Bortezomib-induced painful neuropathy in rats: a behavioral, neurophysiological and pathological study in rats.
Bortezomib is a proteasome inhibitor showing strong antitumor activity against many tumors, primarily multiple myeloma. Bortezomib-induced neuropathic pain is the main side effect and the dose-limiting factor of the drug in clinical practice. In order to obtain a pre-clinical model to reproduce the characteristic pain symptoms in bortezomib-treated patients, we developed an animal model of bortezomib-induced nociceptive sensory neuropathy. In this study, bortezomib (0.15 or 0.20mg/kg) was administered to Wistar rats three times/week for 8 weeks, followed by a 4 week follow-up period. At the end of the treatment period a significant decrease in weight gain was observed in the treated groups vs. controls, and hematological and histopathological parameters were evaluated. After the treatment period, both doses of bortezomib induced a severe reduction in nerve conduction velocity and demonstrated a dose-cumulative effect of the drug. The sensory behavioral assessment showed the onset of mechanical allodynia, while no effect on thermal perception was observed. Sciatic nerves and dorsal root ganglia (DRG) were collected at the end of the 8-week treatment and at the end of the follow-up period. The pathological examination revealed a dose-dependent axonopathy of the unmyelinated fibers in nerves of treated animals. No pathological alteration in most of DRG satellite cells and neurons was observed. Therefore, this animal model may be useful for studying the neurotoxicity and pain onset mechanisms related to bortezomib treatment.
Meregalli
Cristina
C
Department of Neurosciences and Biomedical Technologies, University of Milan-Bicocca, Monza, Italy. c.meregalli2@campus.unimib.it
Canta
Annalisa
A
Carozzi
Valentina A
VA
Chiorazzi
Alessia
A
Oggioni
Norberto
N
Gilardini
Alessandra
A
Ceresa
Cecilia
C
Avezza
Federica
F
Crippa
Luca
L
Marmiroli
Paola
P
Cavaletti
Guido
G
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001522:Behavior, Animal / Q000187:drug effects; D001772:Blood Cell Count; D001774:Blood Chemical Analysis; D001835:Body Weight / Q000187:drug effects; D001897:Boronic Acids / Q000633:toxicity*; D000069286:Bortezomib; D004305:Dose-Response Relationship, Drug; D005260:Female; D006358:Hot Temperature; D009431:Neural Conduction / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000175:diagnosis / Q000473:pathology / Q000503:physiopathology; D010146:Pain / Q000523:psychology; D010147:Pain Measurement / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000473:pathology / Q000523:psychology; D011719:Pyrazines / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D012584:Sciatic Nerve / Q000473:pathology
D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib