[Show abstract][Hide abstract] ABSTRACT: Systemic chemotherapy is a cornerstone of the modern medical management of cancer, although its use is limited by toxicity on normal tissues and organs, including the nervous system. Long-surviving or cured people strongly require a high level of wellness in addition to prolongation of life (the concept of the quality of survival), but neurologic dysfunction can severely affect daily life activities. Chemotherapy-related peripheral neurotoxicity is becoming one of the most worrisome long-term side effects in patients affected by a neoplasm. The central nervous system has a limited capacity to recover from injuries, and it is not surprising that severe damage can determine long-term or permanent neurologic dysfunction. However, the peripheral nervous system also can be permanently damaged by anticancer treatments despite its better regeneration capacities, and the effect on patients' daily life activities might be extremely severe. However, only recently, the paradigms of peripheral neurotoxicity reversibility have been scientifically challenged, and studies have been performed to capture the patients' perspectives on this issue and to measure the effect of peripheral neurotoxicity on their daily life activities. Despite these efforts, knowledge about this problem is still largely incomplete, and further studies are necessary to clarify the several still-unsettled aspects of long-term peripheral neurotoxicity of conventional and targeted anticancer chemotherapy.
[Show abstract][Hide abstract] ABSTRACT: 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 MMinduced 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.
Journal of biological regulators and homeostatic agents 01/2015; 29(1):115-24. · 2.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate neurochemical changes associated with bortezomib-induced painful peripheral neuropathy (PN), we examined the effects of a single-dose intravenous administration of bortezomib and a well-established "chronic" schedule in a rat model of bortezomib-induced PN. The TRPV1 channel and sensory neuropeptides CGRP and substance P (SP) were studied in L4-L5 dorsal root ganglia (DRGs), spinal cord, and sciatic nerve. Behavioral measures, performed at the end of the chronic bortezomib treatment, confirmed a reduction of mechanical nociceptive threshold, whereas no difference occurred in thermal withdrawal latency. Western blot analysis showed a relative increase of TRPV1 in DRG and spinal cord after both acute and chronic bortezomib administration. Reverse transcriptase-polymerase chain reaction revealed a decrease of TRPV1 and CGRP mRNA relative levels after chronic treatment. Immunohistochemistry showed that in the DRGs, TRPV1-, CGRP-, and SP-immunoreactive neurons were mostly small- and medium-sized and the proportion of TRPV1- and CGRP-labeled neurons increased after treatment. A bortezomib-induced increase in density of TRPV1- and CGRP-immunoreactive innervation in the dorsal horn was also observed. Our findings show that bortezomib-treatment selectively affects subsets of DRG neurons likely involved in the processing of nociceptive stimuli and that neurochemical changes may contribute to development and persistence of pain in bortezomib-induced PN.
BioMed Research International 04/2014; 2014:180428. DOI:10.1155/2014/180428 · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To gain a better insight into the neurotoxicity of platinum drugs, it is important to increase our knowledge over the phenomena allowing their entry into dorsal root ganglia neurons. A deeper understanding of platinum-drug transport mechanisms in neurons would represent not only a step forward in the pathogenetic interpretation of their neurotoxicity, but would also disclose possible treatment options to prevent this severe side-effect achievable through modulation of transporter activity. Copper transporters and organic cation transporters have been identified as putative targets for the pharmacological modulation of neuronal cell accumulation of platinum drugs and damage, and this possibility has been demonstrated by animal studies. The modulation of drug transporter activity is a promising strategy to limit the neurotoxicity of platinum drugs, provided that a) complete characterization of drug transporters is obtained and b) selective neuronal activity is targeted without reducing anticancer drug efficacy.
