Peripheral neurotoxicity is one of the most distressing side effects of oxaliplatin therapy for cancer. Indeed, most patients that received oxaliplatin experience acute and/or chronic severe sensory peripheral neuropathy. However, despite similar co-morbidities, cancer stage, demographics and treatment schedule, patients develop oxaliplatin-induced peripheral neurotoxicity with remarkably different severity. This suggests individual genetic variability, which might be used to glean the mechanistic insights into oxaliplatin neurotoxicity. We characterized the susceptibility of different mice strains to oxaliplatin neurotoxicity investigating the phenotypic features of neuropathy and gene expression profiles in dorsal root ganglia of six genetically different mice strains (Balb-c, C57BL6, DBA/2J, AJ, FVB and CD1) exposed to the same oxaliplatin schedule. Differential gene expression in dorsal root ganglia from each mice strain were assayed using a genome-wide expression analysis and selected genes were validated by RT-PCR analysis. The demonstration of consistent differences in the phenotypic response to oxaliplatin across different strains is interesting to allow the selection of the appropriate strain based on the pre-defined read-out parameters. Further investigation of the correlation between gene expression changes and oxaliplatin-induced neurotoxicity phenotype in each strain will be useful to deeper investigate the molecular mechanisms of oxaliplatin neurotoxicity.

Oxaliplatin-induced peripheral neurotoxicity (OIPN) is a severe and potentially permanent side effect of cancer treatment affecting the majority of oxaliplatin-treated patients, mostly with the onset of acute symptoms, but also with the establishment of a chronic sensory loss that is supposed to be due to dorsal root ganglia neuron damage. The pathogenesis of acute as well as chronic OIPN is still not completely known, and this is a limitation in the identification of effective strategies to prevent or limit their occurrence. Despite intense investigation at the preclinical and clinical levels, no treatment can be suggested for the prevention of OIPN, and only limited evidence for the efficacy of duloxetine in the treatment setting has been provided. In this review, ongoing neuroprotection clinical trials in oxaliplatin-treated patients will be analyzed with particular attention paid to the hypothesis leading to the study, to the trial strengths and weaknesses, and to the outcome measures proposed to test the efficacy of the therapeutic approach. It can be concluded that (1) prevention and treatment of OIPN still remains an important and unmet clinical need, (2) further, high-quality research is mandatory in order to achieve reliable and effective results, and (3) dose and schedule modification of OHP-based chemotherapy is currently the most effective approach to limit the severity of OIPN.

Cortical reorganization occurring in multiple sclerosis (MS) patients is thought to play a key role in limiting the effect of structural tissue damage. Conversely, its exhaustion may contribute to the irreversible disability that accumulates with disease progression. Several aspects of MS-related cortical reorganization, including the overall functional effect and likely modulation by therapies, still remain to be elucidated. The aim of this work was to assess the extent of functional cortical reorganization and its brain structural/pathological correlates in Dark Agouti rats with experimental autoimmune encephalomyelitis (EAE), a widely accepted preclinical model of chronic MS. Morphological and functional MRI (fMRI) were performed before disease induction and during the relapsing and chronic phases of EAE. During somatosensory stimulation of the right forepaw, fMRI demonstrated that cortical reorganization occurs in both relapsing and chronic phases of EAE with increased activated volume and decreased laterality index versus baseline values. Voxel-based morphometry demonstrated gray matter (GM) atrophy in the cerebral cortex, and both GM and white matter atrophy were assessed by ex vivo pathology of the sensorimotor cortex and corpus callosum. Neuroinflammation persisted in the relapsing and chronic phases, with dendritic spine density in the layer IV sensory neurons inversely correlating with the number of cluster of differentiation 45-positive inflammatory lesions. Our work provides an innovative experimental platform that may be pivotal for the comprehension of key mechanisms responsible for the accumulation of irreversible brain damage and for the development of innovative therapies to reduce disability in EAE/MS. SIGNIFICANCE STATEMENT Since the early 2000s, functional MRI (fMRI) has demonstrated profound modifications in the recruitment of cortical areas during motor, cognitive, and sensory tasks in multiple sclerosis (MS) patients. Experimental autoimmune encephalomyelitis (EAE) represents a reliable model of the chronic-progressive variant of MS. fMRI studies in EAE have not been performed extensively up to now. This paper reports fMRI studies in a rat model of MS with somatosensory stimulation of the forepaw. We demonstrated modifications in the recruitment of cortical areas consistent with data from MS patients. To the best of our knowledge, this is the first report of cortical remodeling in a preclinical in vivo model of MS.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a severe adverse effect in patients receiving antitumor agents, and no effective treatment is available. Although the mechanisms responsible for the development of CIPN are poorly understood, recent findings make neuroinflammation an attractive target to be investigated, particularly when neuropathic pain is a prominent feature such as after bortezomib administration. The aim of our study was to evaluate the effect of intravenous immunoglobulins (IVIg) delivery in chronic CIPN. The related neuro-immune aspects were investigated in a well-characterized rat model of bortezomib-induced peripheral neurotoxicity (BIPN). After determination of a suitable schedule based on a preliminary pharmacokinetic pilot study, female Wistar rats were treated with IVIg 1 g/kg every 2 weeks. IVIg treatment was started at the beginning of bortezomib administration (“preventive” schedule), or once BIPN was already ensued after 4 weeks of treatment (“therapeutic” schedule). Neurophysiological and behavioral studies were performed to assess the extent of painful peripheral neurotoxicity induced by bortezomib, and these functional assessments were completed by pathologic examination of peripheral nerves and intraepidermal nerve fiber quantification (IENF). The role of the innate immune response in BIPN was investigated by immunochemistry characterization of macrophage infiltration in peripheral nerves. Both schedules of IVIg administration were able to significantly reduce bortezomib-induced heat and mechanical allodynia. Although these changes were not evidenced at the neurophysiological examination of peripheral nerves, they behavioral effects were paralleled in the animals treated with the preventive schedule by reduced axonopathy in peripheral nerves and significant protection from loss of IENF. Moreover, IVIg administration was very effective in reducing infiltration in peripheral nerves of macrophages with the M1, pro-inflammatory phenotype. Our results suggest a prominent role of neuroinflammation in BIPN and that IVIg might be considered as a possible safe and effective therapeutic option preventing M1 macrophage infiltration. However, since neuropathic pain is frequent also in other CIPN types, it also indicates the need for further investigation in other forms of CIPN.

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.

Peripheral neurotoxicity is the dose-limiting factor for clinical use of platinum derivatives, a class of anticancer drugs which includes cisplatin, carboplatin, and oxaliplatin. In particular cisplatin and oxaliplatin induce a severe peripheral neurotoxicity while carboplatin is less neurotoxic. The mechanisms proposed to explain these drugs’ neurotoxicity are dorsal root ganglia alteration, oxidative stress involvement, and mitochondrial dysfunction. Oxaliplatin also causes an acute and reversible neuropathy, supposed to be due by transient dysfunction of the voltage-gated sodium channels of sensory neurons. Recent studies suggest that individual genetic variation may play a role in the pathogenesis of platinum drug neurotoxicity. Even though all these mechanisms have been investigated, the pathogenesis is far from clearly defined. In this review we will summarize the current knowledge and the most up-to-date hypotheses on the mechanisms of platinum drug-induced peripheral neurotoxicity.