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• W1998175056 abstract "Loss of nerve growth factor-mediated neuronal survival has recently been proposed as a candidate mechanism underlying bortezomib-induced peripheral neuropathy (BIPN) (Broyl et al, 2010). However the literature does not reveal any data from patients that can support this hypothesis. Brain-derived neurotrophic factor (BDNF) is a neuronal growth factor that is crucial for neuronal survival and repair (Hofer & Barde, 1988). We report on alterations in BDNF peripheral blood levels and the development of BIPN in patients with multiple myeloma (MM). Following approval of the Ethics Committee and obtaining patient's informed consent, peripheral neuropathy was assessed and graded in 25 MM patients using the abbreviated version of the Total Neuropathy Score (TNS) tool (Argyriou et al, 2008). These patients were examined at diagnosis and after receiving four courses of a bortezomib-based regimen given intravenously either weekly or biweekly (Table 1). Patients that developed TNS ≥ 2 during treatment were determined to have BIPN and three patients with TNS ≥ 2 at diagnosis were excluded from the study. At the time of neurological examination, a venous blood sample was obtained and soluble BDNF (sBDNF) level was determined by a commercial enzyme-linked immunosorbent assay kit (R&D Systems, Minneapolis, MN, USA) in platelet-poor-plasma. One of our patients passed away after two courses of bortezomib. Eight of the remaining patients (36%) developed BIPN. We found lower levels of sBDNF in the plasma of patients that developed BIPN as compared to patients that did not develop BIPN [BDNF level ± standard deviation (SD) in BIPN 2·164 ± 0·721 vs. 4·62 ± 0·61 ng/ml in non-BIPN; P = 0·007; Fig 1A]. By analysing the difference between BDNF levels at diagnosis and after four courses of treatment of each patient, we demonstrated that sBDNF level was reduced in patients developing BIPN while it remained stable or even minimally elevated in patients that did not develop BIPN (difference in BDNF ± SD in BIPN −1·668 ± 0·670 vs. 0·405 ± 0·708 ng/ml in non-BIPN P = 0·02) (Fig 1B). Platelets are thought to be responsible for the homeostasis of BDNF in the blood as they take up, store and secrete BDNF (Fujimura et al, 2002). As we did not observe differences in the platelet counts of patients that developed BIPN compared to patients that did not develop BIPN (data not shown), we reasoned that decreased sBDNF levels in the plasma of patients with BIPN may result from lack of secretion of BDNF from the platelets. To test this hypothesis, we determined the content of BDNF in the platelets of patients that developed BIPN relative to those who did not develop BIPN by two different methods. First, platelets that were collected and stored in −20°C at the time of the patients' examination were lysed and the BDNF immunoreactive band was determined by gel electrophoresis using specific rabbit polyclonal anti-human BDNF mAb (Abcam, Cambridge, MA, USA). Second, BDNF and the platelet activation marker CD62p were determined in freshly isolated platelets of patients with BIPN and patients without BIPN using flow cytometry. Briefly, 20 μl of platelet-rich-plasma from each patient was stained with phycoerythrin-cyanin 5 (PE-CY5) Anti human CD41a monclonal antobody (mAb) (Beckmann Coulter, Brea, CA, USA) and PE anti human CD62p mAb (Biolegends, San Diego, CA, USA) or fixed permeabilized (Invitrogen, Frederick, MD, USA) and stained with ATTO-488 Anti human proBDNF pAb (Alomone Labs Ltd., Jerusalem, Israel). The intensity of surface CD62p or intracellular BDNF signal was determined in 10 000 platelets. Analysis of BDNF in platelets by gel electrophoresis suggested that BDNF content was increased in platelets of patients who developed BIPN as compared to platelets of patients that did not (mean BDNF expression level post-treatment relative to pre-treatment ± SD in BIPN 4·33 ± 1·15-fold vs. 1·67 ± 0·57-fold in non-BIPN P = 0·02) (Fig 1C). Flow cytometric analysis confirmed the increase of BDNF content in platelets of patients with BIPN, as detected by higher intensity of proBDNF compared to platelets of patients without BIPN [mean fluorescence intensity (MFI) of BDNF ± SD in BIPN 43·12 ± 6·04 vs. 18·267 ± 10·162 ng/ml in non-BIPN P = 0·009]. As expected, the increased BDNF signal in platelets of patients with BIPN coincided with lower platelet activity status as detected by their low CD62p expression (MFI of CD62p ± SD in BIPN 22·45 ± 2·70 vs. 28·33 ± 0·72 ng/ml in non-BIPN P = 0·01) (Fig 1D). Taken together, our results show reduced sBDNF levels in the plasma concomitant with elevated BDNF content in platelets of MM patients that developed BIPN. Peripheral neuropathy is a significant side effect of bortezomib treatment. Bortezomib inhibition of nuclear factor (NF)-κB activation was suggested to block the transcription of neurotrophins and thereby prevent neuronal survival (Richardson et al, 2003) and altered peripheral blood levels of BDNF were associated with neurological impairment (Azoulay et al, 2005). While the potential direct inhibitory effect of bortezomib on BDNF expression in the setting of BIPN should be further studied, our data suggest that another potential mechanism may also play an important role in this pathogenesis. BDNF is stored and transported in human platelets and released by agonist stimulation (Fujimura et al, 2002). Therefore, platelets appear to be a unique BDNF transportation system in the human body. Recent data suggest that platelet aggregation is inhibited by exposure to bortezomib (Avcu et al, 2008). In another study, platelets from MM patients treated with bortezomib showed diminished aggregation in response to several agonists (Zangari et al, 2008). The inhibitory effect of bortezomib on platelet aggregation and activation may explain our findings. By diminishing platelet activation, bortezomib inhibits BDNF release from its main storage compartment, therefore preventing its potential use for peripheral nerve repair. Bortezomib has a crucial role in the treatment of MM patients. However, BIPN is a major factor in reducing the quality of life of many MM patients. We believe that a possible explanation for the differences in patient susceptibility to bortezomib could result from background variation in the BDNF gene or in the level and function of BDNF maturation enzymes, both of which regulate BDNF secretion (Farhadi et al, 2000; Egan et al, 2003). We also cannot exclude the possibility that, in our study, the patients who developed BIPN had undetectable subclinical disease-related-neuropathy before starting treatment. These patients are highly dependent on BDNF in order to cope with their on going neuropathy and once they receive bortezomib their sBDNF reservoir is depleted. Further studies of the potential mechanisms underlying the regulation of BDNF in platelets could facilitate the development of new strategies for the diagnosis and prevention of BIPN. This study was supported by the Israeli Cancer Association grant (#20120086C). D. Azoulay designed and performed the research, analysed and interpreted data, performed statistical analysis and wrote the manuscript. D. Lavie designed and performed the research, collected data and analysed data. N. Horowitz interpreted data, wrote and critically revised the manuscript. C. Suriu, L. Akria and M. E. Gatt perform research and analysed data. R. Perlman critically revised the manuscript. A. Braester and D. Ben Yehuda interpreted data and critically revised the manuscript. The authors declare no potential conflict of interest." @default.
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• W1998175056 date "2013-10-25" @default.
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• W1998175056 title "Bortezomib‐induced peripheral neuropathy is related to altered levels of brain‐derived neurotrophic factor in the peripheral blood of patients with multiple myeloma" @default.
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