Gianfranco Di Renzo
e-mail: gianfranco.direnzo AT unina.it
website: www.unina.it
affiliation: Università di Napoli Federico II
research area(s): Neuroscience
Course:
Neurosciences
University/Istitution: Università di Napoli Federico II
University/Istitution: Università di Napoli Federico II
Full Professor of Pharmacology.
Department of Neuroscience
School of Medicine
University of Naples "Federico II"
Director of Pharmacovigilance Unit of School of Medicine
University of Naples "Federico II"
Past Director of the Dept. of Pharmacobiological Science and Past Coordinator of Research Doctorate in Pharmaceutical Science of the University "Magna Graecia di Catanzaro, Past President of Scientific Council of the Institute of Biotechnology Applied to Pharmacology of the National Research Council( Catanzaro)
Member of Research and Development Group of experts for AIFA
Member of Italian Pharmacological Society
Member of Italian Toxicology Society
Member of Italian Society of Neuroscience
Grants from CNR ,MURST, MIUR, National Health Service, AIFA
Publications: author of 90 full papers in internationally indexed journals
Referee for prestigeous.internationally recognized scientific journals.
Referee for research projects submitted to MIUR
Department of Neuroscience
School of Medicine
University of Naples "Federico II"
Director of Pharmacovigilance Unit of School of Medicine
University of Naples "Federico II"
Past Director of the Dept. of Pharmacobiological Science and Past Coordinator of Research Doctorate in Pharmaceutical Science of the University "Magna Graecia di Catanzaro, Past President of Scientific Council of the Institute of Biotechnology Applied to Pharmacology of the National Research Council( Catanzaro)
Member of Research and Development Group of experts for AIFA
Member of Italian Pharmacological Society
Member of Italian Toxicology Society
Member of Italian Society of Neuroscience
Grants from CNR ,MURST, MIUR, National Health Service, AIFA
Publications: author of 90 full papers in internationally indexed journals
Referee for prestigeous.internationally recognized scientific journals.
Referee for research projects submitted to MIUR
Athletes often take simultaneously anabolic steroids and aromatase inhibitors. Therefore neurotoxic potential of anabolic steroids can be increase by the simultaneous intake of aromatase inhibitors that cause an enhancement of these hormones in Central Nervous System. Furthermore these compounds should possess a neurotoxic potential that could esacerbate that of anabolic steroids.
The final aim of the present research project is the evaluation of neurotoxic effects of the association between anabolic steroids and aromatase inhibitors and the characterization of the molecular mechanisms involved. To this purpose cell damage induced by the exposure to anastrozole and letrozole, two aromatase inhibitors , for different times, associated or not with anabolic steroids, at different concentrations will be investigated in primary culture of rat astrocytes
The final aim of the present research project is the evaluation of neurotoxic effects of the association between anabolic steroids and aromatase inhibitors and the characterization of the molecular mechanisms involved. To this purpose cell damage induced by the exposure to anastrozole and letrozole, two aromatase inhibitors , for different times, associated or not with anabolic steroids, at different concentrations will be investigated in primary culture of rat astrocytes
