INVESTIGACION y LABORATORIOS

10.         LABORATORIO DE NEUROFARMACOLOGIA CELULAR Y MOLECULAR

Fono: 9786057

Investigador Principal:
Profesor Titular Juan Segura-Aguilar
Fono: 9786057
jsegura@med.uchile.cl

Académicos Participantes:
Profesor Asociado Pablo Caviedes Fernández
Fono: 9786559
pcaviede@med.uchile.cl

      Profesor Asistente Irmgard Paris

      Fono 9786637

      iparis@med.uchile.cl

Personal de colaboración:

Ayudante Técnico:

Sra. Verónica Toro Hidalgo

Línea de Investigación:

¨        1. Estudios de los mecanismos moleculares de la degeneración de los sistemas dopaminérgicos en la enfermedad de Parkinson

¨        2. Estudios de factores geneticos en la enfermedad del Parkinson

Palabras claves: Neurodegeneración, Dopamina, Neuromelanina, Aminochrome, DT-diaphorase, Parkinson's disease, Neurotoxicidad.

Técnicas empleadas:

-  Biología Molecular

-  Cultivo celular

-  Transducción con particulas retro- y lentivirales

-  Bioquímica

-  Proteinas recombinantes

-  Estudios de polimorfismo

Proyectos de Investigación:

01.        Proyecto FONDECYT 1100165. Años 2010-2014. Studies on degeneration mechanism of dopaminergic neurons induced by aminochrome and polymorphism prevalence in chilean parkinson's patients. $224.287.000. Investigador principal: Juan Segura-Aguilar.

02.       Proyecto Fondecyt Nº 1090160, Años 2009-2012. Role of DYRK1A and DSCR1 overespression in genetic regulatory circuits and cellular dysfunction of immortalized neuronal cells derived from trisomy 16 mouse, an animal model of human down síndrome: posible therapeutic targets. Investigador Principal Dr. Pablo Caviedes. Co-Investigador Dr. Juan Segura-Aguilar.

03.       Proyecto Fondecyt Nº 1061083. Años 2006-2009.  Studies on the molecular mechanism of Parkinson’s disease: Possible neuroprotective role of DT-diaphorase and GST M2-2 in cel cultures and association and coexistence of DT-diaphorase and alpha-synuclein polymorphism.  $156.297.000. Investigador principal Dr. Juan Segura-Aguilar.

04.       Proyecto Fondecyt Nº 1020672, Años 2002-2005. Studies on the mechanism of degeneration of o-quinonas derived from  dopamine and possible polymorphism of  DT-diaphorase and GST M2-2 / M1-1 in Parkinson’s disease’ s patients  ($)137.495 .  

             Investigador principal Dr. Juan Segura-Aguilar.

05.        Proyecto S-CONICYT Nº C01S02. Años 2002-2004.  Studies on Dopamine oxidation in dopamine and L-dopa. Investigador principal en Chile Dr. Juan Segura-Aguilar.

06.        Oxidative stress in Neurons: Role of aminochrome. 96000 USD. Proyecto FIRCA Grant (NIH, USA) Award# 1 R03 TW007044-Investigador principal en Chile. Juan Segura-Aguilar

Publicaciones (2002 a la fecha):

