Paola Alberti
@unimib.it
Assistant Professor (Human Anatomy)
University of Milano-Bicocca
Her main expertise is related to peripheral nervous system diseases, especially Chemotherapy-Induced Peripheral Neurotoxicity (CIPN). She is an active member of the Toxic Neuropathy Consortium (TNC), part of the Peripheral Nervous System (PNS) society. During the Residency in Neurology, she was a visiting fellow at Johns Hopkins University (Prof. D.R. Cornblath, MD) to refine her knowledge of neurophysiological techniques. Since 2015 she has been pursuing an interest for preclinical research and joined the Experimental Neurology Unit (ENU, University of Milano-Bicocca) team, where she completed the PhD program in Neuroscience (2019). Her PhD project was focused on Oxaliplatin Induced Peripheral Neurotoxicity in preclinical models: she introduced advanced neurophysiological techniques, nerve excitability testing, to ENU after having learnt them from Prof H. Bostock, (UCL, London). She was a visiting fellow at University of Baltimore (Prof. S.G. Dorsey and Prof C. Renn) where learned DRG
EDUCATION
EDUCATION AND TRAINING
July 2010: Degree: MD – 110/110 cum laude – University of Milano-Bicocca (Monza, Italy)
June 2016 – Degree: Board in Neurology – 70/70 cum laude – University of Milano-Bicocca (Monza, Italy)
February 2019 – Degree: PhD in Neuroscience – University of Milano-Bicocca (Monza, Italy)
RESEARCH, TEACHING, or OTHER INTERESTS
Medicine, Anatomy, Neurology (clinical)
FUTURE PROJECTS
Sodium-calcium exchanger (NCX) and ion channels: pivotal elements leading to axonal damage in peripheral nerves?
The project investigates mechanisms leading to peripheral neuropathies (PN), with a specific interest for axonal damage. PN have many different causes: genetic, metabolic, toxic, dysimmune(Scuteri and Cavaletti, 2016). Patients affected by PN can experience impaired strength, sensation and involuntary functions (e.g. control of the gastrointestinal tract). Unfortunately, in the majority of cases there are only symptomatic treatments; this is partly due to the incomplete knowledge of axonal damage mechanisms. The project investigates a possible pathogenetic cascade, shared by different PN, with the aim of shedding light on the chronological and causative sequence of events leading to peripheral nerve axon damage. Goals Verifying the role of a particular molecular family, the sodium/calcium exchangers (NCX) family, as downstream pivotal elements leading to axonal damage.
Applications Invited
PhD students, postdoc. technicians
Scopus Publications
Scholar Citations
Scholar h-index
Scholar i10-index
Scopus Publications
Paola Alberti and Luis Querol
Wiley
Eleonora Pozzi, Maria Pina Serra, Marianna Boi, Annalisa Canta, Alessia Chiorazzi, Chiara Capelli, Chiara Invernizzi, Elisa Ballarini, Virginia Rodriguez‐Menendez, Margherita Francesca Kraus,et al.
Wiley
ABSTRACT Background and Aims Oxaliplatin (OHP) induced peripheral neurotoxicity (OIPN) is a complex spectrum comprising an acute and a chronic form. Acute OIPN leads to unpleasant transient sensations in the 24–72 h after chemotherapy, due to a temporary dysfunction in ion channels (i.e., axonal hyperexcitability in the absence of anatomical damage). Whereas chronic OIPN is characterized by painful manifestations. Literature data showed that a more pronounced acute OIPN could be an early predictor of chronic OIPN; thus, acute OIPN is becoming a possible target to prevent chronic OIPN. We went back to the bench side to characterize the complexity of painful phenomena experienced by OHP‐treated patients. Methods Female OHP‐treated (3 mg/Kg, 2qwx4ws, iv) and control rats ( n = 10/group) were studied. Acute OIPN was detected via nerve excitability testing (NET), whereas chronic OIPN was assessed via behavioral tests, nerve conduction studies (NCS), and neuropathology (including immunohistochemistry on lumbar spinal cord specimens) both at the end of the full chemotherapy treatment (4 weeks) and at 6 weeks of follow‐up. NET was also performed 1 week after treatment completion. Results NET alterations related to acute OIPN were resolved within a week after chemotherapy. Whereas, chronic OIPN encountered only partial recovery over time, with prominent small fiber damage. Immunolabeling of the spinal cord at the end of treatment and after the follow‐up period was consistent with persistent neuropathic pain. Interpretation Our data supports the statement that unpleasant manifestations due to acute and chronic OIPN mirror different underlying phenomena and assessment as two separate entities should be considered in both clinical and preclinical studies.