Anticancer research 01/2014; 34(1):483-486. · 1.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bortezomib (BTZ) is the first proteasome inhibitor entered in clinical practice. Peripheral neuropathy is likely to be a class side effect of these drugs, although its severity is largely variable, and it deserves to be further investigated, since the mechanisms of BTZ-induced peripheral neurotoxicity (BiPN) are still unknown. In our study, we investigated in vivo and in vitro possible pathogenic events relevant to BiPN using a well-established rat model, with particular reference to the extent of proteasome inhibition and the effects on α-tubulin polymerization in sciatic nerves and dorsal root ganglia specimens obtained from animals treated with chronic regimens at a dose of 0.2 mg/kg intravenously. The same assessments were also performed after a single injection. Moreover, these studies were replicated in vitro using embryonic DRG neurons exposed to 100 nM BTZ and adult DRG neurons exposed to 10-50 nM BTZ for 24 h and 48 h. A significant increase in the polymerized fraction of a-tubulin and prolonged proteasome inhibition were observed after the chronic BTZ treatment in vivo. Recovery to physiological levels was observed after a 4-week follow-up post-treatment period. Proteasome inhibition and increased a-tubulin polymerization were also observed following BTZ treatment of both embryonic and adult DRG neurons in vitro. Our in vivo results suggest that proteasome inhibition and alteration of tubulin dynamics contribute to BiPN. The in vitro systems here described reliably replicate the in vivo results, and might therefore be used for further mechanistic studies on the effects of proteasome inhibitors on neurons.
[Show abstract][Hide abstract] ABSTRACT: Mucopolysaccharidosis type II (MPSII or Hunter Syndrome) is a lysosomal storage disorder caused by the deficit of iduronate 2-sulfatase (IDS) activity and characterized by progressive systemic and neurological impairment. As the early mechanisms leading to neuronal degeneration remain elusive, we chose to examine the properties of neural stem cells (NSCs) isolated from an animal model of the disease in order to evaluate whether their neurogenic potential could be used to recapitulate the early phases of neurogenesis in the brain of Hunter disease patients. Experiments here reported show that NSCs derived from the subventricular zone (SVZ) of early symptomatic IDS-knockout (IDS-ko) mouse retained self-renewal capacity in vitro, but differentiated earlier than wild-type (wt) cells, displaying an evident lysosomal aggregation in oligodendroglial and astroglial cells. Consistently, the SVZ of IDS-ko mice appeared similar to the wt SVZ, whereas the cortex and striatum presented a disorganized neuronal pattern together with a significant increase of glial apoptotic cells, suggesting that glial degeneration likely precedes neuronal demise. Interestingly, a very similar pattern was observed in the brain cortex of a Hunter patient. These observations both in vitro, in our model, and in vivo suggest that IDS deficit seems to affect the late phases of neurogenesis and/or the survival of mature cells rather than NSC self-renewal. In particular, platelet-derived growth factor receptor-α-positive (PDGFR-α+) glial progenitors appeared reduced in both the IDS-ko NSCs and in the IDS-ko mouse and human Hunter brains, compared with the respective healthy controls. Treatment of mutant NSCs with IDS or PDGF throughout differentiation was able to increase the number of PDGFR-α+ cells and to reduce that of apoptotic cells to levels comparable to wt. This evidence supports IDS-ko NSCs as a reliable in vitro model of the disease, and suggests the rescue of PDGFR-α+ glial cells as a therapeutic strategy to prevent neuronal degeneration.
[Show abstract][Hide abstract] ABSTRACT: Islet transplantation is a poorly investigated long-term strategy for insulin replacement and for treatment of complications in patients with diabetes. We investigated whether islet transplantation and insulin treatment can relieve diabetic neuropathy and rescue the residual endogenous pancreatic β cells. We used a multimodal approach, with five groups of Sprague-Dawley rats studied for 8 months: control rats, diabetic rats, insulin-treated diabetic rats with moderate or mild hyperglycemia, and diabetic rats transplanted with microencapsulated islets. Islet transplantation normalized glycemia and increased body and muscle weight; it was also effective in reducing proteinuria and altered liver function. Transplantation significantly improved tail nerve conduction velocity, Na(+)-K(+)-ATPase activity, and morphological alterations in the sciatic nerve as evidenced by decrease in g-ratio; it also restored thermal and ameliorated mechanical nociceptive thresholds. Morphometric analysis of pancreas indicated a significant β-cell volume increase in transplanted rats, compared with mildly and moderately hyperglycemic rats. Thus, allogeneic islet transplantation had a positive systemic effect in diabetic rats and induced regression of the established neuropathy and restitution of the typical characteristics of the islets. These findings strongly reinforce the need for improving glycemic control, not only to reverse established diabetic complications but also to improve β-cell status in diabetic pancreas.