Formisano L, Guida N, Cocco S, Secondo A, Sirabella R, Ulianich L, Paturzo F, Di Renzo G, Canzoniero LM(2011) The transcription factor REST is a novel molecular target for the neurotoxic effect of the polychlorinated biphenyl mixture Aroclor 1254 in neuroblastoma SH-SY5Y cells.J Pharmacol Exp Ther
Russo M, Cocco S, Secondo A, Adornetto A, Bassi A, Nunziata A, Polichetti G, De Felice B, Damiano S, Serù R, Mondola P, Di Renzo G.(2011) Cigarette smoke condensate causes a decrease of the gene expression of Cu-Zn superoxide dismutase, mn superoxide dismutase, glutathione peroxidase, catalase, and free radical-induced cell injury in SH-SY5Y human neuroblastoma cells. Neurotox Res.19:49-54
Molinaro P, Viggiano D, Nisticò R, Sirabella R, Secondo A, Boscia F, Pannaccione A, Scorziello A, Mehdawy B, Sokolow S, Herchuelz A, Di Renzo GF, Annunziato L (2011) Na+-Ca2+ Exchanger (NCX3) Knock-Out Mice Display an Impairment in Hippocampal Long-Term Potentiation and Spatial Learning and Memory. J Neurosci 31:7312-7321
Valsecchi V, Pignataro G, Del Prete A, Sirabella R, Matrone C, Boscia F, Scorziello A, Sisalli MJ, Esposito E, Zambrano N, Di Renzo G, Annunziato L (2011) NCX1 is a novel target gene for hypoxia-inducible factor-1 in ischemic brain preconditioning. Stroke 42:754-63
Secondo A, Molinaro P, Pannaccione A, Esposito A, Cantile M, Lippiello P, Sirabella R, Iwamoto T, Di Renzo G, Annunziato L (2011) Nitric oxide stimulates NCX1 and NCX2 but inhibits NCX3 isoform by three distinct molecular determinants. Mol Pharmacol 79:558-68
Pignataro G, Esposito E, Cuomo O, Sirabella R, Boscia F, Guida N, Di Renzo G, Annunziato L (2010) The NCX3 isoform of the Na+/Ca2+ exchanger contributes to neuroprotection elicited by ischemic postconditioning. J Cereb Blood Flow Metab 31:362-70
Esposito F, Pignataro G, Di Renzo G, Spinali A, Paccone A, Tedeschi G, Annunziato L (2010) Alcohol increases spontaneous BOLD signal fluctuations in the visual network. Neuroimage. 53:534-43
Boscia F, Gala R, Pannaccione A, Secondo A, Scorziello A, Di Renzo G, Annunziato L (2009) NCX1 expression and functional activity increase in microglia invading the infarct core. Stroke 40:3608-17
Secondo A, Pannaccione A, Molinaro P, Ambrosino P, Lippiello P, Esposito A, Cantile M, Khatri PR, Melisi D, Di Renzo G, Annunziato L (2009) Molecular pharmacology of the amiloride analog 3-amino-6-chloro-5-[(4-chloro-benzyl)amino]-n-[[(2,4-dimethylbenzyl)-amino]iminomethyl]-pyrazinecarboxamide (CB-DMB) as a pan inhibitor of the Na+-Ca2+ exchanger isoforms NCX1, NCX2, and NCX3 in stably transfected cells. J Pharmacol Exp Ther 331:212-21
Sirabella R, Secondo A, Pannaccione A, Scorziello A, Valsecchi V, Adornetto A, Bilo L, Di Renzo G, Annunziato L (2009) Anoxia-induced NF-kappaB-dependent upregulation of NCX1 contributes to Ca2+ refilling into endoplasmic reticulum in cortical neurons. Stroke 40:922-9
Pignataro G, Scorziello A, Di Renzo G, Annunziato L (2009) Post-ischemic brain damage: effect of ischemic preconditioning and postconditioning and identification of potential candidates for stroke therapy. FEBS J. 276:46-57
Molinaro P, Cuomo O, Pignataro G, Boscia F, Sirabella R, Pannaccione A, Secondo A, Scorziello A, Adornetto A, Gala R, Viggiano D, Sokolow S, Herchuelz A, Schurmans S, Di Renzo G, Annunziato L (2008) "Target distruption of Na+-Ca2+ exchanger 3 (NCX3) gene leads to a worsening of ischemic brain damage". J Neurosc 28:1179-1184
Cuomo O, Gala R, Pignataro G, Boscia F, Secondo A, Scorziello A, Pannaccione A, Viggiano D, Adornetto A, Molinaro P, Li XF, Lytton J, Di Renzo G, Annunziato L (2008) "A critical role for the potassium-dependent sodium-calcium exchanger NCKX2 in protection against focal ischemic brain damage". J Neurosc 28:2053-63