Paola Alberti and Eleonora Pozzi
MDPI AG
An exciting and relevant topic is addressed in this paper collection encompassing both peripheral and central nervous system mechanisms of damage [...]
Guido Cavaletti, Annalisa Canta, Alessia Chiorazzi, Eleonora Pozzi, Valentina Carozzi, Cristina Meregalli, Paola Alberti, Paola Marmiroli, Arianna Scuteri, Luca Crippa,et al.
MDPI AG
Chemotherapy-induced peripheral neuropathy remains a significant side effect of cancer treatment, often requiring dose reductions or even discontinuation of therapy. Paclitaxel (PTX), a widely used chemotherapeutic agent for solid tumors, is particularly neurotoxic, and no effective treatment exists for paclitaxel-induced peripheral neuropathy (PIPN). Histone deacetylases (HDACs) are enzymes that remove acetyl groups from histone and non-histone proteins, including transcription factors and cytoskeletal components. This study evaluates the HDAC6 inhibitor ITF6475 for its potential to prevent PIPN and compares its effects with ricolinostat, a well-established HDAC6 inhibitor previously studied in cisplatin-induced neuropathy models. Female C57BL/6 mice received PTX vehicle (VEH) or PTX (70 mg/kg intravenously, once per week for four weeks), and the remaining four groups received PTX with co-treatment of either ricolinostat (50 mg/kg orally, daily) or ITF6475 (1, 6, or 12.5 mg/kg orally, daily). Neurophysiological assessments at the end of treatment showed a significant reduction in caudal sensory nerve action potential amplitude across all PTX-treated groups compared to the VEH group. At the same time, PTX treatment led to the development of mechanical allodynia. However, co-treatment with the HDAC6 inhibitor prevented significant differences compared to the VEH group. PTX-induced reduction in intraepidermal nerve fiber density was significantly prevented in the PTX + ITF6475 (1 mg/kg) group, and PTX-induced increase in neurofilament light levels was reduced in all ITF6475 co-treated groups. These findings support the potential of ITF6475 in preventing small fiber damage in a severe, chronic PIPN model.
Daniel L. Hertz, Mary Tanay, Cindy Tofthagen, Emanuela Rossi, Davide Paolo Bernasconi, Katharine E. Sheffield, Martha Carlson, Larissa Nekhlyudov, Lisa Grech, Diane Von Ah,et al.
Springer Science and Business Media LLC
Sara Di Girolamo, Giulia Terribile, Paola Alberti, and Guido Cavaletti
Informa UK Limited
Irina Utkina-Sosunova, Alessia Chiorazzi, Mariangels de Planell-Saguer, Hai Li, Cristina Meregalli, Eleonora Pozzi, Valentina Alda Carozzi, Annalisa Canta, Laura Monza, Paola Alberti,et al.
Springer Science and Business Media LLC
Antonio Giuliano Zippo, Virginia Rodriguez‐Menendez, Eleonora Pozzi, Annalisa Canta, Alessia Chiorazzi, Elisa Ballarini, Laura Monza, Paola Alberti, Cristina Meregalli, Alberto Bravin,et al.