1. Paris I, Perez-Pastene C, Cardenas S, Iturra P, Muñoz P, Couve E, Caviedes P, Segura-Aguilar J (2010). Aminochrome Induces Disruption of Actin, Alpha-, and Beta-Tubulin Cytoskeleton Networks in Substantia-Nigra-Derived Cell Line. Neurotox Res. Jan 20. [Epub ahead of print]
2. Pérez P C, Miranda C M, Segura-Aguilar J. (2009)Availability of genetic diagnosis of Huntington disease in Chile Rev Med Chil. Aug;137(8):1128-9.
3. Paris I, Perez-Pastene C, Caviedes P, Couve E, LeDoux L and Segura-Aguilar J. (2009)   Caspase-independent autophagic cell death induced by copper-dopamine complex. J Biol Chem. 284, 13306-13315
4. Paris I, Perez-Pastene C, Caviedes P, Couve E, LeDoux L and Segura-Aguilar J. (2009). Caspase-independent autophagic cell death induced by copper-dopamine complex. J Biol Chem. Mar 5. [Epub ahead of print] . Impact Factor: 5.581;
5. Paris I., Lozano J., Perez-Pastene C, Muñoz P and Segura-Aguilar J. (2009). Molecular and neurochemical mechanisms in PD pathogenesis. Neurotox. Res. In press. Impact Factor:5.234;
6. Segura-Aguilar, J. (2009). Molecular Aspects of Neurotoxins in dopaminergic neurons. Advances in Molecular Toxicology, Volume 3, 105-121. (Ed. J.C. Fishbein) Editorial Elsevier B.V., The Netherlands. ISN 1872-0854.
7. Paris, I., Perez-Pastene, C., Couve, E., Caviedes, P., Ledoux, S. y Segura-Aguilar J. (2009). Copper-dopamine complex induces mitochondrial autophagy preceding caspase-independent apoptotic cell death. J Biol Chem. Mar 5, in press. ISI: 5.581.
8.  Rojas, G , Cárdenas AM , Fernández-Olivares P , Shimahara T , Segura-Aguilar J , Caviedes R, Caviedes P. Effect of the knockdown of amyloid precursor protein on intracellular calcium increases in a neuronal cell line derived from the cerebral cortex of a trisomy 16 mouse. Experimental Neurology, 209, 234-242 (2008). Impact Factor: 3.982.
9. Paris I, Lozano J, Cardenas S, Perez-Pastene C, Saud K, Fuentes P, Dagnino-Subiabre A, Raisman-Vozari R, ShimaharaT, Kostrzewa JP, Chi D, Kostrzewa RM, Caviedes P, Segura-Aguilar J. (2008). The catecholaminergic RCSN-3 cell line: a model to study dopamine metabolism. Neurotox Res,  13, 221-230 Impact Factor: 5.234.
10. Diaz-Veliz, G., Paris, I.,  Mora, S.,  Raisman-Vozari, R.,  Segura-Aguilar, J. (2008).  Copper neurotoxicity in rat substantia nigra and Striatum is dependent on DT-diaphorase inhibition. Chem. Res. Toxicol. 21, 1180–1185 Impact Factor: 3.508.
11. Paula-Lima, A. C., Arriagada, C., Toro, R. Cárdenas, A.M., Caviedes, R., Ferreira, S.T. y Caviedes, P. .(2008). Amyloid aggregation inhibitors reduce excess amyloid in a trisomy 16 mouse cortical cell line. Biol Res41, 129-136. ISI: 1.177. # citations: 0
12. Paris I, Lozano J, Cardenas S, Perez-Pastene C, Saud K, Fuentes P, Caviedes P, Dagnino-Subiabre A, Raisman-Vozari R, Shimahara T, Kostrzewa JP, Chi D, Kostrzewa RM, Caviedes R, Segura-Aguilar J. (2008). The catecholaminergic RCSN-3 cell line: a model to study dopamine metabolism. Neurotox Res. May;13(3-4):221-230. ISI: 5.234. # citations: 0
13. Rojas, G., Cárdenas, A.M., Fernández-Olivares, P., Shimahara, T.,  Segura-Aguilar, J., Caviedes, R., Caviedes, P. (2008). Effect of APP knockdown on intracellular calcium increases in a neuronal cell line derived from the cerebral cortex of a trisomy 16 mouse, an animal model of Down syndrome. Exp. Neurol. 209, 234–242. ISI: 4.156. # citations: 0
