[en] A small library of phorbol 12,13-diesters bearing low lipophilicity ester chains was prepared as potential neurogenic agents in the adult brain. They were also used in a targeted UHPLC-HRMS screening of the latex of Euphorbia resinifera. Two new 12-deoxy-16-hydroxyphorbol 13,16-diesters were isolated, and their structures were deduced using two-dimensional NMR spectroscopy and NOE experiments. The ability of natural and synthetic compounds to stimulate transforming growth factor alpha (TFGα) release, to increase neural progenitor cell proliferation, and to stimulate neurogenesis was evaluated. All compounds that facilitated TGFα release promoted neural progenitor cell proliferation. The presence of two acyloxy moieties on the tigliane skeleton led to higher levels of activity, which decreased when a free hydroxyl group was at C-12. Remarkably, the compound bearing isobutyryloxy groups was the most potent on the TGFα assay and at inducing neural progenitor cell proliferation in vitro, also leading to enhanced neurogenesis in vivo when administered intranasally to mice.
Ezzanad, Abdellah; Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Puerto Real, 11510 Cádiz, Spain
Gómez Oliva, Ricardo ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques ; Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, 11002 Cádiz, Spain ; Instituto de Investigación e Innovación Biomédica de Cádiz (INIBICA), 11009 Cádiz, Spain
Escobar-Montaño, Felipe; Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Puerto Real, 11510 Cádiz, Spain
Díez-Salguero, Mónica; Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, 11002 Cádiz, Spain
Geribaldi-Doldan, Noelia; Departamento de Anatomía y Embriología Humanas, Universidad de Cádiz, 11002 Cádiz, Spain
Dominguez-Garcia, Samuel; Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, 11002 Cádiz, Spain ; Instituto de Investigación e Innovación Biomédica de Cádiz (INIBICA), 11009 Cádiz, Spain
Botubol-Ares, José Manuel ; Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Puerto Real, 11510 Cádiz, Spain ; Instituto de Investigación e Innovación Biomédica de Cádiz (INIBICA), 11009 Cádiz, Spain
Reyes, Carolina de Los; Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Puerto Real, 11510 Cádiz, Spain
Durán-Patrón, Rosa ; Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Puerto Real, 11510 Cádiz, Spain ; Instituto de Investigación e Innovación Biomédica de Cádiz (INIBICA), 11009 Cádiz, Spain
Nunez-Abades, Pedro; Departamento de Fisiología, Facultad de Farmacia, Universidad de Sevilla, 41012 Sevilla, Spain
Macías-Sánchez, Antonio J ; Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Puerto Real, 11510 Cádiz, Spain ; Instituto de Investigación e Innovación Biomédica de Cádiz (INIBICA), 11009 Cádiz, Spain ; Instituto de Investigación en Biomoléculas (INBIO), Universidad de Cádiz, Puerto Real, 11510 Cádiz, Spain
Castro, Carmen; Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, 11002 Cádiz, Spain ; Instituto de Investigación e Innovación Biomédica de Cádiz (INIBICA), 11009 Cádiz, Spain
Hernández-Galán, Rosario ; Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Puerto Real, 11510 Cádiz, Spain ; Instituto de Investigación e Innovación Biomédica de Cádiz (INIBICA), 11009 Cádiz, Spain ; Instituto de Investigación en Biomoléculas (INBIO), Universidad de Cádiz, Puerto Real, 11510 Cádiz, Spain
MICINN - Ministerio de Ciencia, Innovación y Universidades ERDF - European Regional Development Fund Junta de Andalucía. Consejería de Economía, Conocimiento, Empresas y Universidad
Funding text :
Ministerio de Ciencia, Innovación y Universidades (grant nos RTI2018–099908-B-C21, and RTI2018–099908-B-C22 MICINN/FEDER) and Consejería de Economía, Conocimiento, Empresas y Universidades Junta de Andalucía (grant no FEDER-ANDALUCÍA 2018–00106647).This work was supported by the Spanish Ministerio de Ciencia, Innovación y Universidades (grant nos RTI2018–099908-B-C21 and RTI2018–099908-B-C22 MICINN/FEDER granted to CC and RHG, respectively) and Consejería de Economía, Conocimiento, Empresas y Universidades Junta de Andalucía (grant no FEDER-ANDALUCÍA sol2018–00106647-tra). We thank the “Servicio de experimentación y producción animal (SEPA) de la Universidad de Cádiz” as well as the “Servicios Centrales de apoyo a la investigación en Ciencias de la Salud (SCICS) de la Universidad de Cádiz” and “Servicios centrales de Ciencia y tecnología (SC-ICYT) de la Universidad de Cádiz”.