Wiley
AbstractBackground and AimsChemotherapy‐induced peripheral neurotoxicity (CIPN), with paraesthesia, numbness, dysesthesia and neuropathic pain ranks among the most common dose‐limiting toxicity of several widely used anticancer drugs. Recent studies revealed the microvascular angiogenesis as a new important actor, beside peripheral neurons, in the neurotoxicity and neuropathic pain development and chronicisation. The aim of this work is to elucidate the role of vascular alterations in CIPN.MethodsWe evaluated the severity of CIPN with neurophysiological, behavioural and neuropathological analysis together with the microvascular network in central and peripheral nervous systems of rats in order to correlate the features of the CIPN and the vascular abnormalities. The vascular network was quantitatively evaluated through synchrotron radiation‐based X‐ray phase‐contrast micro‐tomography imaging, measuring four specific parameters: vascular density, vessel diameter, vessel tortuosity and branching.ResultsRats exposed to paclitaxel and affected by a severe painful sensory axonopathy showed an increased vascular density (putative sprouting angiogenesis) in the crucial districts of the central (somatosensory cortex and lumbar spinal cord) and peripheral nervous system (lumbar dorsal root ganglia). In addition, the complexity of the vascular network and the size of neo‐formed vessels were significantly decreased in specific regions. On the other hand, less significant changes were observed in rats exposed to cisplatin, affected by a painless peripheral neuropathy, suggesting a specific involvement of neo‐angiogenesis in the development of severe neurotoxicity and neuropathic pain.InterpretationsThese new ground‐breaking results can shed light on new pathogenetic mechanisms and potential novel therapeutic approaches for painful‐CIPN.
Roser Velasco, Andreas A. Argyriou, David R. Cornblath, Pere Bruna, Paola Alberti, Emanuela Rossi, Ingemar S. J. Merkies, Dimitri Psimaras, Chiara Briani, Roy I. Lalisang,et al.
Wiley
AbstractBackground and PurposeChemotherapy‐induced peripheral neuropathy (CIPN) is perceived differently by patients and physicians, complicating its assessment. Current recommendations advocate combining clinical and patient‐reported outcomes measures, but this approach can be challenging in patient care. This multicenter European study aims to bridge the gap between patients' perceptions and neurological impairments by aligning both perspectives to improve treatment decision‐making.MethodsData were pooled from two prospective studies of subjects (n = 372) with established CIPN. Patient and physician views regarding CIPN were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI‐CTCAE), Total Neuropathy Scale–clinical version (TNSc) items, and the disease‐specific quality of life ‐ Chemotherapy‐Induced Peripheral Neuropathy questionnaire (QLQ‐CIPN20) from the European Organization for Research and Treatment of Cancer (EORTC). To identify inherent neurotoxic severity patterns, we employed hierarchical cluster analysis optimized with k‐means clustering and internally validated by discriminant functional analysis.ResultsBoth NCI‐CTCAE and TNSc demonstrated a significant difference in the distribution of severity grades in relation to QLQ‐CIPN20 scores. However, a proportion of subjects with different neurotoxic severity grades exhibited overlapping QLQ‐CIPN20 scores. We identified three distinct clusters classifying subjects as having severely impaired, intermediately impaired, and mildly impaired CIPN based on TNSc and QLQ‐CIPN20 scores. No differences in demographics, cancer type distribution, or class of drug received were observed.ConclusionsOur results confirm the heterogeneity in CIPN perception between patients and physicians and identify three well‐differentiated subgroups of patients delineated by degree of CIPN impairment based on scores derived from TNSc and QLQ‐CIPN20. A more refined assessment of CIPN could potentially be achieved using the calculator tool derived from the cluster equations in this study. This tool, which facilitates individual patient classification, requires prospective validation.
Guido Cavaletti, Paola Alberti, Annalisa Canta, Valentina Carozzi, Laura Cherchi, Alessia Chiorazzi, Luca Crippa, Paola Marmiroli, Cristina Meregalli, Eleonora Pozzi,et al.
