INVESTIGACION Y LABORATORIOS

13.  LABORATORIO DE FARMACOLOGIA DE NEUROCIRCUITOS & NEUROPSICOFARMACOLOGIA

Fono: 9786788

Académicos Participantes:

Profesor Titular Mario Herrera-Marschitz

Fono: 9786186

mh-marschitz@med.uchile.cl

Profesor Asociado Diego Bustamante Cadiz

Fono: 9786238

dbustama@med.uchile.cl

Profesora Asociado Paola Morales Retamales

Fono: 9786788

pmorales@med.uchile.cl

Académicos Asociados en Chile:

Profesor Titular Bruce Cassels Mac Niven

Fono: 9786050

bcassels@uchile.cl

Profesor Titular Jedy Israel Jacquard

Fono: 9782943

yisrael@uchile.cl   

Profesora Asociada Lutske Tampier de Jong

Fono: 9786908

ltampier@med.uchile.cl

Profesora Asociada Mª Elena Quintanilla

Fono: 9786908

equintanilla@med.uchile.cl

Profesora Asistente Andrea Slachevsky Chonchol

Fono: 9786050

aslachevsky@med.uchile.cl

Académicos Asociados Internacionales:

Peter Gebicker-Haerter (Mannheim, Germany)

R. Andrew Tasker (Charlottetwon, UPI, Canada)

Micaela Morelli (Cagliari, Italy)

Tomas Hokfelt, Michel Goiny (Stockholm, Sweden)

Personal de Colaboración:

Ayudantes Técnicos: Sra. Carmen Almeyda Jabalquinto y Sr. Juan Santibañez Serrano

Líneas de Investigación.

The Project is to identify early diagnostic markers for long-term effects produced by metabolic insults at birth. A main insult is produced at birth, when the bioavailability of oxygen is affected by a prolonged or difficult delivery, producing an immediate shift to an anaerobic metabolism and acidosis, leading to death if oxygenation is not re-establish. Low oxygen supply at birth can cause kidney, lever and cardio-respiratory insufficiency, as well as damage of the central nervous system (CNS), predisposing to deficits and diseases detected first at adulthood and/or senescence. There are already results showing differential gene expression after perinatal asphyxia, indicating that reperfusion/re-oxygenation causes extensive DNA fragmentation associated to hyper-activation of DNA damage-dependent genes responsible for cell suicidal, affecting vulnerable systems, such as immune, cardiovascular and CNS. There is an obvious need to develop early and preventive diagnostic approaches, predicting individual stress reactions as well as outcomes. We are investigating on several markers, including protein changes in peripheral tissue, such as S100 and COX2 evaluated in blood and urine samples by transcriptomics and proteomics based methodology. We have found that these markers are highly expressed in leukocytes of asphyxiated newborns, and the same markers have been found to be elevated in samples from Alzheimer’s and Parkinson’s diseases, as well as from patients suffering of glaucoma, breast and prostate cancer. The goal is to identify biomarkers in blood and peripheral tissue reflecting long-term changes occurring in the CNS as consequence of metabolic insults occurring at birth. Several deliverables are expected, including early diagnostic markers and targets for neuroprotection and neurorescue. A main issue is on postnatal neurogenesis and apoptosis, which is increased by perinatal asphyxia. We have focused on neurogenesis observed in dentate gyrus and subventricular zone (SVZ) at postnatal periods, modulated by dopamine and FGF signals, implying activation of the MAPK/ERK pathway. 

Dra. Andrea Slachevsky develops a line of research focusing on Neuropsychoneurologyl and Neuropsycopharmacology of Dementia of Alzheimer type.

¨       Unidad in vitro para generar cultivos organotípicos (Culture room; Laminar Flow cabinets, Incubator, microslicer, microscopes). Facility for virus transfection.

¨       Unidad in vivo. Con facilidades para cirugía estereotáxica (anestesia de gases, esterilzacion, taladros, microjeringas, etc.); microdialysis (microbombas, switchers, sampling collectors, etc); asfixia perinatal; rotometers; computarised behavioural monitor systems; perfusion intracardial y fijación de tejido; etc. Campana de seguridad.

¨       Unidad analítica. HPLC con detector electroquímico, fluorescencia. Software de integración. PH meter, Campana de seguridad, sistemas de filtro.

¨       Facilities for histochemistry, including immunocytochemistry (perfusion systems, cryostate, epifluorecent microscopy, imaging analysis and quantification).

¨       qPCR and molecular biology units (termocyclers, electrophoresis chambers, spectrophotometers. Luminometer, unit for photocaptures, etc.).

PROYECTOS 2002 a la fecha:

01. Proyecto Fondecyt Regular Nº 1095021. Años 2009 – 2012. Ethanol as a prodrug. Investigador Principal: Yedy Israel; Co Investigadores:  Lutske Tampier,  Mª Elena Quintanilla, Mario Herrera-Marschitz y  Eduardo Karahanian.

02. Proyecto Fondecyt Regular Nº 108-0447, años 2008-2011. Long term changes in brain neurocircuitries produced by perinatal asphyxia: is Poly(ADP-Ribose) Polymerase-1 (PARP-1) inhibition a strategy for neuroprotection?. Investigador principal: Mario Herrera-Marschitz Co-Investigadores: Diego Bustamante y Paola Morales R.

03.  Proyecto Fondecyt 11070192 Años 2007-2009. Neurogénesis postnatal inducida por injuries cerebrales y su modulación por vías de señalización asociadas al factor de crecimiento a fibroblasto bFGF.  Investigador principal  Paola Morales R.

04.  Proyecto CONICYT DAAD 1378-090529 Años 2009-2010. Molecular markers for brain damage. Investigador Principal  Mario Herrera-Marschitz.

05.  Proyecto CONICYT DAAD 186-10-2006 Años 2007-2008. Perinatal asphyxia on rat  model: molecular markers for brain damage. Investigador Principal  Mario Herrera-Marschitz.

06.  Proyecto CONICET/LARC (Argentina/IBRO). Años (2006-2007). El estres prenatal como factor desencadenante de alteraciones del sistema dopaminérgico del cerebro adulto. Investigador principal Mario Herrera-Marschitz together with Prof. Dr. Marta Antonelli.

07. Proyecto ICBM/ENLACE Años 2006-2007. Plasticity of the CNS following perinatal asphyxia: is poly(ADP-ribose) Polimerase-1 (PARP-1) inhibition a strategy for neuroprotection? Investigador Principal Mario Herrera-Marschitz.

08. Proyecto SARDEGNA LR19-ITALY. Años 2005-2006. Pesticidi naturali e neurotossicita . Investigador principal Mario Herrera-Marschitz together with Prof.  Micaela Morelli.

09. Proyecto Fondecyt 103-0521. Años  2003-2005 Plasticity of the central nervous system: effect of perinatal asphyxia and metabolic insults. Investigador Principal Mario Herrera- Marschitz.

10. Proyecto DID I2-02/8-2, University of Chile, Años 2002-2004. Efectos de la asfixia perinatal en la neurogénesis hipocampal: modulación por el factor de crecimiento a fibroblasto básico (bFGF). Investigador Principal  Paola Morales.

11. Proyecto DID/University of Concepción.  Años 2003-2004.  Participacion de la transmission glutamatérgica como un mecanisamo comun de neuroadaptacion  en el proceso de sensibilizacion inducida por morfina o anfetamina. Investigador principal Mario Herrera-Marschitz together with Prof.  Jaqueline Sepúlveda.

12.        Proyecto Fondecyt 1000-626. Años 2000-2002Neurocircuitries of the basal ganglia studies with in vivo and in vitro techniques. Investigador principal Mario Herrera-Marschitz.

13. Swedish Medical Research Council (K2001-04X-08669-13B). Años 2000-2003. Neurocircuitry of the basal ganglia studied  with in vivo and in vitro models: effects of intracerebral and perinatal asphyxia lesions. Investigador principal Mario Herrera- Marschitz.

Publicaciones  (2002 a la fecha):

01.  Morales P, Simola N, Bustamante D, Lisboa F, Cardenas S, Fiedler J, Morelli M, Tasker RA, Herrera-Marschitz M (2010) Long lasting effects of perinatal asphyxia on behaviour and hippocampal plasticity: effect of nicotinamide. Exp. Brain Res 202: 1-14; 2010.

02.  Herrera-Marschitz M, Arbuthnott G, Ungerstedt U (2010). The rotational model and microdialysis: significance for dopamine signalling, clinical studies and beyond. Progress in Neurobiology 90:176-189., 2010.

03.  Espina-Marchant P, Pinto-Hamuy T, Bustamante D, Morales P, Herrera-Marschitz M (2009) Rat strain influences the use of egocentric learning strategies mediated by neostriatum. Experimental Brain Research 193: 205-212.

04.  Herrera-Marschitz M (2009) Neuromoduladores y transducción celular. Tema 10, Sección III. Comunicación interneuronal. JM Delgado, JV Fuentes (Eds) Master On Line en Neurociencia y Biología del Comportamiento 2009; Viguera Editores, S.L., Barcelona, Spain (ISBN 978-84-85424-73-3; pp 342-364.

05.  Morales P (2008). Long lasting structural changes in primary motor cortex after motor skill learning: a behavioural and stereological study.  Biol Res 41: 397-404

06.  Morales P, Fiedler JL, Andres S, Berrios C, Huaiquín P, Bustamante D, Cardenas S, Parra E, Herrera-Marschitz M (2008) Plasticity of the hippocampus following perinatal asphyxia: effects on postnatal apoptosis and neurogenesis. Journal Neuroscience Research 86: 2650-2662

07.  Bustamante D, Quintanilla ME, Tampier L, Gonzalez-Lira V, Israel Y, Herrera-Marschitz M (2008) Ethanol induces stronger dopamine release in nucleus accumbens (shell) of alcohol-preferring (bibulous) than in alcohol-avoiding (abstainer) rats. European journal of Pharmacology 591: 153-158

08.  Simola N, Bustamante D, Pinna A, Pontis S, Morales P, Morelli M, Herrera-Marschitz M. (2008). Acute perinatal asphyxia impairs non-spatial memory and alters motor coordination in adult male rats. Exp Brain Res. 185(4):595-601

09.  Quintanilla ME, Bustamante D, Tampier L, Israel Y, Herrera-Marschitz M. (2007).  Dopamine release in the nucleus accumbens (shell) of two lines of rats selectively bred to prefer or avoid ethanol. Eur J Pharmacol. Nov 14;573(1-3):84-92.

10.  Herrera-Marschitz M, Lubec G. In Memoriam Werner J. Schmidt. Amino Acids. 2007 Jul;33(1):1.

11.  Morales P, Huaiquín P, Bustamante D, Fiedler J, Herrera-Marschitz M. Perinatal asphyxia induces neurogenesis in hippocampus: an organotypic culture study. Neurotox Res. 2007 Jul;12(1):81-4.

12.  Herrera-Marschitz M, Bustamante D, Morales P, Goiny M. Exploring neurocircuitries of the basal ganglia by intracerebral administration of selective neurotoxins. Neurotox Res. 2007 Apr;11(3-4):169-82.

13.  Klawitter V, Morales P, Bustamante D, Gomez-Urquijo S, Hökfelt T, Herrera-Marschitz M.

Plasticity of basal ganglia neurocircuitries following perinatal asphyxia: effect of nicotinamide.

Exp Brain Res. 2007 Jun;180(1):139-52.

14.  Herrera-Marschitz M. On postnatal CNS plasticity. Amino Acids. 2006 Nov;31(4):357-8.

15.  Bustamante D, Morales P, Pereyra JT, Goiny M, Herrera-Marschitz M. Nicotinamide prevents the effect of perinatal asphyxia on dopamine release evaluated with in vivo microdialysis 3 months after birth. Exp Brain Res. 2007 Mar;177(3):358-69.

16.  Espina-Marchant P, Pinto-Hamuy T, Bustamante D, Morales P, Robles L, Herrera-Marschitz M.

(2006). Spatial cognition and memory: a reversible lesion with lidocaine into the anteromedial/posterior parietal cortex (AM/PPC) affects differently working and long-term memory on two foraging tasks. Biol Res.;39(4):601-9

17.  Romero CA, Bustamante DA, Zapata-Torres G, Goiny M, Cassels B, Herrera-Marschitz M. (2006). Neurochemical and behavioural characterisation of alkoxyamphetamine derivatives in rats. Neurotox Res. Aug;10(1):11-22.

18.  Andrés S, Cárdenas S, Parra C, Bravo J, Greiner M,  Rojas P, Morales P, Lara H, Fiedler JL. (2006). Effects of long-term adrenalectomy on apoptosis and neuroprotection in the rat hippocampus. Endocrine 29(2):299-307.

19.  Klawitter V, Morales P, Bustamante D, Goiny M, Herrera-Marschitz M. (2006). Plasticity of the central nervous system (CNS) following perinatal asphyxia: Does nicotinamide provide neuroprotection? Amino Acids. Nov;31(4):377-84. Epub Jul 31.

