LABORATORY OF PHARMACOLOGY

Mechanisms of neuronal death in aging and neurodegenerative disorders. Determination of Targets of Drug Action

The research work of the “Grup de Recerca en Envelliment i Neurodegeneració” (GREN) is focused in neuronal cell death mechanisms in aging and neurodegenerative disorders using several in vitro and in vivo models. The study of cyclin dependent kinases (CDKs) as modulators of these processes is the main goal at present. Our results suggest that inhibitors of CDKs may be potential therapies in Alzheimer’s disease, Parkinson’s disease and in other neurological disorders. Moreover, it is clear the implication of reactive oxygen species (ROS) in neuronal death associated to aging or neuronal damage, therefore the study of antioxidants, as melatonin or tocopherol, is an interesting point to develop to prevent or delay the neuronal death.

• Molecular basis of neuronal cell death and mitochondria dysfunction. Modulation by drugs
• Experimental models of Senescence: Senescence accelerated mouse R1 and P8. Molecular basis and drug activity.

• Experimental models of neuronal cell death, apoptosis
• Experimental Pharmacology on aging
• Mammalian cell culture. Primary cultures of cerebellar granule cells
• Experimental Pharmacology on neuroprotective drugs and drugs acting on cell cycle.

• Centros de Investigación de Biomedicina en Red de Enfermedades Neurodegenerativas (CIBERNED)
• Mechanism of cerebral ageing: role of GSKß/cdk5 and Sirtuins. (2006, CiCYT Dra. M. Pallàs)
• The senescence-accelerated-mouse: a bona fide model to characterize early neuronal changes in Alzheimer's disease. (2006, Fundació La Marató TV3)
• Neuropharmacology research group: prevention of senescence and neuronal death (GREN). (2006, DURSI. 2005SGR00893).
• Regional and functional characterization of tau protein, cdk5 and gsk3beta in senescence accelerated mice (SAM) brain. (2005, CiCYT).
• Pathways implicated in apoptotic neuronal death after mitochondrial complex (I, II, II and IV. (2005, CICYT). Dr. Antoni Camins.
• Role of mitochondria in neuronal death: implication of DNA damage in apoptotic cell death. Ataxia Telangiectasia Mutated (ATM) modulation. (2004, FISS) Dr. Antoni Camins.

