title: Electrophysiological, behavioral and histological characterization of paclitaxel, cisplatin, vincristine and bortezomib-induced neuropathy in C57Bl/6 mice.
abstract: Polyneuropathy is a frequent and potentially severe side effect of clinical tumor chemotherapy. The goal of this study was to characterize paclitaxel-, cisplatin-, vincristine- and bortezomib-induced neuropathy in C57BL/6 mice with a comparative approach. The phenotype of the animals was evaluated at four time points with behavioral and electrophysiological tests, followed by histology. Treatment protocols used in this study were well tolerated and induced a sensory and predominantly axonal polyneuropathy. Behavioral testing revealed normal motor coordination, whereas all mice receiving verum treatment developed mechanical allodynia and distinct gait alterations. Electrophysiological evaluation showed a significant decrease of the caudal sensory nerve action potential amplitude for all cytostatic agents and a moderate reduction of nerve conduction velocity for cisplatin and paclitaxel. This finding was confirmed by histological analysis of the sciatic nerve which showed predominantly axonal damage: Paclitaxel and vincristine affected mostly large myelinated fibers, bortezomib small myelinated fibers and cisplatin damaged all types of myelinated fibers to a similar degree. Neuropathic symptoms developed faster in paclitaxel and vincristine treated animals compared to cisplatin and bortezomib treatment. The animal models in this study can be used to elucidate pathomechanisms underlying chemotherapy-induced polyneuropathy and for the development of novel therapeutic and preventative strategies.
authors.affiliation: 1] Klinik und Hochschulambulanz für Neurologie, Charité Universitätsmedizin Berlin, Berlin, Germany [2] Cluster of Excellence NeuroCure, Charité Universitätsmedizin Berlin, Berlin, Germany [3].
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Boehmerle
authors.affiliation: 1] Klinik und Hochschulambulanz für Neurologie, Charité Universitätsmedizin Berlin, Berlin, Germany [2] Cluster of Excellence NeuroCure, Charité Universitätsmedizin Berlin, Berlin, Germany [3].
authors.forename: Petra
authors.initials: P
authors.lastname: Huehnchen
authors.affiliation: Klinik und Hochschulambulanz für Neurologie, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Peruzzaro
authors.affiliation: 1] Klinik und Hochschulambulanz für Neurologie, Charité Universitätsmedizin Berlin, Berlin, Germany [2] Center for Stroke Research Berlin, Charité Universitätsmedizin Berlin, Berlin, Germany [3] Neurovascular research laboratory, Department of Radiology, Massachusetts general hospital and Harvard medical school, Boston, MA, USA.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Balkaya
authors.affiliation: 1] Klinik und Hochschulambulanz für Neurologie, Charité Universitätsmedizin Berlin, Berlin, Germany [2] Cluster of Excellence NeuroCure, Charité Universitätsmedizin Berlin, Berlin, Germany [3] Center for Stroke Research Berlin, Charité Universitätsmedizin Berlin, Berlin, Germany [4] German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Endres
mesh_terms: D000200:Action Potentials; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity; D001522:Behavior, Animal / Q000187:drug effects*; D001897:Boronic Acids / Q000633:toxicity*; D000069286:Bortezomib; D002945:Cisplatin / Q000633:toxicity*; D004594:Electrophysiology; D005684:Gait / Q000187:drug effects; D006930:Hyperalgesia / Q000139:chemically induced / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017239:Paclitaxel / Q000633:toxicity*; D011115:Polyneuropathies / Q000139:chemically induced / Q000473:pathology*; D011719:Pyrazines / Q000633:toxicity*; D014750:Vincristine / Q000633:toxicity*
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D001897:Boronic Acids; D011719:Pyrazines; D014750:Vincristine; D000069286:Bortezomib; D017239:Paclitaxel; D002945:Cisplatin