets for reducing Parkinson's disease progression and for the management of the dyskinesias that arise with l-dopa therapy.","author":[{"dropping-particle":"","family":"Quik","given":"Maryka","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Danhui","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McGregor","given":"Matthew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bordia","given":"Tanuja","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Biochemical Pharmacology","id":"ITEM-2","issue":"4","issued":{"date-parts":[["2015"]]},"note":"Nicotinic Acetylcholine Receptors as Therapeutic Targets: Emerging Frontiers in Basic Research and Clinical Science (Satellite to the 2015 Meeting of the Society for Neuroscience) Oct 14-15, Chicago, IL USA","page":"399-407","title":"Alpha7 nicotinic receptors as therapeutic targets for Parkinson's disease","type":"article-journal","volume":"97"},"uris":["http://www.mendeley.com/documents/?uuid=a0c52f3e-e870-4575-ae32-4a04bb0aa3de"]},{"id":"ITEM-3","itemData":{"DOI":"10.1007/s12035-018-1163-0","ISBN":"1203501811","ISSN":"15591182","abstract":"Parkinson’s disease (PD) is a neurodegenerative pathology characterized by resting tremor, rigidity, bradykinesia, and loss of dopamine-producing neurons in the pars compacta of the substantia nigra in the central nervous system (CNS) that result in dopamine depletion in the striatum. Oxidative stress has been documented as a key pathological mechanism for PD. Epidemiological studies have shown that smokers have a lower incidence of PD. In this aspect, different studies have shown that nicotine, a chemical compound found in cigarette, is capable of exerting beneficial effects in PD patients, but it can hardly be used as a therapeutic agent because of its inherent toxicity. Several studies have suggested that the use of nicotine analogs can have the same benefits as nicotine but lack its toxicity. In this study, we assessed the effects of two nicotine analogs, (E)-nicotinaldehyde O-cinnamyloxime and 3-(pyridin-3-yl)-3a,4,5,6,7,7a-hexahidrobenzo[d]isoxazole, in an in vitro model of PD. Initially, we performed a computational prediction of the molecular interactions between the nicotine analogs with the α7 nicotinic acetylcholine receptor (nAChR). Furthermore, we evaluated the effect of nicotine, nicotine analogs and rotenone on cell viability and reactive oxygen species (ROS) production in the SH-SY5Y neuronal cell line to validate possible protective effects. We observed that pre-treatment with nicotine or (E)-nicotinaldehyde O-cinnamyloxime (10 μM) improved cell viability and diminished ROS production in SH-SY5Y cells insulted with rotenone. These findings suggest that nicotine analogs have a potential protective effect against oxidative damage in brain pathologies.","author":[{"dropping-particle":"","family":"Jurado-Coronel","given":"Juan Camilo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Loaiza","given":"Alix E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Díaz","given":"John E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cabezas","given":"Ricardo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ashraf","given":"Ghulam Md","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sahebkar","given":"Amirhossein","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Echeverria","given":"Valentina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"González","given":"Janneth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Barreto","given":"George E.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Molecular Neurobiology","id":"ITEM-3","issue":"2","issued":{"date-parts":[["2019"]]},"page":"1221-1232","publisher":"Molecular Neurobiology","title":"(E)-Nicotinaldehyde O-Cinnamyloxime, a Nicotine Analog, Attenuates Neuronal Cells Death Against Rotenone-Induced Neurotoxicity","type":"article-journal","volume":"56"},"uris":["http://www.mendeley.com/documents/?uuid=0b771f3f-d440-4255-aaab-fa68f4c4e659"]}],"mendeley":{"formattedCitation":"14–16","plainTextFormattedCitation":"14–16","previouslyFormattedCitation":"14–16"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}14–16 Alzheimer,ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2174/138161206778793010","ISSN":"13816128","abstract":"Neuritic plaques composed mainly of amyloid β-protein (Aβ) in the brain are an early and invariant neuro-pathological feature of Alzheimer's disease (AD). The current search for anti-AD drugs is mainly focused on modification of the process of Aβ deposition in the brain. In this article, the recent development of the molecules that inhibit the formation of β-amyloid fibrils (fAβ), as well as destabilize preformed fAβ is reviewed. Recently, various compounds such as curcumin, nicotine and wine-related polyphenols have been reported to inhibit the formation, extension of fAβ, as well as destabilize preformed fAβ at pH 7.5 at 37°C in vitro. In cell culture experiments, destabilized fAβ were suggested to be less toxic than intact fAβ. In transgenic mice model study, some coumpounds such as curcumin and nicotine have also been reported to reduce plaque burden in vivo. Although the mechanisms by which these compounds inhibit fAβ formation from Aβ, and destabilize preformed fAβ are still unclear, they could be key molecules for the development of preventives and therapeutics for AD. © 2006 Bentham Science Publishers Ltd.","author":[{"dropping-particle":"","family":"Ono","given":"Kenjiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Naiki","given":"Hironobu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yamada","given":"Masahito","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Current Pharmaceutical Design","id":"ITEM-1","issue":"33","issued":{"date-parts":[["2006"]]},"page":"4357-4375","title":"The Development of Preventives and Therapeutics for Alzheimers Disease that Inhibit the Formation of β-Amyloid Fibrils (fAβ), as Well as Destabilize Preformed fAβ","type":"article-journal","volume":"12"},"uris":["http://www.mendeley.com/documents/?uuid=e98ff8b4-5dba-46b9-8056-d774859bd92d"]}],"mendeley":{"formattedCitation":"17","plainTextFormattedCitation":"17","previouslyFormattedCitation":"17"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}17 esquizofrenia y otras patologías que afectan al sistema nervioso central. A su vez, se ha demostrado que tiene la capacidad de regular el árbol dendrítico.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00429-014-0897-3","ISSN":"18632661","abstract":"© 2014, Springer-Verlag Berlin Heidelberg. Chronic nicotine exposure during adolescence induces dendritic remodeling of medium spiny neurons (MSNs) in the nucleus accumbens (NAcc) shell. While nicotine-induced dendritic remodeling has frequently been described as persistent, the trajectory of dendrite remodeling is unknown. Specifically, no study to date has characterized the structural plasticity of dendrites in the NAcc immediately following chronic nicotine, leaving open the possibility that dendrite remodeling emerges gradually over time. Further, the neuropharmacological mechanisms through which nicotine induces dendrite remodeling are not well understood. To address these questions, rats were co-administered chronic nicotine (0.5 mg/kg) and the D1-dopamine receptor (D1DR) antagonist SCH-23390 (0.05 mg/kg) subcutaneously every other day during adolescence. Brains were then processed for Golgi–Cox staining either 1 day or 21 days following drug exposure and dendrites from MSNs in the NAcc shell digitally reconstructed in 3D. Spine density was also measured at both time points. Our morphometric results show (1) the formation of new dendritic branches and spines 1 day following nicotine exposure, (2) new dendritic branches, but not spine density, remains relatively stable for at least 21 days, (3) the co-administration of SCH-23390 completely blocked nicotine-induced dendritic remodeling of MSNs at both early and late time points, suggesting the formation of new dendritic branches in response to nicotine is D1DR-dependent, and (4) SCH-23390 failed to block nicotine-induced increases in spine density. Overall this study provides new insight into how nicotine influences the normal trajectory of adolescent brain development and demonstrates a persistent form of nicotine-induced neuroplasticity in the NAcc shell that develops rapidly and is D1DR dependent.","author":[{"dropping-particle":"","family":"Ehlinger","given":"D. G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bergstrom","given":"H. C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Burke","given":"J. C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fernandez","given":"G. M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McDonald","given":"C. G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smith","given":"R. F.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Brain Structure and Function","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2016"]]},"page":"133-145","publisher":"Springer Berlin Heidelberg","title":"Adolescent nicotine-induced dendrite remodeling in the nucleus accumbens is rapid, persistent, and D1-dopamine receptor dependent","type":"article-journal","volume":"221"},"uris":["http://www.mendeley.com/documents/?uuid=861ce81c-9356-4006-8f2f-2862db8f8848"]},{"id":"ITEM-2","itemData":{"DOI":"https://doi.org/10.1016/j.neuroscience.2017.05.036","ISSN":"0306-4522","abstract":"Nicotine is one of the most addictive substances known, targeting multiple memory systems, including the ventral and dorsal striatum. One form of neuroplasticity commonly associated with nicotine is dendrite remodeling. Nicotine-induced dendritic remodeling of ventral striatal medium spiny neurons (MSNs) is well-documented. Whether MSN dendrites in the dorsal striatum undergo a similar pattern of nicotine-induced structural remodeling is unknown. A morphometric analysis of Golgi-stained MSNs in rat revealed a natural asymmetry in dendritic morphology across the mediolateral axis, with larger, more complex MSNs found in the dorsolateral striatum (DLS). Chronic nicotine produced a lasting (at least 21day) expansion in the dendritic complexity of MSNs in the DLS, but not dorsomedial striatum (DMS). Given prior evidence that MSN subtypes can be distinguished based on dendritic morphology, MSNs were segregated into morphological subpopulations based on the number of primary dendrites. Analysis of these subpopulations revealed that DLS MSNs with more primary dendrites were selectively remodeled by chronic nicotine exposure and remodeling was specific to the distal-most portions of the dendritic arbor. Co-administration of the dopamine D1 receptor (D1R) antagonist SCH23390 completely reversed the selective effects of nicotine on DLS MSN dendrite morphology, supporting a causal role for dopamine signaling at D1 receptors in nicotine-induced dendrite restructuring. Considering the functional importance of the DLS in shaping and expressing habitual behavior, these data support a model in which nicotine induces persistent and selective changes in the circuit connectivity of the DLS that may promote and sustain addiction-related behavior.","author":[{"dropping-particle":"","family":"Ehlinger","given":"Daniel G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Burke","given":"Julian C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McDonald","given":"Craig G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smith","given":"Robert F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bergstrom","given":"Hadley C","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Neuroscience","id":"ITEM-2","issued":{"date-parts":[["2017"]]},"page":"242-254","title":"Nicotine-induced and D1-receptor-dependent dendritic remodeling in a subset of dorsolateral striatum medium spiny neurons","type":"article-journal","volume":"356"},"uris":["http://www.mendeley.com/documents/?uuid=fc1bbb6d-3ed7-47e4-a1d7-02cb70ec7448"]},{"id":"ITEM-3","itemData":{"DOI":"10.1002/syn.20106","ISSN":"08874476","abstract":"The effect of the premature commitment of neurons to exuberant growth by nicotine on concurrent and subsequent learning is unknown and was the focus of the present study. Animals were trained on a tray reaching for food task (where lots of pieces of chicken feed were available) for 3 weeks before they received two daily injections of nicotine (0.3 mg/kg) or 0.9% saline for 12 days. Measures of tray-reaching performance were obtained before the administration of nicotine and every other week for a total of 7 weeks. Starting on week 8, animals were given a novel motor skill problem that required them to learn to use a forepaw to reach through a slot in a cage for single food pellets located on an external shelf. Pyramidal cells in the forelimb area of both hemispheres were then examined for dendritic length and branching using a Golgi-Cox procedure. Animals treated with saline displayed excellent performance in both reaching tasks and an increase in neuronal branching in Layer V pyramidal cells in the motor cortex contralateral to the reaching paw. In contrast, animals treated with nicotine showed bilateral increases in neuronal branching. Behavioral results showed that nicotine improved forelimb use in the concurrently administered tray-reaching task, but severely degraded quantitative and qualitative scores of skilled forelimb use in the subsequently administered single-pellet reaching task. The results suggest that plasticity coincidence with skilled training is essential to skilled motor learning, but this expenditure can impair subsequent learning. © 2005 Wiley-Liss, Inc.","author":[{"dropping-particle":"","family":"Gonzalez","given":"Claudia L.R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gharbawie","given":"Omar A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Whishaw","given":"Ian Q.