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Abstracts of the 8th Meeting of the Italian Peripheral Nerve Study Group: 72
Author(s) -
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
Publication year - 2003
Publication title -
journal of the peripheral nervous system
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 67
eISSN - 1529-8027
pISSN - 1085-9489
DOI - 10.1046/j.1529-8027.2003.00072.x
Subject(s) - paclitaxel , cisplatin , neurotoxicity , neuroprotection , pharmacology , in vivo , chemotherapy induced peripheral neuropathy , peripheral neuropathy , in vitro , medicine , nerve growth factor , toxicity , chemistry , chemotherapy , biology , biochemistry , receptor , endocrinology , microbiology and biotechnology , diabetes mellitus
Peripheral neurotoxicity is a severe side effect of several effective antineoplastic drugs. Different attempts have been previously performed in order to reduce the neurotoxicity of antineoplastic compounds, but so far an effective neuroprotective treatment is not available. Acetyl‐l‐carnitine (ALC) is a natural occurring compound with a neuroprotective activity in several experimental paradigms and in clinical use for the treatment of painful neuropathies. In this study we have tested in two rat models the hypothesis that ALC may have a protective role on cisplatin‐ and paclitaxel‐induced neuropathy. Preliminary in vitro and in vivo experiments in different tumor systems indicated the lack of interference of ALC in the antitumor effects of cisplatin and paclitaxel. ALC co‐treatment was able to significantly reduce the neurotoxicity of both cisplatin and paclitaxel in well‐established rat models and this effect was correlated with a modulation of the plasma levels of nerve growth factor (NGF) in the cisplatin model. The protective effect of ALC was confirmed also in in vitro studies on differentiated rat pheochromocytoma PC12 cells, where ALC treatment counteracted the paclitaxel and cisplatin‐induced cell damage, as measured by reduction of neurite elongation. In a search for the mechanism(s) of ALC neuroprotection, the transcriptional profile of gene expression in PC12 cells determined by microarray analysis indicated that ALC, in the presence of NGF, was able to modulate various genes relevant in the tissue‐specific toxicity, such as NGFI‐A. Moreover, we observed that labeled acetyl groups derived from ALC were transferred into histones and that cells co‐treatment with NGF and ALC increased the level of histones H4 acetylation. These findings suggest that up‐regulation of genes implicated in the protection against specific damage induced by neurotoxic agent may be the result of modulation of histone acetylation mediated by transfer of ALC acetyl groups. Overall, these results provide the first evidence that ALC is a neuroprotective agent acting through a novel mechanism that appears to be important for counteracting the chemotherapy‐induced neurotoxicity secondary to cisplatin and paclitaxel treatment.