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ABSTRACT: Erythropoietin (EPO) has neuroprotective effects in many models of damage and disease of the nervous system where neuroinflammation plays a substantial role, including experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). Since the first pioneering studies, in which EPO was shown to protect rats with acute EAE mainly by inhibiting inflammation, many other studies have pointed out other mechanisms of protection, including oligodendrogenesis and inhibition of axonal damage.Here we review the preclinical studies in which EPO has shown therapeutic efficacy in several models of EAE in mice and rats. Moreover, we report in detail the protocol to administer EPO to mice with myelin oligodendrocyte glycoprotein (MOG)-induced chronic progressive EAE, and a representative result. In this model, EPO inihibits the clinical score of the disease when administered according to a preventive but also to a therapeutic schedule, and therefore at disease onset, suggesting that it might not only inhibit inflammation but also actively stimulate repair.
Methods in molecular biology (Clifton, N.J.) 01/2013; 982:163-73.
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Ilaria Cervellini,
Ezia Bello,
Roberta Frapolli,
Carla Porretta-Serapiglia,
Norberto Oggioni,
Annalisa Canta,
Raffaella Lombardi,
Francesca Camozzi,
Ilaria Roglio,
Roberto Cosimo Melcangi,
Maurizio D'incalci,
Giuseppe Lauria,
Pietro Ghezzi,
Guido Cavaletti,
Roberto Bianchi
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ABSTRACT: Taxanes, including docetaxel (DOCE), are severely neurotoxic, causing disabling peripheral neuropathy. Co-treatment with neuroprotective agents has been proposed to prevent or reverse this. Besides its hemopoietic effects, erythropoietin (EPO) has neuroprotective and neurotrophic properties and when administered systemically it has a wide range of neuroprotective action in animal models of nervous system damage, including cisplatin-induced peripheral neurotoxicity. The present study investigated the effects of EPO on chemotherapy-induced peripheral neurotoxicity (CINP) by DOCE in vivo and whether it interfered with tumor growth or antitumor activity. Female Fischer rats bearing 13762 mammary carcinoma were randomly divided into four groups: untreated, treated with EPO, DOCE, or DOCE + EPO. DOCE was given once a week (5 mg/kg, i.v.) and EPO three times a week (50 microg/kg i.p.), for 4 weeks. Three other groups of rats without tumors were left untreated or given DOCE or DOCE + EPO. The rats were observed for 4 weeks after treatment. CINP and neuroprotection were evaluated by measuring nociception, electrophysiological, and biochemical parameters. EPO protected against CINP, and tumor growth in EPO-treated rats was the same as in controls. EPO significantly improved the thermal threshold, tail nerve conduction velocity, and intra-epidermal nerve fiber density. These benefits lasted through the follow-up period and EPO speeded-up spontaneous recovery after treatment withdrawal. EPO did not impair DOCE antitumor activity. Since CINP induced by DOCE reproduces the clinical utility of taxane in humans, the findings reported might provide a basis for investigating EPO as a neuroprotective agent in patients receiving therapy with DOCE.
Neurotoxicity Research 10/2009; 18(2):151-60. · 3.51 Impact Factor
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Alessia Chiorazzi,
Gabriella Nicolini,
Annalisa Canta,
Norberto Oggioni,
Roberta Rigolio,
Giacomo Cossa,
Raffaella Lombardi,
Ilaria Roglio, Ilaria Cervellini,
Giuseppe Lauria,
Roberto Cosimo Melcangi,
Roberto Bianchi,
Donatella Crippa,
Guido Cavaletti
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ABSTRACT: Epothilones are a novel class of microtubule-targeting anticancer agents that are neurotoxic. In this study, we investigated the epothilone B toxic effect in vitro and we characterized in vivo the general and neurological side effects of epothilone B administration in Wistar and Fischer rats. The in vitro experiments made it possible to explore a wide concentration range (0.1 nM-1 muM) and evidenced a dose-dependent effect of epothilone B exposure on neuron neurite elongation. This dose-dependent neurotoxic effect was confirmed in both in vivo studies performed on two different rat strains at the neurophysiological, behavioral and pathological levels in the dose range 0.25-1.5 mg/kg iv weekly x 4 weeks and tubulin hyper-polymerization was demonstrated in sciatic nerve specimens. These are the first studies of the neurological effects of epothilone B and they can provide a basis for extending pre-clinical investigation to other members of the epothilone family.
Neurobiology of Disease 06/2009; 35(2):270-7. · 5.40 Impact Factor
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ABSTRACT: Peripheral neurotoxicity is a frequent complication limiting docetaxel chemotherapy in patients with cancer. We developed an experimental model that closely mimics the course of neuropathy in patients, aiming to investigate both the mechanisms of neurotoxicity at biochemical, functional and morphological levels and the potential neuroprotective role of neuroactive steroids. We demonstrated that treatment with dihydroprogesterone (DHP) or progesterone (P) counteracts docetaxel-induced neuropathy, preventing nerve conduction and thermal threshold changes, and degeneration of skin nerves in the foodpad. Neuroactive steroids also counteract the changes in gene expression of several myelin proteins and calcitonin gene-related peptide induced by docetaxel in sciatic nerve and lumbar spinal cord, respectively. Most nerve abnormalities observed during the treatment with docetaxel spontaneously recovered after drug withdrawal, similarly to what occurs in patients. However, results of midterm follow-up experiments indicated that animals cotreated with DHP or P have a faster recovery of the neuropathy compared with docetaxel-treated rats. Our study confirmed that neuroactive steroids exert a protective effect on peripheral nerves at different levels, suggesting that they might represent a new therapeutic frontier for patients with chemotherapy-induced neuropathy.
Journal of the Peripheral Nervous System 04/2009; 14(1):36-44. · 2.80 Impact Factor
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Manuela Mengozzi, Ilaria Cervellini,
Paolo Bigini,
Sara Martone,
Antonella Biondi,
Rosetta Pedotti,
Barbara Gallo,
Sara Barbera,
Tiziana Mennini,
Mariaserena Boraso,
Marina Marinovich,
Edwige Petit,
Myriam Bernaudin,
Roberto Bianchi,
Barbara Viviani,
Pietro Ghezzi
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ABSTRACT: Erythropoietin (EPO) is of great interest as a therapy for many of the central nervous system (CNS) diseases and its administration is protective in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Endogenous EPO is induced by hypoxic/ischemic injury, but little is known about its expression in other CNS diseases. We report here that EPO expression in the spinal cord is induced in mouse models of chronic or relapsing-remitting EAE, and is prominently localized to motoneurons. We found a parallel increase of hypoxia-inducible transcription factor (HIF)-1 alpha, but not HIF-2 alpha, at the mRNA level, suggesting a possible role of non-hypoxic factors in EPO induction. EPO mRNA in the spinal cord was co-expressed with interferon (IFN)-gamma and tumor necrosis factor (TNF), and these cytokines inhibited EPO production in vitro in both neuronal and glial cells. Given the known inhibitory effect of EPO on neuroinflammation, our study indicates that EPO should be viewed as part of the inflammatory/anti-inflammatory network in MS.
Molecular Medicine 09/2008; 14(11-12):682-8. · 3.76 Impact Factor
