Bortezomib at therapeutic doses poorly passes the blood–brain barrier and does not impair cognition

Abstract

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. In addition, 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 analysed in the human CSF as well as the brain tissue and serum of adult C57Bl/6 mice at various time points after the 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 show that bortezomib is a safe medication in terms of central nervous system toxicity.

The Antagonism of the Prokineticin System Counteracts Bortezomib Induced Side Effects: Focus on Mood Alterations

“…In all these brain areas we find increased mRNA expression levels of the proinflammatory cytokines IL-6 and TNF-α associated with increased mRNA levels of CD11b in PFC or CD11b and GFAP in hypothalamus. It is known that BTZ poorly passes [ 39 , 40 , 41 ] BBB and it is possible to hypothesize that the absence of a complete BBB barrier [ 42 ] makes hypothalamus more susceptible to a direct BTZ action. As far as we know, no papers in literature report increased mRNA expression of CD11b or GFAP in brain regions following BTZ.…”

“…BBB integrity is fundamental for preventing drug entry into CNS and several papers suggest that BTZ poorly passes BBB [ 39 , 40 , 41 ]. However, our ultrastructural observations show endothelial cells morphologically intact surrounded by astrocytic processes extremely dilated/swollen so, we cannot rule out that BTZ or its metabolites could reach CNS exerting a cytotoxic effect.…”

Predicting Absorption-Distribution Properties of Neuroprotective Phosphine-Borane Compounds Using In Silico Modeling and Machine Learning

“…Among phosphine compounds the correlation between the QikProp and network predicted logBB was 0.994 and among phosphine oxide compounds the correlation was 0.995. The network predicted the logBB for boric acid to be 0.36 (actual 0.31) and for bortezomib to be −2.46 (actual −1.36 to −1.15) [ 17 , 18 ].…”

Targeting the apoptosis pathway to treat tumours of the paediatric nervous system

“…Encouragingly, this effect was also observed in an in vivo model of neuroblastoma [ 31 ], underscoring the potential clinical relevance of this combination. However, no clinical trials have been undertaken to assess the efficacy of this, as Bortezomib lacks the ability to cross the blood-brain barrier, limiting its relevance in the context of CNS tumours [ 33 ]. In this regard, another proteasome inhibitor, Marizomib, has increased potential as it can penetrate the blood-brain barrier, and is currently in a phase III trial in adult GBM patients (NCT03345095).…”