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kolb","given":"Bryan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Synapse","id":"ITEM-3","issue":"3","issued":{"date-parts":[["2005"]]},"page":"183-191","title":"Nicotine stimulates dendritic arborization in motor cortex and improves concurrent motor skill but impairs subsequent motor learning","type":"article-journal","volume":"55"},"uris":["http://www.mendeley.com/documents/?uuid=022fc91b-c34a-49e6-a476-fe9b7f88564c"]}],"mendeley":{"formattedCitation":"18–20","plainTextFormattedCitation":"18–20","previouslyFormattedCitation":"18–20"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}18–20 Sin embargo, los efectos secundarios y el potencial riesgo de adicción, limitan su utilidad como agente terapéutico.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.3389/fnagi.2014.00340","ISSN":"16634365","abstract":"© 2015 Barreto, Iarkov and Moran.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. However, several metabolites of nicotine, such as cotinine, also increase in the brain after nicotine administration. The effect of nicotine and some of its derivatives on dopaminergic neurons viability, neuroinflammation, and motor and memory functions, have been investigated using cellular and rodent models of PD. Current 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.","author":[{"dropping-particle":"","family":"Barreto","given":"George E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Iarkov","given":"Alexander","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moran","given":"Valentina Echeverria","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Frontiers in Aging Neuroscience","id":"ITEM-1","issue":"JAN","issued":{"date-parts":[["2015"]]},"page":"1-13","title":"Beneficial effects of nicotine, cotinine and its metabolites as potential agents for Parkinson's disease","type":"article-journal","volume":"7"},"uris":["http://www.mendeley.com/documents/?uuid=bc00d1e9-3198-48ba-8570-587609983129"]}],"mendeley":{"formattedCitation":"21","plainTextFormattedCitation":"21","previouslyFormattedCitation":"21"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}21 Por lo anterior es importante el estudio de análogos de esta sustancia, que ejerzan los efectos benéficos de la nicotina pero que posean baja toxicidad. Es por ello que compuestos análogos de nicotina, podrían exhibir una potente actividad biológica con perfiles farmacológicos deseables, entre los que se podrían incluir la inducción de plasticidad estructural. En la actualidad, una tendencia en el diseño racional de nuevos fármacos son los híbridos moleculares, los cuales se definen como entidades químicas con dos (o más) dominios estructurales que presentan diferentes funciones biológicas, en la cual la doble actividad indica que una molécula híbrida actúa como dos farmacóforos distintos. Con base en lo anterior, en este proyecto se realizará un estudio sistemático donde se evalúe el efecto neuroplástico de flavonoides 1 del tipo flavona, flavonol e isoflavona, así como de compuestos análogos de la nicotina 2 y moléculas híbridas flavonoide-nicotina 3, para relacionar el efecto de la naturaleza química y la posición de diversos grupos sustituyentes en el esqueleto básico de los quimiotipos con la actividad dendritogénica (Figura 2). En esta dirección, en la fase I se realizará la síntesis de alrededor de 50 flavonoides y derivados, análogos de nicotina y moléculas hibridas de las dos anteriores mediante reacciones conocidas de la química orgánica. Figura 2. Resumen gráfico del proyecto de investigación. En la fase II, se realizará la evaluación de la actividad dendritogénica in vitro sobre neuronas hipocampales de rata de las moléculas generadas. De esta manera el presente proyecto pretende hacer una búsqueda sistemática y rigurosa de compuestos con actividad neuroplástica prominente, que constituyan un primer paso hacia el desarrollo de fármacos eficaces para el tratamiento de problemas de salud que afectan de manera severa a la sociedad. También se busca hacer un aporte en el conocimiento de la relación existente entre la estructura, la actividad y los mecanismos de acción de flavonoides y sus derivados, análogos nicotínicos y sus híbridos, de tal manera que provean información relevante que permita agilizar el descubrimiento de moléculas líderes hacia el desarrollo de nuevos agentes terapéuticos eficaces, selectivos y cuya ruta de síntesis sea expedita.