Bortezomib-induced peripheral neurotoxicity in human multiple myeloma-bearing mice.

The proteasome inhibitor bortezomib is an antineoplastic drug mainly used for the treatment of multiple myeloma (MM). Despite its effectiveness, bortezomib clinical use is often limited by the onset of peripheral neuropathy (BiPN). To better understand the mechanisms of BiPN several rat and mice models have been proposed, but no studies in MM-bearing animals allowing to test the antitumor activity of the selected schedules and the role of MM by itself in peripheral nervous system damage have been reported to date. Here, we carried out a study using immunodeficient C.B-17/Prkdcscid (SCID) mice injected with RPMI8266 human MM cells and treated with bortezomib 1 mg/kg once a week for five weeks. Animals were assessed with neurophysiological, behavioral and pathological methods and tumor volume measurement was performed along the study. At the end of the study BiPN was evident in bortezomib-treated animals, and this neurotoxic effect was evident using a schedule able to effectively prevent tumor growth. However, neurophysiological and pathological evidence of MM induced peripheral nervous system damage was also reported. This model based on MM-bearing animals is more reliable in the reproduction of the clinical setting and it is, therefore, more suitable than the previously reported models of BiPN to study its pathogenesis. Moreover, it represents an optimal model to test the efficacy of neuroprotective agents and at the same time their non-interference with bortezomib antineoplastic activity.

Neuropathological changes in the peripheral nervous system and spinal cord in a transgenic mouse model of Niemann-Pick disease type A.

OBJECTIVE: Type A Niemann-Pick is a severe neurological disease, caused by a mutation of the gene of acid sphingomyelinase (ASM) and reduced enzyme activity. Some studies reported neuropathological changes occurring in the central nervous system of ASM deficient transgenic (ASMKO) mice, while a detailed study on the peripheral nervous system (PNS) at different ages is currently lacking. The aim of our study was to examine the pathological changes occurring in the PNS and in the spinal cord in an AMSKO model of Niemann-Pick disease (NPD) Type A. MATERIAL AND METHOD: Dorsal root ganglia (DRG), peripheral nerves and spinal cord specimens were obtained from ASMKO mice and age-matched wild type animals (age range = 1-7 months). They were observed at the light and electron microscope. Behavioral testing was performed to assess motor coordination and reactivity. Fluoro-Jade B was used as a high affinity fluorescent marker for degenerating neurons. RESULTS: Typical NPD cytoplasmic inclusions were observed in DRG neurons and satellite cells, in peripheral nerve Schwann cells, in spinal cord neurons and in endothelial cells. All these inclusions were present from the age of 1 month and increased with aging. By Fluoro-Jade B staining we demonstrated the occurrence of neuronal degeneration starting from 5 months of age. CONCLUSION: Despite the fact that a definite diagnosis of NPD Type A depends on enzymatic assays and/or molecular analysis, morphological investigation remains an important diagnostic procedure. Well-defined and complete neuropathological information about the ASMKO mouse model, inclusive of PNS examination, may be crucial in the pre-clinical evaluation of new therapies.

Human platelets express the synaptic markers VGLUT1 and 2 and release glutamate following aggregation.

Vesicular glutamate transporters (VGLUTs) are involved in storing glutamate for secretion at the level of glutamatergic axon terminals, and for this reason they have been extensively used as markers to identify glutamate-releasing cells. Platelets have been considered as a suitable model for studying glutamatergic dysfunction because they perform glutamate uptake and express both external transporters, and NMDA-like receptors. Here, we show that platelets express the pre-synaptic markers VGLUT1 and VGLUT2 and release glutamate following aggregation, implying a possible contributory role in the pathophysiology of stroke, migraine, and other excitotoxic disorders.

Targeting cancer and neuropathy with histone deacetylase inhibitors: two birds with one stone?

Histone deacetylase inhibitors (HDACi) belong to a novel class of drugs able to act on the epigenome, indirectly remodeling the spatial conformation of the chromatin: by increasing histone acetylation these drugs ultimately promote the detachment of the DNA from the nucleosome octamer, therefore allowing the access of transcription factors to the double helix. Such a mechanism of action is of particular interest in the field of cancer treatment, considering the reactivation of silenced tumor suppressor genes as an important target at which aiming; indeed, it is currently believed that dysregulation of the epigenome plays a major role in cancer. Interestingly, some of the compounds belonging to the HDACi family have also additional therapeutic properties, as in the case of valproate that may ameliorate neuropathic pain in animal models and in patients. Conceivably, this is a remarkable observation, since peripheral neuropathy is a potentially severe side effect of several classes of anticancer agents, such as platinum-derived drugs, antitubulins or protesome inhibitors, limiting an effective treatment of the underlying cancer. Based on these data, in this review we will argue that, with respect to other nowadays available anticancer agents, HDACi might offer the advantage not only to target the neoplastic disorder, but also to prevent peripheral neuropathies, possibly displaying a complementary mechanism of action.