Molinaro P, Cuomo O, Pignataro G, Boscia F, Sirabella R, Pannaccione A, Secondo A, Scorziello A, Adornetto A, Gala R, Viggiano D, Sokolow S, Herchuelz A, Schurmans S, Di Renzo G, Annunziato L (2008) "Targeted disruption of Na+/Ca2+ exchanger 3 (NCX3) gene leads to a worsening of ischemic brain damage". J Neurosc 28:1179-1184
Formisano L, Saggese M, Secondo A, Sirabella R, Vito P, Valsecchi V, Molinaro P, Di Renzo G, Annunziato L (2008) "The two isoforms of the Na+/Ca2+ exchanger, NCX1 and NCX3, constitute novel additional targets for the prosurvival action of Akt/protein kinase B pathway". Mol Pharm 73:727-37
Scorziello A, Santillo M, Adornetto A, Dell'aversano C, Sirabella R, Damiano S, Canzoniero LM, Renzo GF, Annunziato L (2007) "NO-induced neuroprotection in ischemic preconditioning stimulates mitochondrial Mn-SOD activity and expression via RAS/ERK1/2 pathway". J Neuroch 103:1472-80
Cataldi M, Lariccia V, Marzaioli V, Cavaccini A, Curia G, Viggiano D, Canzoniero LM, Di Renzo G, Avoli M, Annunziato L (2007) "Zn2+ Slows Down Cav3.3 Gating Kinetics: Implications for Thalamocortical Activity". J Neurophysiol 98:2274-84
Russo M, Cocco S, Secondo A, Adornetto A, Bassi A, Nunziata A, Polichetti G, De Felice B, Damiano S, Serù R, Mondola P, Di Renzo G.(2011) Cigarette smoke condensate causes a decrease of the gene expression of Cu-Zn superoxide dismutase, mn superoxide dismutase, glutathione peroxidase, catalase, and free radical-induced cell injury in SH-SY5Y human neuroblastoma cells. Neurotox Res.19:49-54
Molinaro P, Viggiano D, Nisticò R, Sirabella R, Secondo A, Boscia F, Pannaccione A, Scorziello A, Mehdawy B, Sokolow S, Herchuelz A, Di Renzo GF, Annunziato L (2011) Na+-Ca2+ Exchanger (NCX3) Knock-Out Mice Display an Impairment in Hippocampal Long-Term Potentiation and Spatial Learning and Memory. J Neurosci 31:7312-7321
Valsecchi V, Pignataro G, Del Prete A, Sirabella R, Matrone C, Boscia F, Scorziello A, Sisalli MJ, Esposito E, Zambrano N, Di Renzo G, Annunziato L (2011) NCX1 is a novel target gene for hypoxia-inducible factor-1 in ischemic brain preconditioning. Stroke 42:754-63
Secondo A, Molinaro P, Pannaccione A, Esposito A, Cantile M, Lippiello P, Sirabella R, Iwamoto T, Di Renzo G, Annunziato L (2011) Nitric oxide stimulates NCX1 and NCX2 but inhibits NCX3 isoform by three distinct molecular determinants. Mol Pharmacol 79:558-68
Pignataro G, Esposito E, Cuomo O, Sirabella R, Boscia F, Guida N, Di Renzo G, Annunziato L (2010) The NCX3 isoform of the Na+/Ca2+ exchanger contributes to neuroprotection elicited by ischemic postconditioning. J Cereb Blood Flow Metab 31:362-70
Esposito F, Pignataro G, Di Renzo G, Spinali A, Paccone A, Tedeschi G, Annunziato L (2010) Alcohol increases spontaneous BOLD signal fluctuations in the visual network. Neuroimage. 53:534-43
Boscia F, Gala R, Pannaccione A, Secondo A, Scorziello A, Di Renzo G, Annunziato L (2009) NCX1 expression and functional activity increase in microglia invading the infarct core. Stroke 40:3608-17
Secondo A, Pannaccione A, Molinaro P, Ambrosino P, Lippiello P, Esposito A, Cantile M, Khatri PR, Melisi D, Di Renzo G, Annunziato L (2009) Molecular pharmacology of the amiloride analog 3-amino-6-chloro-5-[(4-chloro-benzyl)amino]-n-[[(2,4-dimethylbenzyl)-amino]iminomethyl]-pyrazinecarboxamide (CB-DMB) as a pan inhibitor of the Na+-Ca2+ exchanger isoforms NCX1, NCX2, and NCX3 in stably transfected cells. J Pharmacol Exp Ther 331:212-21