14. Ardiles, A.O., González-Jamett, A. M., Maripillan, J., Naranjo, D., Caviedes, P., Cárdenas, A.M. (2007). Calcium channel subtypes differentially regulate fusion pore stability and expansion. J. Neurochem. 103:1574–1581. ISI: 4.260. # citations: 0
15. Paris I, Lozano J, Cardenas S, Perez-Pastene C, Saud K, Fuentes P, Dagnino-Subiabre A, Raisman-Vozari R, ShimaharaT, Kostrzewa JP, Chi D, Kostrzewa RM, Caviedes P, Segura-Aguilar J. (2008). The catecholaminergic RCSN-3 cell line: a model to study dopamine metabolism. Neurotox Res,  13, In press.
16. Kostrzewa R.M., Segura-Aguilar, J. and Brus R. (2007). Neurotoxins – Refined and Redefined. Neurotox Res. 12, 275-290.
17. Kostrzewa RM, Segura-Aguilar J. (2007).  Botulinum neurotoxin: evolution from poison, to research tool - onto medicinal therapeutic and future pharmaceutical panacea. Neurotox Res. 12, 275-290.
18. Rojas, G , Cárdenas AM , Fernández-Olivares P , Shimahara T , Segura-Aguilar J , Caviedes R, Caviedes P (2007). Effect of the knockdown of amyloid precursor protein on intracellular calcium increases in a neuronal cell line derived from the cerebral cortex of a trisomy 16 mouse. Experimental Neurology, Oct 5; [Epub ahead of print]
19. Kostrzewa R.M., Segura-Aguilar, J. and Brus R. (2007)  Neurotoxins – Refined and Redefined. Neurotox Res. 12, 125-134
20. Paris, I., Cárdenas, S., Perez-Pastene, C., Lozano, J., Graumann, R., Riveros, A., Caviedes, P., and Segura-Aguilar, J. (2007).  Aminochrome as preclinical model to study degeneration of dopaminergic neurons in Parkinson´s Disease. Neurotox. Res. 12, 1-10
21. Perez-Pastene C, Cobb SA, Diaz-Grez F, Hulihan MM, Miranda M, Venegas P, Godoy OT, Kachergus JM, Ross OA, Layson L, Farrer MJ, Segura-Aguilar J. (2007).  Lrrk2 mutations in South America: A study of Chilean Parkinson's disease. Neurosci Lett. 422, 193-197
22. Perez-Pastene C, Graumann R, Diaz-Grez F, Miranda M, Venegas P, Godoy OT, Layson L, Villagra R, Matamala JM, Herrera L, Segura-Aguilar J. (2007). Association of GST M1 null polymorphism with Parkinson's disease in a Chilean population with a strong Amerindian genetic component. Neurosci Lett.418, 181-185.
23. Fuentes P, Paris I, Nassif M, Caviedes P, Segura-Aguilar J. (2007) Inhibition of VMAT-2 and DT-diaphorase induce cell death in a substantia nigra-derived cell line--an experimental cell model for dopamine toxicity studies. Chem Res Toxicol. 20, 776-783.
24. Opazo P, Saud K, de Saint Pierre M, Cardenas AM, Allen DD, Segura-Aguilar J, Caviedes R, Caviedes P.  (2006).  Knockdown of amyloid precursor protein normalizes cholinergic function in a cell line derived from the cerebral cortex of a trisomy 16 mouse: An animal model of down syndrome. J Neurosci Res. 84, 1303-1310
25. Segura-Aguilar J, Kostrzewa RM. (2006) Neurotoxins and neurotoxicity mechanisms. An overview. Neurotox Res. 10, 263-287
26. Allen DD, Caviedes R, Cardenas AM, Shimahara T, Segura-Aguilar J, Caviedes PA. (2005)  Cell lines as in vitro models for drug screening and toxicity studies. Drug Dev Ind Pharm. 31, 757-768
27. Paris I, Martinez-Alvarado P, Perez-Pastene C, Vieira MN, Olea-Azar C, Raisman-Vozari R, Cardenas S, Graumann R, Caviedes P, Segura-Aguilar J. (2005) Monoamine transporter inhibitors and norepinephrine reduce dopamine-dependent iron toxicity in cells derived from the substantia nigra. J Neurochem. 92, 1021-1032
28. Paris I, Martinez-Alvarado P, Cardenas S, Perez-Pastene C, Graumann R, Fuentes P, Olea-Azar C, Caviedes P, Segura-Aguilar J. (2005) Dopamine-dependent iron toxicity in cells derived from rat hypothalamus. Chem Res Toxicol. 18, 415-419.
