Research Projects In vivo and in vitro models of chemotherapy-induced peripheral neurotoxicity
General aim of the project
The aim of this project is to establish and characterize the features of chemotherapy-induced peripheral neurotoxicity, with emphasis on the new compounds and on their mechanism(s) of action.
Background
Chemotherapy-induced peripheral neurotoxicity (CIPN) is a major clinical problem and should be prevented or cured because 1) it represents the dose-limiting side effect of a significant number of antineoplastic drugs, 2) it severely impairs the quality of life of cancer survivors.
CIPN is difficult to be investigated in humans, because patients are cured with combined schedules, frequently are treated more than once and target tissue biopsies cannot be performed for ethical reasons. Therefore, pre-clinical research may allow 1) to characterize reliable animal models of CIPN to better understand its pathogenesis and 2) to identify strategies to prevent or to treat CIPN in cancer survivors.
This proposal has 3 endpoints:
1) the determination and characterization of reliable animal and in vitro models
2) the investigation of the mechanism(s) of neural damage at the molecular level
3) the evaluation of a combined pharmacological approach to chemotheraphy-induced peripheral neurotoxicity (CIPN) neuroprotection.
Methods
Behavioral tests; neurophysiological examination; LM, LCSM and EM evaluation; molecular biology, flow cytometry.
References (2003-2007)
• Roglio I, Giatti S, Pesaresi M, Bianchi R, Cavaletti G, Lauria G, Garcia-Segura LM, Melcangi RC. Neuroactive steroids and peripheral neuropathy. Brain Res Rev. 2007 May 6; [Epub ahead of print]
• Roglio I, Bianchi R, Giatti S, Cavaletti G, Caruso D, Scurati S, Crippa D, Garcia-Segura LM, Camozzi F, Lauria G, Melcangi RC. Testosterone derivatives are neuroprotective agents in experimental diabetic neuropathy. Cell Mol Life Sci. 2007 May;64(9):1158-68.
• Bianchi R, Gilardini A, Rodriguez-Menendez V, Oggioni N, Canta A, Colombo T, De Michele G, Martone S, Sfacteria A, Piedemonte G, Grasso G, Beccaglia P, Ghezzi P, D'Incalci M, Lauria G, Cavaletti G. Cisplatin-induced peripheral neuropathy: neuroprotection by erythropoietin without affecting tumour growth. Eur J Cancer. 2007 Mar;43(4):710-7. Epub 2007 Jan 23.
• Cavaletti G, Gilardini A, Canta A, Rigamonti L, Rodriguez-Menendez V, Ceresa C, Marmiroli P, Bossi M, Oggioni N, D'Incalci M, De Coster R. Bortezomib-induced peripheral neurotoxicity: A neurophysiological and pathological study in the rat. Exp Neurol. 2007 Mar;204(1):317-25.
• Leonelli E, Bianchi R, Cavaletti G, Caruso D, Crippa D, Garcia-Segura LM, Lauria G, Magnaghi V, Roglio I, Melcangi RC. Progesterone and its derivatives are neuroprotective agents in experimental diabetic neuropathy: A multimodal analysis. Neuroscience. 2006 Dec 19;
• Cavaletti G, Marmiroli P The role of growth factors in the prevention and treatment of chemotherapy-induced peripheral neurotoxicity Curr Drug Safety. 2006 Jan;1:35-42
• Bianchi R, Brines M, Lauria G, Savino C, Gilardini A, Nicolini G, Rodriguez-Menendez V, Oggioni N, Canta A, Penza P, Lombardi R, Minoia C, Ronchi A, Cerami A, Ghezzi P, Cavaletti G. Protective effect of erythropoietin and its carbamylated derivative in experimental Cisplatin peripheral neurotoxicity. Clin Cancer Res. 2006 Apr 15;12(8):2607-12.
• Scuteri A, Nicolini G, Miloso M, Bossi M, Cavaletti G, Windebank AJ, Tredici G. Paclitaxel toxicity in post-mitotic dorsal root ganglion (DRG) cells. Anticancer Res. 2006 Mar-Apr;26(2A):1065-70.
• Villa D, Miloso M, Nicolini G, Rigolio R, Villa A, Cavaletti G, Tredici G. Low-dose cisplatin protects human neuroblastoma SH-SY5Y cells from paclitaxel-induced apoptosis. Mol Cancer Ther. 2005 Sep;4(9):1439-47.
• Lauria G, Lombardi R, Borgna M, Penza P, Bianchi R, Savino C, Canta A, Nicolini G, Marmiroli P, Cavaletti G. Intraepidermal nerve fiber density in rat foot pad: europathologic-neurophysiologic correlation. J Peripher Nerv Syst. 2005 Jun;10(2):202-8.
• Persohn E, Canta A, Schoepfer S, Traebert M, Mueller L, Gilardini A, Galbiati S, Nicolini G, Scuteri A, Lanzani F, Giussani G, Cavaletti G. Morphological and morphometric analysis of paclitaxel and docetaxel-induced peripheral neuropathy in rats. Eur J Cancer. 2005 Jul;41(10):1460-6.