Sirabella R, Secondo A, Pannaccione A, Scorziello A, Valsecchi V, Adornetto A, Bilo L, Di Renzo G, Annunziato L (2009) Anoxia-induced NF-kappaB-dependent upregulation of NCX1 contributes to Ca2+ refilling into endoplasmic reticulum in cortical neurons. Stroke 40:922-9
Pignataro G, Scorziello A, Di Renzo G, Annunziato L (2009) Post-ischemic brain damage: effect of ischemic preconditioning and postconditioning and identification of potential candidates for stroke therapy. FEBS J. 276:46-57
Molinaro P, Cuomo O, Pignataro G, Boscia F, Sirabella R, Pannaccione A, Secondo A, Scorziello A, Adornetto A, Gala R, Viggiano D, Sokolow S, Herchuelz A, Schurmans S, Di Renzo G, Annunziato L (2008) "Target distruption of Na+-Ca2+ exchanger 3 (NCX3) gene leads to a worsening of ischemic brain damage". J Neurosc 28:1179-1184
Cuomo O, Gala R, Pignataro G, Boscia F, Secondo A, Scorziello A, Pannaccione A, Viggiano D, Adornetto A, Molinaro P, Li XF, Lytton J, Di Renzo G, Annunziato L (2008) "A critical role for the potassium-dependent sodium-calcium exchanger NCKX2 in protection against focal ischemic brain damage". J Neurosc 28:2053-63
Molinaro P, Cuomo O, Pignataro G, Boscia F, Sirabella R, Pannaccione A, Secondo A, Scorziello A, Adornetto A, Gala R, Viggiano D, Sokolow S, Herchuelz A, Schurmans S, Di Renzo G, Annunziato L (2008) "Targeted disruption of Na+/Ca2+ exchanger 3 (NCX3) gene leads to a worsening of ischemic brain damage". J Neurosc 28:1179-1184
Formisano L, Saggese M, Secondo A, Sirabella R, Vito P, Valsecchi V, Molinaro P, Di Renzo G, Annunziato L (2008) "The two isoforms of the Na+/Ca2+ exchanger, NCX1 and NCX3, constitute novel additional targets for the prosurvival action of Akt/protein kinase B pathway". Mol Pharm 73:727-37
Scorziello A, Santillo M, Adornetto A, Dell'aversano C, Sirabella R, Damiano S, Canzoniero LM, Renzo GF, Annunziato L (2007) "NO-induced neuroprotection in ischemic preconditioning stimulates mitochondrial Mn-SOD activity and expression via RAS/ERK1/2 pathway". J Neuroch 103:1472-80
Cataldi M, Lariccia V, Marzaioli V, Cavaccini A, Curia G, Viggiano D, Canzoniero LM, Di Renzo G, Avoli M, Annunziato L (2007) "Zn2+ Slows Down Cav3.3 Gating Kinetics: Implications for Thalamocortical Activity". J Neurophysiol 98:2274-84
Project Title:
Project Title:
Characterization of the neurotoxic effects of association anabolic steroids and aromatase inhibitors
Athletes often take simultaneously anabolic steroids and aromatase inhibitors. Therefore neurotoxic potential of anabolic steroids can be increase by the simultaneous intake of aromatase inhibitors that cause an enhancement of these hormones in Central Nervous System. Furthermore these compounds should possess a neurotoxic potential that could esacerbate that of anabolic steroids.
The final aim of the present research project is the evaluation of neurotoxic effects of the association between anabolic steroids and aromatase inhibitors and the characterization of the molecular mechanisms involved. To this purpose cell damage induced by the exposure to anastrozole and letrozole, two aromatase inhibitors , for different times, associated or not with anabolic steroids, at different concentrations will be investigated in primary culture of rat astrocytes.
The final aim of the present research project is the evaluation of neurotoxic effects of the association between anabolic steroids and aromatase inhibitors and the characterization of the molecular mechanisms involved. To this purpose cell damage induced by the exposure to anastrozole and letrozole, two aromatase inhibitors , for different times, associated or not with anabolic steroids, at different concentrations will be investigated in primary culture of rat astrocytes.
