Neurophysiological, histological and immunohistochemical characterization of bortezomib-induced neuropathy in mice.
Bortezomib, a proteasome inhibitor, is an antineoplastic drug to treat multiple myeloma and mantle cell lymphoma. Its most clinically significant adverse event is peripheral sensory neuropathy. Our objective was to characterize the neuropathy induced by bortezomib in a mouse model. Two groups were used; one group received vehicle solution and another bortezomib (1mg/kg/twice/week) for 6weeks (total dose as human schedule). Tests were performed during treatment and for 4weeks post dosing to evaluate electrophysiological, autonomic, pain sensibility and sensory-motor function changes. At the end of treatment and after washout, sciatic and tibial nerves, dorsal ganglia and intraepidermal innervation were analyzed. Bortezomib induced progressive significant decrease of sensory action potential amplitude, mild reduction of sensory velocities without effect in motor conductions. Moreover, it significantly increased pain threshold and sensory-motor impairment at 6weeks. According to these data, histopathological findings shown a mild reduction of myelinated (-10%; p=0.001) and unmyelinated fibers (-27%; p=0.04), mostly involving large and C fibers, with abnormal vesicular inclusion body in unmyelinated axons. Neurons were also involved as shown by immunohistochemical phenotypic switch. After washout, partial recovery was observed in functional, electrophysiological and histological analyses. These results suggest that axon and myelin changes might be secondary to an initial dysfunctional neuronopathy.
Bruna
Jordi
J
Group of Neuroplasticity and Regeneration, Institute of Neurosciences and Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Bellaterra, Spain.
Udina
Esther
E
Alé
Albert
A
Vilches
Jorge J
JJ
Vynckier
Ann
A
Monbaliu
Johan
J
Silverman
Lee
L
Navarro
Xavier
X
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001897:Boronic Acids / Q000633:toxicity*; D000069286:Bortezomib; D004594:Electrophysiology; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000473:pathology; D007150:Immunohistochemistry; D051379:Mice; D008854:Microscopy, Electron; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology; D009186:Myelin Sheath / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D009431:Neural Conduction / Q000187:drug effects; D010146:Pain / Q000139:chemically induced / Q000473:pathology; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000473:pathology*; D011480:Protease Inhibitors / Q000633:toxicity*; D011719:Pyrazines / Q000633:toxicity*; D012584:Sciatic Nerve / Q000187:drug effects / Q000473:pathology; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000473:pathology; D012867:Skin / Q000294:innervation; D013979:Tibial Nerve / Q000187:drug effects / Q000473:pathology
D000970:Antineoplastic Agents; D001897:Boronic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib