Influence of bortezomib on cognition in patients and C57Bl/6 mice

Published: 04-05-2020| Version 1 | DOI: 10.17632/nrj467zmj2.1
Petra Huehnchen,
Wolfgang Boehmerle


The 26S proteasome inhibitor bortezomib is currently used to treat multiple myeloma, but also is effective in the treatment of antibody-mediated autoimmune disorders. One clinical concern is bortezomib’s toxicity towards the (central) nervous system. We used standardized neuropsychological testing to assess cognitive function in six patients with myasthenia gravis and systemic lupus erythematodes before and after treatment with a mean cumulative dose of 9.4 mg m-2 bortezomib (TAVAB study, NCT02102594) . Additionally, cognitive performance was measured in adult C57Bl/6 mice after treatment with a human equivalent cumulative dose of 15.6 mg m-2. Bortezomib concentrations were analyzed in the human cerebral spinal fluid (CSF) as well as the brain tissue and serum of adult C57Bl/6 mice at various time points after injection of 1.3 mg m-2 bortezomib with liquid chromatography-tandem mass spectrometry. Neither patients nor mice showed signs of cognitive impairment after bortezomib therapy. Bortezomib concentrations in the human CSF and murine brain tissue reached only 5-7% of serum concentrations with comparable concentrations measured in the hippocampus and the neocortex. Five-fold higher concentrations were needed to damage neuronal cells in vitro. In conclusion, penetration of the intact blood-brain-barrier by bortezomib is low. Overall, our data shows that bortezomib is a safe medication in terms of central nervous system toxicity