• Inhibition of cyclin-dependent kinases is neuroprotective in 1-methyl-4-phenylpyridinium (MPP+)-induced apoptosis in neurons Alvira, Daniel, Tajes Marta, Verdaguer Esther, García de Arriba, Susana, Allgaier Clemens, Matute, Carlos, Trullas Ramón, Jiménez, Andrés, Pallàs, Mercè and Camins Antoni. Neuroscience 2007
• Verdaguer E, de Arriba Susana G, Clemens A, Pallas M, Camins A. Implication of the transcription factor E2F-1 in the modulation of neuronal apoptosis. Biomed Pharmacother. 2007
• Camins A, Verdaguer E, Folch J, Canudas AM, Pallas M. The role of CDK5/P25 formation/inhibition in neurodegeneration. Drug News Perspect. 2006 19:453-460.
• Crespo-Biel N, Canudas AM, Camins A, Pallas M. Kainate induces AKT, ERK and cdk5/GSK3beta pathway deregulation, phosphorylates tau protein in mouse hippocampus. Neurochem Int. 2006
• Pallas M, Camins A. Molecular and biochemical features in Alzheimer's disease. Curr Pharm Des. 2006;12:4389-4408.
• Camins A, Verdaguer E, Folch J, Pallas M. Involvement of calpain activation in neurodegenerative processes. CNS Drug Rev. 2006 12:135-48
• Yeste M, Alvira D, Verdaguer E, Tajes M, Folch J, Rimbau V, Pallas M, Camins A. Evaluation of acute antiapoptotic effects of Li(+) in neuronal cell cultures. J Neural Transm. 2006
• Garcia de Arriba S, Wegner F, Gruner K, Verdaguer E, Pallas M, Camins A, Wagner A, Wohlfahrt K, Allgaier C. Different capacities of various NMDA receptor antagonists to prevent ischemia-induced neurodegeneration in human cultured NT2 neurons. Neurochem Int. 2006 49:466-474
• Sureda FX, Gutierrez-Cuesta J, Romeu M, Mulero M, Canudas AM, Camins A, Mallol J, Pallas M. Changes in oxidative stress parameters and neurodegeneration markers in the brain of the senescence-accelerated mice SAMP-8. Exp Gerontol. 2006 41:360-367.
• De Arriba SG, Krugel U, Regenthal R, Vissiennon Z, Verdaguer E, Lewerenz A, Garcia-Jorda E, Pallas M, Camins A, Munch G, Nieber K, Allgaier C. Carbonyl stress and NMDA receptor activation contribute to methylglyoxal neurotoxicity. Free Radic Biol Med. 2006 40:779-90.
• Alvarez-Garcia O, Vega-Naredo I, Sierra V, Caballero B, Tomas-Zapico C, Camins A, Garcia JJ, Pallas M, Coto-Montes A. Elevated oxidative stress in the brain of senescence-accelerated mice at 5 months of age. Biogerontology. 2006 7:43-52.
• Alvira D, Tajes M, Verdaguer E, Acuna-Castroviejo D, Folch J, Camins A, Pallas M. Inhibition of the cdk5/p25 fragment formation may explain the antiapoptotic effects of melatonin in an experimental model of Parkinson's disease. J Pineal Res. 2006 40:251-8.
• Jaekel B, Muhlberg K, Garcia de Arriba S, Reichenbach A, Verdaguer E, Pallas M, Camins A, Norenberg W, Allgaier C. Neuroprotection associated with alternative splicing of NMDA receptors in rat cortical neurons. Br J Pharmacol. 2006 147:622-33.
• Canudas AM, Gutierrez-Cuesta J, Rodriguez MI, Acuna-Castroviejo D, Sureda FX, Camins A, Pallas M. Hyperphosphorylation of microtubule-associated protein tau in senescence-accelerated mouse (SAM).Mech Ageing Dev. 2005
• Jorda EG, Verdaguer E, Canudas AM, Jimenez A, Garcia de Arriba S, Allgaier C, Pallas M, Camins A. Implication of cyclin-dependent kinase 5 in the neuroprotective properties of lithium. Neuroscience. 2005;134(3):1001-11.
• Verdaguer E, Jorda EG, Alvira D, Jimenez A, Canudas AM, Folch J, Rimbau V, Pallas M, Camins A. Inhibition of multiple pathways accounts for the antiapoptotic effects of flavopiridol on potassium withdrawal-induced apoptosis in neurons. J Mol Neurosci. 2005;26(1):71-84.
• Jorda EG, Verdaguer E, Jimenez A, Arriba SG, Allgaier C, Pallas M, Camins A. Evaluation of the neuronal apoptotic pathways involved in cytoskeletal disruption-induced apoptosis. Biochem Pharmacol. 2005 Aug 1;70(3):470-80.
• Verdaguer E, Alvira D, Jimenez A, Rimbau V, Camins A, Pallas M. Inhibition of the cdk5/MEF2 pathway is involved in the antiapoptotic properties of calpain inhibitors in cerebellar neurons. Br J Pharmacol. 2005 Aug;145(8):1103-11.
• Pubill D, Chipana C, Camins A, Pallas M, Camarasa J, Escubedo E. Free radical production induced by methamphetamine in rat striatal synaptosomes.Toxicol Appl Pharmacol. 2005 Apr 1;204(1):57-68.
• Jorda EG, Jimenez A, Verdaguer E, Canudas AM, Folch J, Sureda FX, Camins A, Pallas M. Evidence in favour of a role for peripheral-type benzodiazepine receptor ligands in amplification of neuronal apoptosis.Apoptosis. 2005 Jan;10(1):91-104.
• Jorda EG, Verdaguer E, Jimenez A, Canudas AM, Rimbau V, Camps P, Munoz-Torrero D, Camins A, Pallas M. (+/-)-huprine Y, (-)-huperzine A and tacrine do not show neuroprotective properties in an apoptotic model of neuronal cytoskeletal alteration. J Alzheimers Dis. 2004 Dec;6(6):577-83;.
• Verdaguer E, Jorda EG, Canudas AM, Jimenez A, Folch J, Rimbau V, Pallas M, Camins A. p21(WAF1/Cip1) is not involved in kainic acid-induced apoptosis in murine cerebellar granule cells. Brain Res. 2004 Dec 31;1030(2):297-302.
• Pallas M, Verdaguer E, Jorda EG, Jimenez A, Canudas AM, Camins A. Flavopiridol: an antitumor drug with potential application in the treatment of neurodegenerative diseases. Med Hypotheses. 2005;64(1):120-3.
• Jimenez A, Jorda EG, Verdaguer E, Pubill D, Sureda FX, Canudas AM, Escubedo E, Camarasa J, Camins A, Pallas M. Neurotoxicity of amphetamine derivatives is mediated by caspase pathway activation in rat cerebellar granule cells. Toxicol Appl Pharmacol. 2004 Apr 15;196(2):223-34.
• Verdaguer E, Jorda EG, Stranges A, Canudas AM, Jimenez A, Sureda FX, Pallas M, Camins A. Inhibition of CDKs: a strategy for preventing kainic acid-induced apoptosis in neurons. Ann N Y Acad Sci. 2003 Dec;1010:671-4.
• Verdaguer E, Jorda EG, Stranges A, Canudas AM, Jimenez A, Sureda FX, Pallas M, Camins A. Inhibition of CDKs: a strategy for preventing kainic acid-induced apoptosis in neurons. Ann N Y Acad Sci. 2003 Dec;1010:671-4.
• Canudas AM, Jorda EG, Verdaguer E, Jimenez A, Sureda FX, Rimbau V, Camins A, Pallas M. Cyclosporin A enhances colchicine-induced apoptosis in rat cerebellar granule neurons. Br J Pharmacol. 2004 Feb;141(4):661-9.
• Verdaguer E, Jimenez A, Canudas AM, Jorda EG, Sureda FX, Pallas M, Camins A. Inhibition of cell cycle pathway by flavopiridol promotes survival of cerebellar granule cells after an excitotoxic treatment. J Pharmacol Exp Ther. 2004 Feb;308(2):609-16.
• Verdaguer E, Jorda EG, Canudas AM, Jimenez A, Pubill D, Escubedo E, Camarasa J, Pallas M, Camins A. Antiapoptotic effects of roscovitine in cerebellar granule cells deprived of serum and potassium: a cell cycle-related mechanism. Neurochem Int. 2004 Mar;44(4):251-61.
• Jorda EG, Verdaguer E, Canudas AM, Jimenez A, Bruna A, Caelles C, Bravo R, Escubedo E, Pubill D, Camarasa J, Pallas M, Camins A. Neuroprotective action of flavopiridol, a cyclin-dependent kinase inhibitor, in colchicine-induced apoptosis. Neuropharmacology. 2003 Oct;45(5):672-83.
• Verdaguer E, Jorda EG, Canudas AM, Jimenez A, Sureda FX, Rimbau V, Pubill D, Escubedo E, Camarasa J, Pallas M, Camins A. 3-Amino thioacridone, a selective cyclin-dependent kinase 4 inhibitor, attenuates kainic acid-induced apoptosis in neurons. Neuroscience. 2003;120(3):599-603.
• Pubill D, Canudas AM, Pallas M, Camins A, Camarasa J, Escubedo E. Different glial response to methamphetamine- and methylenedioxymethamphetamine-induced neurotoxicity.Naunyn Schmiedebergs Arch Pharmacol. 2003 May;367(5):490-9.
• Canudas AM, Pubill D, Sureda FX, Verdaguer E, Camps P, Munoz-Torrero D, Jimenez A, Camins A, Pallas M. Neuroprotective effects of (+/-)-huprine Y on in vitro and in vivo models of excitoxicity damage. Exp Neurol. 2003 Apr;180(2):123-30.