• Cavaletti G, Marmiroli P. Chemotherapy-induced peripheral neurotoxicity. Expert Opin Drug Saf. 2004 Nov;3(6):535-46.
• Donzelli E, Carfi M, Miloso M, Strada A, Galbiati S, Bayssas M, Griffon-Etienne G, Cavaletti G, Petruccioli MG, Tredici G. Neurotoxicity of platinum compounds: comparison of the effects of cisplatin and oxaliplatin on the human neuroblastoma cell line SH-SY5Y. J Neurooncol. 2004 Mar-Apr;67(1-2):65-73.
• Bianchi R, Buyukakilli B, Brines M, Savino C, Cavaletti G, Oggioni N, Lauria G, Borgna M, Lombardi R, Cimen B, Comelekoglu U, Kanik A, Tataroglu C, Cerami A, Ghezzi P. Erythropoietin both protects from and reverses experimental diabetic neuropathy. Proc Natl Acad Sci U S A. 2004 Jan 20;101(3):823-8. Epub 2004 Jan 12.
• Pisano C, Pratesi G, Laccabue D, Zunino F, Lo Giudice P, Bellucci A, Pacifici L, Camerini B, Vesci L, Castorina M, Cicuzza S, Tredici G, Marmiroli P, Nicolini G, Galbiati S, Calvani M, Carminati P, Cavaletti G. Paclitaxel and Cisplatin-induced neurotoxicity: a protective role of acetyl-L-carnitine. Clin Cancer Res. 2003 Nov 15;9(15):5756-67.
Rodent models of human multiple sclerosis (Experimental Autoimmune Encephalomyelitis, EAE)
General aim of the project
The aim of this project is to investigate in well-characterized EAE models the pathogenesis of multiple sclerosis.
Background
Depite multiple sclerosi is a major cause of disability in young people and a wide body of knowledge is available regarding its clinical, radiological and pathological features, the basic mechanism of the disease are so far poorly understood.
The use of reliable animal (rodent) models of multiple sclerosis such as EAE allows to reproduce many of the aspects of the disease and to manipulate its course using different strategies of immune intervention.
This proposal aims at the investigation on the early events in the course of EAE with particular reference to cell activation and transendotheliam migration, in order
1) to increase the current knowledge on these crucial aspects of the autoimmune attack to central nervous system myelin
2) to modulate through pharmacological and non-pharmacological strategies the course of EAE.
Methods
Behavioral tests; LM, LCSM and EM evaluation; molecular biology; flow cytometry.
References
• Cavaletti G. Current status and future prospective of immunointervention in multiple sclerosis. Curr Med Chem. 2006;13(19):2329-43.
• Cavaletti G, Perseghin P, Dassi M, Cavarretta R, Frigo M, Caputo D, Stanzani L, Tagliabue E, Zoia C, Grimaldi M, Isella V, Rota S, Ferrarese C, Frattola L. Extracorporeal photochemotherapy: a safety and tolerability pilot study with preliminary efficacy results in refractory relapsing-remitting multiple sclerosis. Neurol Sci. 2006 Apr;27(1):24-32.
• Mazzanti B, Biagioli T, Aldinucci A, Cavaletti G, Cavalletti E, Oggioni N, Frigo M, Rota S, Tagliabue E, Ballerini C, Massacesi L, Riccio P, Lolli F. Effects of pixantrone on immune-cell function in the course of acute rat experimental allergic encephalomyelitis. J Neuroimmunol. 2005 Nov;168(1-2):111-7. Epub 2005 Aug 24.
• Cavaletti G, Perseghin P, Dassi M, Oggioni N, Sala F, Braga M, Lolli F, Riccio P, Carlone G, Zoia C, Tagliabue E, Stanzani L, Galbiati S, Rigamonti L, Marmiroli P, Ferrarese C, Frattola L, Tredici G. Extracorporeal photochemotherapy reduces the severity of Lewis rat experimental allergic encephalomyelitis through a modulation of the function of peripheral blood mononuclear cells. J Biol Regul Homeost Agents. 2004 Jan-Mar;18(1):9-17.
• Cavaletti G, Cavalletti E, Crippa L, Di Luccio E, Oggioni N, Mazzanti B, Biagioli T, Sala F, Sala V, Frigo M, Rota S, Tagliabue E, Stanzani L, Galbiati S, Rigolio R, Zoia C, Tredici G, Perseghin P, Dassi M, Riccio P, Lolli F. Pixantrone (BBR2778) reduces the severity of experimental allergic encephalomyelitis. J Neuroimmunol. 2004 Jun;151(1-2):55-65.
• Cavaletti G, Perseghin P, Dassi M, Oggioni N, Sala F, Lolli F, Riccio P, Tredici G, Frattola L. Extracorporeal photochemotherapy reduces the incidence of relapses in experimental allergic encephalomyelitis in DA rats. J Neurol. 2001 Jun;248(6):535-6.
• Cavaletti G, Perseghin P, Buscemi F, Dassi M, Oggioni N, Sala F, Lolli F, Liuzzi GM, Riccio P, Frattola L, Tredici G. Immunomodulating effects of extracorporeal photochemotherapy in rat experimental allergic encephalomyelitis. Int J Tissue React. 2001;23(1):21-31.
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