Ovid Technologies (Wolters Kluwer Health)
Abstract Paclitaxel-induced peripheral neurotoxicity (PIPN) is a potentially dose-limiting side effect in anticancer chemotherapy. Several animal models of PIPN exist, but their results are sometimes difficult to be translated into the clinical setting. We compared 2 widely used PIPN models characterized by marked differences in their methodologies. Female C57BL/6JOlaHsd mice were used, and they received only paclitaxel vehicle (n = 38) or paclitaxel via intravenous injection (n = 19, 70 mg/kg) once a week for 4 weeks (Study 1) or intraperitoneally (n = 19, 10 mg/kg) every 2 days for 7 times (Study 2). At the end of treatment and in the follow-up, mice underwent behavioral and neurophysiological assessments of PIPN. At the same time points, some mice were killed and dorsal root ganglia, skin, and sciatic and caudal nerve samples underwent pathological examination. Serum neurofilament light levels were also measured. The differences in the neurotoxicity parameters were analyzed using a nonparametric Mann-Whitney test, with significance level set at P < 0.05. Study 1 showed significant and consistent behavioral, neurophysiological, pathological, and serological changes induced by paclitaxel administration at the end of treatment, and most of these changes were still evident in the follow-up period. By contrast, study 2 evidenced only a transient small fiber neuropathy, associated with neuropathic pain. Our comparative study clearly distinguished a PIPN model recapitulating all the clinical features of the human condition and a model showing only small fiber neuropathy with neuropathic pain induced by paclitaxel.
Raymond Javan Chan, Reegan Knowles, Fredrick D. Ashbury, Joanne Bowen, Alexandre Chan, Melissa Chin, Ian Olver, Carolyn Taylor, Stacey Tinianov, Paola Alberti,et al.
Elsevier BV
Eleonora Pozzi, Giulia Terribile, Laura Cherchi, Sara Di Girolamo, Giulio Sancini, and Paola Alberti
MDPI AG
The peripheral nervous system can encounter alterations due to exposure to some of the most commonly used anticancer drugs (platinum drugs, taxanes, vinca alkaloids, proteasome inhibitors, thalidomide), the so-called chemotherapy-induced peripheral neurotoxicity (CIPN). CIPN can be long-lasting or even permanent, and it is detrimental for the quality of life of cancer survivors, being associated with persistent disturbances such as sensory loss and neuropathic pain at limb extremities due to a mostly sensory axonal polyneuropathy/neuronopathy. In the state of the art, there is no efficacious preventive/curative treatment for this condition. Among the reasons for this unmet clinical and scientific need, there is an uncomplete knowledge of the pathogenetic mechanisms. Ion channels and transporters are pivotal elements in both the central and peripheral nervous system, and there is a growing body of literature suggesting that they might play a role in CIPN development. In this review, we first describe the biophysical properties of these targets and then report existing data for the involvement of ion channels and transporters in CIPN, thus paving the way for new approaches/druggable targets to cure and/or prevent CIPN.
Alessia Chiorazzi, Annalisa Canta, Valentina Alda Carozzi, Cristina Meregalli, Eleonora Pozzi, Elisa Ballarini, Virginia Rodriguez‐Menendez, Paola Marmiroli, Guido Cavaletti, and Paola Alberti
Wiley
AbstractBackground and AimsChemotherapy‐induced peripheral neurotoxicity (CIPN) is a common and long‐lasting adverse event of several anticancer compounds, for which treatment has not yet been developed. To fill this gap, preclinical studies are warranted, exploiting highly translational outcome measure(s) to transfer data from bench to bedside. Nerve excitability testing (NET) enables to test in vivo axonal properties and can be used to monitor early changes leading to axonal damage.MethodsWe tested NET use in two different CIPN rat models: oxaliplatin (OHP) and paclitaxel (PTX). Animals (female) were chronically treated with either PTX or OHP and compared to respective control animals. NET was performed as soon as the first injection was administered. At the end of the treatment, CIPN onset was verified via a multimodal and robust approach: nerve conduction studies, nerve morphometry, behavioural tests and intraepidermal nerve fibre density.ResultsNET showed the typical pattern of axonal hyperexcitability in the 72 h following the first OHP administration, whereas it showed precocious signs of axonal damage in PTX animals. At the end of the month of treatment, OHP animals showed a pattern compatible with a mild axonal sensory polyneuropathy. Instead, PTX cohort was characterised by a rather severe sensory axonal polyneuropathy with minor signs of motor involvement.InterpretationNET after the first administration demonstrated the ongoing OHP‐related channelopathy, whereas in PTX cohort it showed precocious signs of axonal damage. Therefore, NET could be suggested as an early surrogate marker in clinical trials, to detect precocious changes leading to axonal damage.