• Signal transduction pathway activated in cerebral ischemia. TGF-alfa modulation. By Bibiana Friguls (2003). Project Directors: Anna Maria Planas and Mercè Pallàs
• Study of pathways implicaten in excitotoxicity in rat cerebellar granules cell. By Ester Verdaguer Cardona. (2004). Project Directors Dra. Mercè Pallàs y Dr. Antonio Camins
• Colchicine-induced cytoskeletal alteration and neuronal cell death in rat cerebellar granules cell. By Elvira Garcia Jordà. Project Directors Dra. Mercè Pallàs y Dr. Antonio Camins

6. Current collaborations 

• Dr. Francesc X. Sureda. Departament de Ciències Mèdiques Bàsiques. Universitat Rovira i Virgili.
• Dr. Jaume Folch. Departament deBioquímica. Universitat Rovira i Virgili.
• Dr. Ramon Trullás. Neurobiology Unit. IDIBABS. CSIC. Barcelona.
• Dr. Pelayo Camps and Dr. Diego Muñoz-Torrero. Unitat de Química Farmacèutica. Universitat de Barcelona (Spain)
• Dr. Clemens Allgaier. Rüdolf-Boehm- Institut für Pharmakology und Toxicology. University Leipzig. Germany.
• Reinhald Shliebs, Paul-Fleshing-Institut für Hirforchung. Lepzig. Germany.
• Dr. Mark Smith and Dra Gemma Casadesus. Institute of Pathology. Case Western Reserve University. Cleveland. USA.
• Dr. Carlos Beas, Molecular and Cell Biology Deparment. University of Guadalajara. Mexico.

8. Group members

Dr. Antoni Camins Espuny camins@ub.edu Dra. Mercè Pallàs Lliberia pallas@ub.edu Dr. Víctor Rimbau rimbau@ub.edu Dr. Andrés Jiménez Guerrero andresjimenez@ub.edu Dra. Anna Maria Canudas Teixidó canudas@ub.edu

9. Pre-doctoral students

• Daniel Alvira Cardona
• Natalia Crespo Biel
• Javier Garcia Pizarro
• Javier Gutierrez Cuesta
• Marta Tajes
• Marc Yeste Velasco