Fleminger, S.; Ponsford, J. Long term outcome after traumatic brain injury. Br. Med. J. 2005, 331, 1419-1420, 10.1136/bmj.331.7530.1419
Ratcliff, G.; Colantonio, A.; Escobar, M.; Chase, S.; Vernich, L. Long-term survival following traumatic brain injury. Disability and rehabilitation 2005, 27, 305-314, 10.1080/09638280400018338
Schachar, R. J.; Park, L. S.; Dennis, M. Mental Health Implications of Traumatic Brain Injury (TBI) in Children and Youth. Can. Acad. Child Adolesc. Psychiatr. 2015, 24, 100-108
Doetsch, F.; García-Verdugo, J. M.; Alvarez-Buylla, A. Cellular composition and three-dimensional organization of the subventricular germinal zone in the adult mammalian brain. J. Neurosci. 1997, 17, 5046-5061, 10.1523/jneurosci.17-13-05046.1997
Gage, F. H.; Coates, P. W.; Palmer, T. D.; Kuhn, H. G.; Fisher, L. J.; Suhonen, J. O.; Peterson, D. A.; Suhr, S. T.; Ray, J. Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 11879-11883, 10.1073/pnas.92.25.11879
Carrasco, M.; Rabaneda, L. G.; Murillo-Carretero, M.; Ortega-Martínez, S.; Martínez-Chantar, M. L.; Woodhoo, A.; Luka, Z.; Wagner, C.; Lu, S. C.; Mato, J. M.; Micó, J. A.; Castro, C. Glycine N-methyltransferase expression in the hippocampus and its role in neurogenesis and cognitive performance. Hippocampus 2014, 24, 840-852, 10.1002/hipo.22274
Hierro-Bujalance, C.; Del Marco, A.; Ramos-Rodriguez, J.; Infante-Garcia, C.; Gomez-Santos, S. B.; Herrera, M.; Garcia-Alloza, M. Cell proliferation and neurogenesis alterations in Alzheimer's disease and diabetes mellitus mixed murine models. J. Neurochem. 2020, 154, 673-692, 10.1111/jnc.14987
Berdugo-Vega, G.; Arias-Gil, G.; López-Fernández, A.; Artegiani, B.; Wasielewska, JM.; Lee, C.-C.; Lippert, MT.; Kempermann, G.; Takagaki, K.; Calegari, F. Increasing neurogenesis refines hip-pocampal activity rejuvenating navigational learning strategies and contextual memory throughout life. Nat. Commun. 2020, 11, 1138, 10.1038/s41467-020-14935-4
Geribaldi-Doldán, N.; Flores-Giubi, E.; Murillo-Carretero, M.; García-Bernal, F.; Carrasco, M.; Macías-Sánchez, AJ.; Domínguez-Riscart, J.; Verástegui, C.; Hernández-Galán, R.; Castro, C. 12-Deoxyphorbols promote adult neurogenesis by inducing neural progenitor cell proliferation via PKC activation. Int. J. Neuropsychopharmacol. 2016, 19, pyv085, 10.1093/ijnp/pyv085
Domínguez-García, S.; Gómez-Oliva, R.; Geribaldi-Doldán, N.; Hierro-Bujalance, C.; Sendra, M.; Ruiz, F. A.; Carrascal, L.; Macías-Sánchez, A. J.; Verástegui, C.; Hernández-Galán, R.; García-Alloza, M.; Nunez-Abades, P.; Castro, C. Effects of classical PKC activation on hippocampal neurogenesis and cognitive performance: mechanism of action. Neuropsychopharmacology 2021, 46, 1207, 10.1038/s41386-020-00934-y