Roberta Bonomo, Annalisa Canta, Alessia Chiorazzi, Valentina Alda Carozzi, Cristina Meregalli, Eleonora Pozzi, Paola Alberti, Cecile F. Frampas, Daan R. Van der Veen, Paola Marmiroli,et al.
Wiley
AbstractBackground and AimsChemotherapy‐induced peripheral neurotoxicity (CIPN) is one of the most common dose‐limiting side effects of paclitaxel (PTX) treatment. Many age‐related changes have been hypothesized to underlie susceptibility to damage or impaired regeneration/repair after nerve injury. The results of these studies, however, are inconclusive and other potential biomarkers of nerve impairment need to be investigated.MethodsTwenty‐four young (2 months) and 24 adult (9 months) Wistar male rats were randomized to either PTX treatment (10 mg/kg i.v. once/week for 4 weeks) or vehicle administration. Neurophysiological and behavioral tests were performed at baseline, after 4 weeks of treatment and 2‐week follow‐up. Skin biopsies and nerve specimens collected from sacrificed animals were examined for intraepidermal nerve fiber (IENF) density assessment and nerve morphology/morphometry. Blood and liver samples were collected for targeted metabolomics analysis.ResultsAt the end of treatment, the neurophysiological studies revealed a reduction in sensory nerve action potential amplitude (p < .05) in the caudal nerve of young PTX‐animals, and in both the digital and caudal nerve of adult PTX‐animals (p < .05). A significant decrease in the mechanical threshold was observed only in young PTX‐animals (p < .001), but not in adult PTX‐ones. Nevertheless, both young and adult PTX‐rats had reduced IENF density (p < .0001), which persisted at the end of follow‐up period. Targeted metabolomics analysis showed significant differences in the plasma metabolite profiles between PTX‐animals developing peripheral neuropathy and age‐matched controls, with triglycerides, diglycerides, acylcarnitines, carnosine, long chain ceramides, sphingolipids, and bile acids playing a major role in the response to PTX administration.InterpretationOur study identifies for the first time multiple related metabolic axes involved in PTX‐induced peripheral neurotoxicity, and suggests age‐related differences in CIPN manifestations and in the metabolic profile.
Paola Alberti, Andreas A. Argyriou, Jordi Bruna, M. Imad Damaj, Sara Faithfull, Alice Harding, Ahmet Hoke, Robert Knoerl, Noah Kolb, Tiffany Li,et al.
Springer Science and Business Media LLC
Paola Alberti, Andreas A. Argyriou, Jordi Bruna, M. Imad Damaj, Sara Faithfull, Alice Harding, Ahmet Hoke, Robert Knoerl, Noah Kolb, Tiffany Li,et al.