20.  Bravo JA, Parra CS, Arancibia S, Andrés S, Morales P, Herrera-Marschitz M, Herrera L, Lara HE, Fiedler JL. (2006). Adrenalectomy promotes a permanent decrease of plasma corticoid levels and a transient increase of apoptosis and the expression of Transforming Growth Factor beta1 (TGF-beta1) in hippocampus: effect of a TGF-beta1 oligo-antisense. BMC Neurosci. May 19;7:40.

21.  Morales P, Reyes P, Klawitter V, Huaiquín P, Bustamante D, Fiedler J, Herrera-Marschitz M. (2005). Effects of perinatal asphyxia on cell proliferation and neuronal phenotype evaluated with organotypic hippocampal cultures. Neuroscience. 135(2):421-31.

22.  Gross J, Andersson K, Chen Y, Müller I, Andreeva N, Herrera-Marschitz M. (2005).  Effect of perinatal asphyxia on tyrosine hydroxylase and D2 and D1 dopamine receptor mRNA levels expressed during early postnatal development in rat brain. Brain Res Mol Brain Res. Apr 4;134(2):275-81.

23.  Klawitter V, Morales P, Johansson S, Bustamante D, Goiny M, Gross J, Luthman J, Herrera-Marschitz M.  (2005). Effects of perinatal asphyxia on cell survival, neuronal phenotype and neurite growth evaluated with organotypic triple cultures. Amino Acids. Mar;28(2):149-55.

24.  Grasshoff C, Herrera-Marschitz M, Goiny M, Kretschmer BD. (2005). Modulation of ventral pallidal dopamine and glutamate release by the intravenous anesthetic propofol studied by in vivo microdialysis. Amino Acids. Mar;28(2):145-8.

25.  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-DOPA and L-deprenyl pre-treated rats. Neurotox Res.;5(8):569-77.

26.  Herrera-Marschitz M. (2004).  Transport proteins: targets for glutamate pharmacology?. Amino Acids. Mar;26(2):107-10.

27.  Morales P, Klawitter V, Johansson S, Huaiquín P, Barros VG, Avalos AM, Fiedler J, Bustamante D, Gomez-Urquijo S, Goiny M, Herrera-Marschitz M. (2003). Perinatal asphyxia impairs connectivity and dopamine neurite branching in organotypic triple culture from rat substantia nigra, neostriatum and neocortex. Neurosci Lett. Sep 18;348(3):175-9.

28.  Bustamante D, Goiny M, Aström G, Gross J, Andersson K, Herrera-Marschitz M. (2003).  Nicotinamide prevents the long-term effects of perinatal asphyxia on basal ganglia monoamine systems in the rat. Exp Brain Res. Jan;148(2):227-32.

29.  Segura-Aguilar J, Diaz-Veliz G, Mora S, Herrera-Marschitz M. (2002).  Inhibition of DT-diaphorase is a requirement for Mn(III) to produce a 6-OH-dopamine like rotational behaviour. Neurotox Res. Mar;4(2):127-31.

30.  Hökfelt T, Blacker D, Broberger C, Herrera-Marschitz M, Snyder G, Fisone G, Cortés R, Morino P, You ZB, Ogren SO. (2002). Some aspects on the anatomy and function of central cholecystokinin systems. Pharmacol Toxicol. Dec;91(6):382-6. Review.

31.  Bustamante D, You ZB, Castel MN, Johansson S, Goiny M, Terenius L, Hökfelt T, Herrera-Marschitz M.  (2002).  Effect of single and repeated methamphetamine treatment on neurotransmitter release in substantia nigra and neostriatum of the rat.J Neurochem. Nov;83(3):645-54.

32.  Cárdenas SP, Parra C, Bravo J, Morales P, Lara HE, Herrera-Marschitz M, Fiedler JL. (2002).  

Corticosterone differentially regulates bax, bcl-2 and bcl-x mRNA levels in the rat hippocampus. Neurosci Lett. Oct 4;331(1):9-12.

33.  Lindgren N, Goiny M, Herrera-Marschitz M, Haycock JW, Hökfelt T, Fisone G. (2002).   Activation of extracellular signal-regulated kinases 1 and 2 by depolarization stimulates tyrosine hydroxylase phosphorylation and dopamine synthesis in rat brain. Eur J Neurosci. Feb;15(4):769-73.