Project Title:
Identification of new molecular targets involved in pathogenesis of Parkinson Disease: new perspectives for a therapeutical approach
Parkinson's disease (PD) is the second most abundant neurodegenerative disease characterized by the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Neuropathologically, PD is characterized by accumulation of cytoplasmic deposits (Lewy bodies and Lewy neurites), with alfa-synuclein as the major fibrillar component. It is currently unclear whether insoluble deposits or, rather, soluble neurotoxic oligomers contribute to diseasemanifestation and progression. Postmortem studies have provided evidence for both oxidative damage and a decrease in the activity of mitochondrial complex-I inthe SNpc of patients with sporadic PD reinforcing the hypothesis that oxidative stress and mitochondrial dysfunction might play a prominent role in the pathogenesisof PD. Recent data reported in the literature demonstrated that a hepatic growth factor, known as Augumenter of Liver Regeneration protein (ALRP), was able to exert a protective effect against apoptosis induced in vitro by exposing SH-SY5Y, a dopaminergic neuroblastoma cell line of human origin, to oxidative stress (H2O2treatment). In this model, ALRP was able to inhibit cytochrome c mitochondrial release into the cytosol, to induce an up-regulation of Bcl2/Bax gene transcription,and to prevent mitochondrial swelling. These results let to hypothesize that ALRP might exert its protective role at the level of mitochondria. The current findingsshowing that ALR, a protein with sulphydryl oxidase activity, up-regulates mtDNA expression and ATP production further support this hypothesis. Interestingly, the gene coding for this protein has been identified, cloned and sequenced and, it has been also demonstrated that ALRP is mainly located in the mitochondrialinter-membrane space. Finally, ALRP mRNA was detected particular abundant in brain, muscle, testis and liver all tissues whose activity is mostly dependent onmitochondrial metabolism. Although it has been described the presence of ALRP in the brain, the information related to its distribution in specific brain regions or in the different cellular populations are still lacking. Moreover, there is no evidence attributing a role to this protein in brain dysfunction observed in neurodegenerativediseases.
On the light of these premise the present research project will be addressed to investigate the role of ALRP in the pathogenesis of Parkinson disease in order to identify new potential targets useful to develop innovative pharmacological strategies for the treatment of Parkinson Disease. To address this issue an animalmodel of PD consisting in a transgenic mice expressing human A30P mutant of alfa-synuclein gene under the control of Thymus cell antigen 1 promoter, will be used. In this animal model the distribution of ALR protein will be investigated in the brain areas particularly involved in the pathogenesis of PD. Moreover, the expression of ALR protein will be also explored in the different cellular population of the brain such as neurons and glial cells. Parallel experiments will be performed in the above mentioned transgenic model in order to identify the expression levels of proteins whose dysfunction is considered marker of oxidative stress such a MnSOD and nNOS. Finally, if an alteration in ALR protein expressionwill be detected in this transgenic model, further experiments will be performed in order to correlate the oxidative stress to the impairment of mitochondrialproteins. To this aim the effect of ALR treatment in transgenic mice will be explored on the expression of 1)mitochondrial proteins DRP1 and Mnf, involved in fixion and fusion processes;
2) MnSOD and nNOS, involved in oxidative stress and
3) VDAC and Cytochrome c involved in mitochondrial permeability control.
Furthermorein vitro studies will be performed in order to :
1) Evaluate mitochondrial function in neurons and glial cells deriving from transgenic mice. To this aim Mitochondrial membrane potential, Calcium concentrationsand free radical production will be considered
2) Evaluate the effect of a treatment with ALR on mitochondrial function in neurons obtained from wild type mice treated with rotenone, as a model of PD. disease
On the light of these premise the present research project will be addressed to investigate the role of ALRP in the pathogenesis of Parkinson disease in order to identify new potential targets useful to develop innovative pharmacological strategies for the treatment of Parkinson Disease. To address this issue an animalmodel of PD consisting in a transgenic mice expressing human A30P mutant of alfa-synuclein gene under the control of Thymus cell antigen 1 promoter, will be used. In this animal model the distribution of ALR protein will be investigated in the brain areas particularly involved in the pathogenesis of PD. Moreover, the expression of ALR protein will be also explored in the different cellular population of the brain such as neurons and glial cells. Parallel experiments will be performed in the above mentioned transgenic model in order to identify the expression levels of proteins whose dysfunction is considered marker of oxidative stress such a MnSOD and nNOS. Finally, if an alteration in ALR protein expressionwill be detected in this transgenic model, further experiments will be performed in order to correlate the oxidative stress to the impairment of mitochondrialproteins. To this aim the effect of ALR treatment in transgenic mice will be explored on the expression of 1)mitochondrial proteins DRP1 and Mnf, involved in fixion and fusion processes;
2) MnSOD and nNOS, involved in oxidative stress and
3) VDAC and Cytochrome c involved in mitochondrial permeability control.
Furthermorein vitro studies will be performed in order to :
1) Evaluate mitochondrial function in neurons and glial cells deriving from transgenic mice. To this aim Mitochondrial membrane potential, Calcium concentrationsand free radical production will be considered
2) Evaluate the effect of a treatment with ALR on mitochondrial function in neurons obtained from wild type mice treated with rotenone, as a model of PD. disease