Springer Science and Business Media LLC
Abstract Purpose This white paper provides guidance regarding the process for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research. Methods An international multidisciplinary group of CIPN scientists, clinicians, research administrators, and legal experts have pooled their collective knowledge regarding recommendations for establishing and maintaining international collaboration to foster advancement of CIPN science. Results Experts provide recommendations in 10 categories: (1) preclinical and (2) clinical research collaboration; (3) collaborators and consortiums; (4) communication; (5) funding; (6) international regulatory standards; (7) staff training; (8) data management, quality control, and data sharing; (9) dissemination across disciplines and countries; and (10) additional recommendations about feasibility, policy, and mentorship. Conclusion Recommendations to establish and maintain international CIPN research collaboration will promote the inclusion of more diverse research participants, increasing consideration of cultural and genetic factors that are essential to inform innovative precision medicine interventions and propel scientific discovery to benefit cancer survivors worldwide. Relevance to inform research policy Our suggested guidelines for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research set forth a challenge to multinational science, clinical, and policy leaders to (1) develop simple, streamlined research designs; (2) address logistical barriers; (3) simplify and standardize regulatory requirements across countries; (4) increase funding to support international collaboration; and (5) foster faculty mentorship.
Paola Alberti
Firenze University Press
Neuroanatomy knowledge is pivotal due to the constantly increased use of neuroimaging in everyday clinical practice, even in the emergency setting as it is for patients potentially affected by stroke. To empower our students, we are relying on innovative 3D digital tools to teach human anatomy, exploiting several approaches among which Anatomage TableTM, also fostering a peer-to-peer tutor program. We present here the results of a pilot phase of these initiatives. First year med students from the Italian and International Course used Anatomage TableTM under the supervision of fourth-, fifth-, or sixth-year med students, as peer-to-peer tutors. Participants were divided into groups (10-12 people each). Three sessions lasting 2 hours were planned with a predefined topic: thorax (topic 1), abdomen/pelvis (topic 2), neuroanatomy (topic 3). A questionnaire was filled at the end of each session rating satisfaction/impact. One-hundred-thirty students (105 from the Italian course and 25 from the international course) participated. More than 90% of students rated the neuroanatomy session as highly satisfactory and more than 95% as highly useful, and 100% of them would suggest others participate. Based on these results, a further implementation is planned for the next year, also exploiting DICOM data to present the students with real clinical cases bearing a highly didactive anatomical content. Specifically, in the international course, based on a vertical track approach, we are also strongly relying on flipped-classroom approach. Digital tools to teach neuroanatomy are also being implemented for clinically oriented teaching for residents/consultants.
Olga Tarasiuk, Chiara Invernizzi, and Paola Alberti
Informa UK Limited
INTRODUCTION
Chemotherapy induced peripheral neurotoxicity (CIPN) is a long-lasting, or even permanent, late toxicity caused by largely used anticancer drugs. CIPN affects a growing population of cancer survivors and diminishes their quality of life since there is no curative/preventive treatment. Among several reasons for this unmet clinical need, there is an incomplete knowledge on mechanisms leading to CIPN. Therefore, bench side research is still greatly needed: in vitro studies are pivotal to both evaluate neurotoxicity mechanisms and potential neuroprotection strategies.
AREAS COVERED
Advantages and disadvantages of in vitro approaches are addressed with respect to their applicability to the CIPN field. Different cell cultures and techniques to assess neurotoxicity/neuroprotection are described. PubMed search-string: (chemotherapy-induced) AND (((neuropathy) OR neurotoxicity) OR neuropathic pain) AND (in vitro) AND (((((model) OR SH-SY5Y) OR PC12) OR iPSC) OR DRG neurons); (chemotherapy-induced) AND (((neuropathy) OR neurotoxicity) OR neuropathic pain) AND (model) AND (((neurite elongation) OR cell viability) OR morphology). No articles published before 1990 were selected.
EXPERT OPINION
CIPN is an ideal experimental setting to test axonal damage and, in general, peripheral nervous system mechanisms of disease and neuroprotection. Therefore, starting from robust preclinical data in this field, potentially, relevant biological rationale can be transferred to other human spontaneous diseases of the peripheral nervous system.