American Journal Of Pathology 11/2013; 183(5):1527-38. DOI:10.1016/j.ajpath.2013.07.032 · 4.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The peripheral nervous system may be involved in several pathological events in patients with cancer and, in some cases, the evaluation and monitoring of nerve damage can be difficult. The target of drug-induced neurotoxicity is mostly dependent on the type and distribution of each substance that can act predominantly on the nerve fibers (axon or myelin) or on the neuronal body (dorsal root ganglia, primary sensory neurons, or, very occasionally, motor neurons). Accordingly, the clinical features of drug-induced neuropathies are also dependent on the type of agent involved, inducing exclusively sensory or sensorimotor neuropathies, with or without autonomic impairment and pain. Neurotoxic antineoplastic agents represent a major clinical problem given their widespread use, the potential severity of their toxicity, and the obvious reluctance of oncologists to change effective schedules of treatment despite the occurrence of side-effects. In view of the above, it is clear that chemotherapy-induced peripheral neurotoxicity should be assessed carefully and reliably. The most suitable tool for assessing and monitoring the neurotoxic effect of antineoplastic agents should be clinically relevant, fast and easy to use, reliable and reproducible, specific and sensitive to severity changes, formally validated, and universally accepted, and patients should be highly compliant with its items. The major advantages and limitations of the different methods used to evaluate and monitor peripheral nerve function in patients with cancer are discussed, with particular reference to the features of chemotherapy-induced peripheral neurotoxicity.
Handbook of Clinical Neurology 12/2012; 104:163-71. DOI:10.1016/B978-0-444-52138-5.00013-X
[Show abstract][Hide abstract] ABSTRACT: Although bortezomib (BTZ) is the frontline treatment for multiple myeloma, its clinical use is limited by the occurrence of painful peripheral neuropathy, whose treatment is still an unmet clinical need. Previous studies have shown chronic BTZ administration (0.20 mg/kg intravenously three times a week for 8 weeks) to female Wistar rats induced a peripheral neuropathy similar to that observed in humans. In this animal model of BTZ-induced neurotoxicity, the present authors evaluated the efficacy of CR4056, a novel I2 ligand endowed with a remarkable efficacy in several animal pain models. CR4056 was administered in a wide range of doses (0.6-60 mg/kg by gavage every day for 2-3 weeks) in comparison with buprenorphine (Bupre) (28.8 μg/kg subcutaneously every day for 2 weeks) and gabapentin (Gaba) (100 mg/kg by gavage every day for 3 weeks). Chronic administration of BTZ reduced nerve conduction velocity and induced allodynia. CR4056, Bupre, or Gaba did not affect the impaired nerve conduction velocity. Conversely, CR4056 dose-dependently reversed BTZ-induced allodynia (minimum effective dose 0.6 mg/kg). The optimal dose found, 6 mg/kg, provided a constant pain relief throughout the treatment period and without rebound after suspension, being effective when coadministered with BTZ, starting before or after allodynia was established, or when administered alone after BTZ cessation. A certain degree of tolerance was seen after 7 days of administration, but only at the highest doses (20 and 60 mg/kg). Bupre was effective only acutely, since tolerance was evident from the fourth day onwards. Gaba showed a significant activity only at the fourth day of treatment. CR4056, over the range of concentrations of 3-30 μM, was unable to hinder BTZ cytotoxicity on several tumor cell lines, which could indicate that this substance does not directly interfere with BTZ antitumor activity. Therefore, CR4056 could represent a new treatment option for BTZ-induced neuropathic pain.
Journal of Pain Research 06/2012; 5:151-67. DOI:10.2147/JPR.S32122
[Show abstract][Hide abstract] ABSTRACT: Glutamate is one of the major neurotrasmitters in mammalian brain and changes in its concentration have been associated with a number of neurological disorders, including neurodegenerative, cerebrovascular diseases and epilepsy. Moreover, recently a possible role for glutamatergic system dysfunction has been suggested also in the peripheral nervous system. This chapter will revise the current knowledge in the distribution of glutamate and of its receptors and transporters in the central nervous system.
Current Medicinal Chemistry 02/2012; 19(9):1269-76. DOI:10.2174/092986712799462711 · 3.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Glutamate carboxypeptidase II, also known as prostate specific membrane antigen or folate hydrolase I, is a type II transmembrane 750 amino acid membrane-bound glycoprotein, with a molecular weight in the human form of approximately 100 kDa and a demonstrated metallopeptidase activity. At the synaptic level it hydrolyzes N-acetylaspartylglutamate to N-acetyl-aspartate and glutamate. Its localization in the animal and human nervous system has only recently been clearly established, since many of the older studies gave conflicting results, likely due to the use of poorly characterized antibodies lacking epitope mapping and proper controls (i.e. immunohistochemistry complemented by western blot analysis and enzyme activity determination). In this chapter, we will review the available literature describing the animal and human distribution of glutamate carboxypeptidase in the central and peripheral nervous system.
Current Medicinal Chemistry 02/2012; 19(9):1277-81. DOI:10.2174/092986712799462568 · 3.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The peripheral nervous system is a frequent target of toxic agents. The accurate identification of the sites of neurotoxic action through the morphological characterization of reliable in vivo models or in vitro systems can give fundamental clues when investigating the pathogenesis and interpreting the clinical features of drug-induced neuropathy. The morphological approach has been used to investigate almost all the anticancer drugs able to induce chemotherapy-induced peripheral neurotoxicity, i.e. platinum drugs, antitubulins and proteasome inhibitors. No models have ever been described for thalidomide. This review demonstrates that any pathogenetic study on chemotherapy-induced peripheral neurotoxicity must be based on solid morphological observations obtained in reliable animal and in vitro models. This is particularly true in this setting, since the availability of tissues of human origin is extremely limited. In fact, peripheral (generally sural) nerve biopsies are never required for diagnostic purposes in chemotherapy-treated cancer patients, and their use for a purely scientific aim, although potentially very informative, is not ethical. Moreover, several neurotoxic drugs target the dorsal root ganglia neurons, and it is very difficult to obtain high-quality specimens even from early autopsies. It is, therefore, our opinion that an extensive morphological assessment of the in vitro and in vivo effect of any potentially neurotoxic antineoplastic drugs, as well as of neuroprotectant agents, should be taken into consideration right from the earliest stages of their development.
Italian journal of anatomy and embryology = Archivio italiano di anatomia ed embriologia 01/2012; 117(2):75-97.
[Show abstract][Hide abstract] ABSTRACT: The peripheral nervous system can be vulnerable to the toxic action of several drugs since it is not protected as effectively as the central nervous system from noxious exogenous agents. Drug-induced neurotoxicity can affect the nerve fibers or the neuronal bodies (generally the dorsal root ganglia of the primary sensory neurons). Among the neurotoxic drugs antineoplastic agents represent a major clinical problem, given their widespread use and the potential severity of their toxicity. In fact, the peripheral neurotoxicity of antineoplastic agents frequently represents one of their dose-limiting side effects. Moreover, even when antineoplastic agents' peripheral neurotoxicity is not dose-limiting, its onset may severely affect the quality of life of cancer patients and cause chronic discomfort. Among the anticancer chemotherapy drugs, platinum derivates, antitubulins, thalidomide and bortezomib can induce the most severe effects on the peripheral nervous system of the treated patients. Therefore, we will review the features of chemotherapy-induced peripheral neurotoxicity (CIPN) resulting from the administration of these drugs with a focus on new classes of promising antineoplastic agents, such as epothilones and proteasome inhibitors.