29. Segura-Aguilar J & Kostrzewa R (2004). Neurotoxins and neurotoxic species implicated in neurodegeneration. Neurotox. Res., 6, 615-630 
30. Arriagada A.,  Paris I.,  Sanchez de las Matas M.J., Martinez-Alvarado P.,  Cardenas S., Castañeda P.,  Graumann R., Perez-Pastene C., Olea-Azar C., Couve E., Herrero M.T., Caviedes P., Segura-Aguilar J. (2004) On the neurotoxicity of leukoaminochrome o-semiquinone radical derived of dopamine oxidation: mitochondria damage, necrosis and hydroxyl radical formation. Neurobiol. Dis., 16, 468-477.
31. Diaz-Veliz G, Mora S, Gomez P, Dossi MT, Montiel J, Arriagada C, Aboitiz F, Segura-Aguilar J. (2004) Behavioral effects of manganese injected in the rat substantia nigra are potentiated by dicumarol, a DT-diaphorase inhibitor. Pharmacol Biochem Behav. 77, 245-251. (Impact Factor = 2.092) (citations = 11)
32. Díaz-Véliz G., Mora S., Lungenstrass H., Segura-Aguilar J. (2004) Inhibition of DT-diaphorase potentiates the in vivo neurotoxic effect of intranigral injection of salsolinol. Neurotox. Res. 5, 629-634.
33. Bustamante D., Bustamante, L., Segura-Aguilar, J., Goiny, M., Herrera-Marschitz M. (2004) Effects of the DT-diaphorase Inhibitor Dicumarol on Striatal Monoamine levels in L-DOPAand L-Deprenyl Pre-treated Rats. Neurotox. Res. 5, 585-594.
34. Aguilar Hernández, R., Sánchez de las Matas, M.J., Arriagada, C., Barcia, C., Caviedes, P., Herrero, M.T., Segura-Aguilar, J. (2003) MPP+ induced degeneration is potentiated by dicoumarol in cultures of RCSN-3 dopaminergic cell line. Implications of neuromelanin in oxidative metabolism of dopamine neurotoxicity. Neurotox. Res. 5, 407-410.
35. Kostrzewa,RM., Segura-Aguilar, J. (2003) Novel Mechanisms and Approaches in the Study of Neurodegeneration and Neuroprotection. A Review. Neurotox. Res. 5, 375-383.
36. Diaz-Veliz G, Mora S, Dossi MT, Gomez P, Arriagada C, Montiel J, Aboitiz F, (2002).   Behavioral effects of aminochrome and dopachrome injected in the rat substantia nigra. Pharmacol Biochem Behav. 73, 843-850. 
37. Paris, I., Arriada, C., Dagnino-Subiabre, A., Montiel J., Caviedes, R., Caviedes, P., Mora, S., Diaz-Veliz, G., Cassel, B.C., Olea Azar, C., Aboitiz, F.and Juan Segura-Aguilar. (2002)  DT-diaphorase: a neuroprotective enzyme of dopaminergic system. Pol. J. Pharmacol. 54, 181-183. 
38. Cardenas, A.M., Allen, D.D., Arriagada, C.,  Olivares, A., Bennett, L.B., Caviedes, R., Dagnino-Subiabre, A., Mendoza, I.E., Segura-Aguilar, J., Rapoport, S.I. & Caviedes, P. (2002). Establishment and characterization of immortalized neuronal cell lines derived from the spinal cord of normal and trisomy 16 fetal mice, an animal model of Down Syndrome. J. Neurosc.Res.  68, 46–58.
39. Kostrzewa, R, & Segura-Aguilar, J. (2002). Neurotoxicological and Neuroprotective elements in Parkinson’s disease. Neurotox. Res. 4, 83-86
40. Segura-Aguilar, J., Diaz-Veliz, G., Mora, S., and Herrera-Marschitz, M. (2002). Inhibition of DT-diaphorase is a requirement for Mn³⁺ to produce a 6-OH-dopamine like rotational behaviour. Neurotox. Res. 4, 127-131.
41. Hurtado-Guzman, C., Martinez-Alvarado, P., Dagnino-Subiabre, A., Paris, I., Caviedes, P., Caviedes, R., Cassels, B.K., and Segura-Aguilar, J. (2002). Neurotoxicity of some MAO inhibitors in adult rat hypothalamic cell culture. Neurotox. Res. 4, 161-163.