Dang, M.; Armbruster, N.; Miller, M. A.; Cermeno, E.; Hartmann, M.; Bell, G. W.; Root, D. E.; Lauffenburger, D. A.; Lodish, H. F.; Herrlich, A. Regulated ADAM17-dependent EGF family ligand release by substrate-selecting signaling pathways. Proc. Natl. Acad. Sci. U.S.A. 2013, 110, 9776-9781, 10.1073/pnas.1307478110
Dang, M.; Dubbin, K.; D'Aiello, A.; Hartmann, M.; Lodish, H.; Herrlich, A. Epidermal growth factor (EGF) ligand release by substrate-specific a disintegrin and metalloproteases (ADAMs) involves different protein kinase C (PKC) isoenzymes depending on the stimulus. J. Biol. Chem. 2011, 286, 17704-17713, 10.1074/jbc.m110.187823
Geribaldi-Doldán, N.; Gómez-Oliva, R.; Dominguez-Garcia, S.; Nunez-Abades, P.; Castro, C. Protein kinase C: targets to regenerate brain injuries?. Front Cell Dev. Biol. 2019, 7, 7-39, 10.3389/fcell.2019.00039
Shi, Q.-W.; Su, X.-H.; Kiyota, H. Chemical and pharmacological research of the plants in genus euphorbia. Chem. Rev. 2008, 108, 4295-4327, 10.1021/cr078350s
Vasas, A.; Hohmann, J. Euphorbia diterpenes: isolation, structure, biological activity, and synthesis (2008-2012). J. Chem. Rev. 2014, 114, 8579-8612, 10.1021/cr400541j
Hecker, E.; Schmidt, R. Phorbolesters-the Irritants and Cocarcinogens of Croton Tiglium L. Fortschr. Chem. Org. Naturst. 1974, 31, 377-467, 10.1007/978-3-7091-7094-6_7
Gschwendi, M.; Hecker, E. Biologically active compounds of Euphorbiaceae. I. Skin irritant and cocarcinogenic factors from Euphorbia cooperi. Z. Krebsforsch. Klin. Onkol. 1973, 80, 335-350, 10.1007/bf00284369
Hergenhahn, M.; Kusumoto, S.; Hecker, E. On the active principles of the spurge family (Euphorbiaceae). J. Canc. Res. Clin. Oncol. 1984, 108, 98-109, 10.1007/bf00390980
Hergenhahn, M.; Fuerstenberger, G.; Opferkuch, H. J.; Adolf, W.; Mack, H.; Hecker, E. Biological assays for irritant tumor-initiating and-promoting activities. I. Kinetics of the irritant response in relation to the initiation-promoting activity of polyfunctional diterpenes representing tigliane and some daphnane types. J. Canc. Res. Clin. Oncol. 1982, 104, 31-39, 10.1007/bf00402051
Bertolini, T. M.; Giorgione, J.; Harvey, D. F.; Newton, A. C. Protein kinase C translocation by modified phorbol esters with functionalized lipophilic regions. J. Org. Chem. 2003, 68, 5028-5036, 10.1021/jo030029w
Jacobi, P.; Härle, E.; Schairer, H. U.; Hecker, E. Zur Chemie des Phorbols, XVI. 4α-Phorbol. Liebigs Ann. Chem. 1970, 741, 13-32, 10.1002/jlac.19707410103
Tseng, S.-S.; Van Duuren, B. L.; Solomon, J. J. Synthesis of 4α-phorbol 9-myristate 9a-acetate and related esters. J. Org. Chem. 1977, 42, 3645, 10.1021/jo00443a002
Plumb, R. S.; Johnson, K. A.; Rainville, P.; Smith, B. W.; Wilson, I. D.; Castro-Perez, J. M.; Nicholson, J. K. UPLC/MSEa new approach for generating molecular fragment information for biomarker structure elucidation. Rapid Commun. Mass Spectrom. 2006, 20, 1989-1994, 10.1002/rcm.2550