[Show abstract][Hide abstract] ABSTRACT: Development of advanced and high-throughput methods to study variability in human genes means we can now use pharmacogenomic analysis not only to predict response to treatment but also to assess the toxic action of drugs on normal cells (so-called toxicogenomics). This technological progress could enable us to identify individuals at high and low risk for a given side-effect. Pharmacogenomics could be very useful for stratification of cancer patients at risk of developing chemotherapy-induced peripheral neurotoxicity, one of the most severe and potentially permanent non-haematological side-effects of modern chemotherapeutic agents. However, study data reported so far are inconsistent, which suggests that methodological improvement is needed in clinical trials to obtain reliable results in this clinically relevant area.
The Lancet Oncology 06/2011; 12(12):1151-61. DOI:10.1016/S1470-2045(11)70131-0 · 24.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Glutamate is the major mediator of excitatory signalling in the mammalian central nervous system, but it has recently been shown to play a role in the transduction of sensory input at the periphery and in peripheral neuropathies. New advances in research have demonstrated that rat peripheral sensory terminals and dorsal root ganglia (DRG) express molecules involved in glutamate signalling, including high-affinity membrane-bound glutamate transporters (GLAST [glutamate aspartate transporter], GLT1 [glutamate transporter 1], EAAC1 [excitatory aminoacid transporter 1]) and that alterations in their expression and/or functionality can be implicated in several models of peripheral neuropathy, neuropathic pain and hyperalgesia. Here we describe, through immunoblotting, immunofluorescence assays and β-counter analysis of [(3)H] l-glutamate uptake, the expression, distribution and activity of the glutamate transporters in in vitro cultures of embryonic dorsal root ganglia sensory neurons, sensory neurons+satellite cells and satellite cells. In this work we demonstrated that glutamate transporters are expressed in all cultures with a peculiar pattern of distribution. Even if GLAST is strongly detected in satellite cells, it is slightly expressed also in sensory neurons. GLT1 immunostaining is very weak in DRG neurons, but it was evident in the satellite cells. Finally, EAAC1 is localized in the soma and in the neuritis of sensory neurons, while it is not detectable in satellite cells. Moreover, all the cell cultures showed a strong sodium-energy-dependent glutamate uptake activity and it is more marked in neurons alone or in co-culture with satellite cells compared to satellite cells alone. Finally, we show that the complete or partial pharmacological inhibition of glutamate transporters virtually completely or partially abolish glutamate uptake in all cell culture. These results, that demonstrate that functionally active glutamate transporters can be studied in dorsal root ganglia cell cultures, provide further evidence for a role of glutamatergic transport in the peripheral nervous system and will be useful for testing whether any changes occur in in vitro models of peripheral nervous system damage.
[Show abstract][Hide abstract] ABSTRACT: Epothilones, belonging to the family of microtubule stabilizing agents, have shown prolonged remissions and improved survival in various types of refractory, treatment-resistant cancer. Ixabepilone (BMS-247550) is the main representative of these compounds. Peripheral neuropathy is a significant toxicity of epothilones, eventually resulting in dose modification and changes in the treatment plan.
This review critically looks at the pathogenesis, incidence, risk factors, characteristics, and management of epothilone-induced peripheral neuropathy (EIPN). We also highlight areas of future research to pursue.
References were identified by searches of PubMed from 2000 until December 2010 with related terms.
The mechanism underlying EIPN remains rather unclear. Damage to the ganglion soma cells and peripheral axons through disruption of microtubules of the mitotic spindle and by interference with the axonal transport in the affected neurons may significantly contribute to the pathogenesis of EIPN. As a result, epothilones primarily produce an axonal, dose-dependent, sensory distal peripheral neuropathy, which is reversible in most cases on discontinuation of treatment. The incidence of EIPN is mainly related to risk factors, including cumulative dose and probably pre-existing neuropathy. To date, apart from the use of dose reduction and schedule change algorithm, there is no effective treatment with neuroprotective agents for EIPN.
EIPN remains a very challenging area in the field of toxic neuropathies. As such, there is a need for further preclinical and prospective clinical studies to elucidate the pathogenesis of EIPN and provide further robust evidence on its incidence, course, and reversibility.
Journal of pain and symptom management 05/2011; 42(6):931-40. DOI:10.1016/j.jpainsymman.2011.02.022 · 2.74 Impact Factor