Nothias-Scaglia, L. F.; Schmitz-Afonso, I.; Renucci, F.; Roussi, F.; Touboul, D.; Costa, J.; Litaudon, M.; Paolini, J. Insights on profiling of phorbol, deoxyphorbol, ingenol and jatrophane diterpene esters by high performance liquid chromatography coupled to multiple stage mass spectrometry. J. Chromatogr. A 2015, 1422, 128-139, 10.1016/j.chroma.2015.09.092
Vogg, G.; Achatz, S.; Kettrup, A.; Sandermann, H. Fast, sensitive and selective liquid chromatographic-tandem mass spectrometric determination of tumor-promoting diterpene esters. J. Chromatogr. A 1999, 855, 563-573, 10.1016/s0021-9673(99)00728-1
Santiskulvong, C.; Rozengurt, E. Protein kinase C alpha mediates feedback inhibition of EGF receptor transactivation induced by Gq-coupled receptor agonists. Cell Signal. 2007, 19, 1348-1357, 10.1016/j.cellsig.2007.01.006
Zhang, G.; Kazanietz, M. G.; Blumberg, P. M.; Hurley, J. H. Crystal structure of the Cys2 activator-binding domain of protein kinase Cδin complex with phorbol ester. Cell 1995, 81, 917-924, 10.1016/0092-8674(95)90011-x
Newton, A. C. Protein kinase C: perfectly balanced. Crit. Rev. Biochem. Mol. Biol. 2018, 53, 208-230, 10.1080/10409238.2018.1442408
Das, J.; Rahman, G. M. C1 Domains: Structure and Ligand-Binding Properties. Chem. Rev. 2014, 114, 12108-12131, 10.1021/cr300481j
Murillo-Carretero, M.; Geribaldi-Doldan, N.; Flores-Giubi, E.; Garcia-Bernal, F.; Navarro-Quiroz, E. A.; Carrasco, M.; Macías-Sánchez, A. J.; Herrero-Foncubierta, P.; Delgado-Ariza, A.; Verástegui, C.; Domínguez-Riscart, J.; Daoubi, M.; Hernández Galán, R.; Castro, C. ELAC (3,12-di-O-acetyl-8-O-tigloilingol), a plant-derived lathyrane diterpene, induces subventricular zone neural progenitor cell proliferation through PKCbeta activation. Br. J. Pharmacol. 2017, 174, 2373-2392
Leonard, T. A.; Różycki, B.; Saidi, L. F.; Hummer, G.; Hurley, J. H. Crystal structure and allosteric activation of protein kinase C βII. Cell 2011, 144, 55-66, 10.1016/j.cell.2010.12.013
Appendino, G.; Cravotto, G.; Palmisano, G.; Annunziata, R.; Szallasi, A. Synthesis and evaluation of phorboid 20-homovanillates: discovery of a class of ligands binding to the vanilloid (capsaicin) receptor with different degrees of cooperativity. J. Med. Chem. 1996, 39, 3123-3131, 10.1021/jm960063l
Appendino, G.; Bertolino, A.; Minassi, A.; Annunziata, R.; Szallasi, A.; de Petrocellis, L.; Di Marzo, V. Synthesis and biological evaluation of phorbol-resiniferatoxin (RTX) hybrids. Eur. J. Org Chem. 2004, 2004, 3413-3421, 10.1002/ejoc.200400122
Szczepanski, C. V.; Schairer, H.-U.; Gschwendt, M.; Hecker, E. Zur chemie des phorbols, III. Mono-und diacetate des phorbols. Justus Liebigs Ann. Chem. 1967, 705, 199-210, 10.1002/jlac.19677050123
Marshall, G. T.; Kinghorn, A. D. Short-chain phorbol ester constituents of croton oil. J. Am. Oil Chem. Soc. 1984, 61, 1220-1225, 10.1007/bf02636256
Zhang, X. L.; Wang, L.; Li, F.; Yu, K.; Wang, M. K. Cytotoxic Phorbol esters of croton tiglium. J. Nat. Prod. 2013, 76, 858-864, 10.1021/np300832n
Kilkenny, C.; Browne, W.; Cuthill, I. C.; Emerson, M.; Altman, D. G. Animal research: reporting in vivo experiments: the ARRIVE guidelines. Br. J. Pharmacol. 2010, 160, 1577-1579, 10.1111/j.1476-5381.2010.00872.x
McGrath, J.; Drummond, G.; McLachlan, E.; Kilkenny, C.; Wainwright, C. Guidelines for reporting experiments involving animals: the ARRIVE guidelines. Br. J. Pharmacol. 2010, 160, 1573-1576, 10.1111/j.1476-5381.2010.00873.x
Gómez-Oliva, R.; Geribaldi-Doldán, N.; Domínguez-García, S.; Carrascal, L.; Verástegui, C.; Nunez-Abades, P.; Castro, C. Vitamin D deficiency as a potential risk factor for accelerated aging, impaired hippocampal neurogenesis and cognitive decline: a role for Wnt/β-catenin signaling. Aging 2020, 12, 13824-13844, 10.18632/aging.103510
Rabaneda, L. G.; Geribaldi-Doldán, N.; Murillo-Carretero, M.; Carrasco, M.; Martínez-Salas, J. M.; Verástegui, C.; Castro, C. Altered regulation of the Spry2/Dyrk1A/PP2A triad by homocysteine impairs neural progenitor cell proliferation. Biochim. Biophys. Acta 2016, 1863, 3015-3026, 10.1016/j.bbamcr.2016.09.018
García-Bernal, F.; Geribaldi-Doldan, N.; Domínguez-García, S.; Carrasco, M.; Murillo-Carretero, M.; Delgado-Ariza, A.; Díez-Salguero, M.; Verástegui, C.; Castro, C. Protein kinase C inhibition mediates neuroblast enrichment in mechanical brain injuries. Front. Cell. Neurosci. 2018, 12, 462, 10.3389/fncel.2018.00462
Thorne, R. G.; Pronk, G. J.; Padmanabhan, V.; Frey, W. H. Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience 2004, 127, 481-496, 10.1016/j.neuroscience.2004.05.029
Francis, G. J.; Martinez, J. A.; Liu, W. Q.; Xu, K.; Ayer, A.; Fine, J.; Tuor, U. I.; Glazner, G.; Hanson, L. R.; Frey, W. H., 2nd; Toth, C. Intranasal insulin prevents cognitive decline, cerebral atrophy and white matter changes in murine type I diabetic encephalopathy. Brain 2008, 131, 3311-3334, 10.1093/brain/awn288
Marks, D. R.; Tucker, K.; Cavallin, M. A.; Mast, T. G.; Fadool, D. A. Awake intranasal insulin delivery modifies protein complexes and alters memory, anxiety, and olfactory behaviors. J. Neurosci. 2009, 29, 6734-6751, 10.1523/jneurosci.1350-09.2009
Rabaneda, L. G.; Carrasco, M.; López-Toledano, M. A.; Murillo-Carretero, M.; Ruiz, F. A.; Estrada, C.; Castro, C. Homocysteine inhibits proliferation of neuronal precursors in the mouse adult brain by impairing the basic fibroblast growth factor signaling cascade and reducing extracellular regulated kinase 1/2-dependent cyclin E expression. FASEB J. 2008, 22, 3823-3835, 10.1096/fj.08-109306