Daniel L Hertz, Cindy Tofthagen, Emanuela Rossi, Davide Paolo Bernasconi, Jiyoon Lim, Martha Carlson, Katharine E. Sheffield, Larissa Nekhlyudov, Lisa Grech, Diane Von Ah,et al.
Springer Science and Business Media LLC
Marianna Dionisi, Beatrice Riva, Marta Delconti, Cristina Meregalli, Alessia Chiorazzi, Annalisa Canta, Paola Alberti, Valentina Carozzi, Eleonora Pozzi, Dmtry Lim,et al.
Springer Science and Business Media LLC
AbstractOxaliplatin (OHP)-induced peripheral neurotoxicity (OIPN), one of the major dose-limiting side effects of colorectal cancer treatment, is characterized by both acute and chronic syndromes. Acute exposure to low dose OHP on dorsal root ganglion (DRG) neurons is able to induce an increase in intracellular calcium and proton concentration, thus influencing ion channels activity and neuronal excitability. The Na+/H+ exchanger isoform-1 (NHE1) is a plasma membrane protein that plays a pivotal role in intracellular pH (pHi) homeostasis in many cell types, including nociceptors. Here we show that OHP has early effects on NHE1 activity in cultured mouse DRG neurons: the mean rate of pHi recovery was strongly reduced compared to vehicle-treated controls, reaching levels similar to those obtained in the presence of cariporide (Car), a specific NHE1 antagonist. The effect of OHP on NHE1 activity was sensitive to FK506, a specific calcineurin (CaN) inhibitor. Lastly, molecular analyses revealed transcriptional downregulation of NHE1 both in vitro, in mouse primary DRG neurons, and in vivo, in an OIPN rat model. Altogether, these data suggest that OHP-induced intracellular acidification of DRG neurons largely depends on CaN-mediated NHE1 inhibition, revealing new mechanisms that OHP could exert to alter neuronal excitability, and providing novel druggable targets.
Susanna B Park, Aysel Cetinkaya-Fisgin, Andreas A Argyriou, Ahmet Höke, Guido Cavaletti, and Paola Alberti
BMJ
Multiple pathological mechanisms are involved in the development of chemotherapy-induced peripheral neurotoxicity (CIPN). Recent work has provided insights into the molecular mechanisms underlying chemotherapy-induced axonal degeneration. This review integrates evidence from preclinical and clinical work on the onset, progression and outcome of axonal degeneration in CIPN. We review likely triggers of axonal degeneration in CIPN and highlight evidence of molecular pathways involved in axonal degeneration and their relevance to CIPN, including SARM1-mediated axon degeneration pathway. We identify potential clinical markers of axonal dysfunction to provide early identification of toxicity as well as present potential treatment strategies to intervene in axonal degeneration pathways. A greater understanding of axonal degeneration processes in CIPN will provide important information regarding the development and progression of axonal dysfunction more broadly and will hopefully assist in the development of successful interventions for CIPN and other neurodegenerative disorders.
Maria Lopez-Garzon, Annalisa Canta, Alessia Chiorazzi, and Paola Alberti
Elsevier BV
Guido Cavaletti, Katherine Forsey, and Paola Alberti
Wiley
AbstractBackground and AimsSeveral widely used medications, with a relevant efficacy profile, are toxic to the peripheral nervous system and an even larger number of agents are suspected to be neurotoxic. There are concerns about the use of these drugs in patients with Charcot–Marie–Tooth disease (CMT), a hereditary motor and sensory neuropathy. This review provides evidence‐based updated recommendations on this clinically relevant topic.MethodsA systematic review of the available studies/reports written in English was performed from July to September 2022 including in the search string all reported putative neurotoxic drugs.ResultsThe results of our systematic review provide evidence‐based support for the statement that use of vincristine, and possibly paclitaxel, can occasionally induce an atypical, and more severe, course of drug‐related peripheral neurotoxicity in CMT patients. It is therefore reasonable to recommend caution in the use of these compounds in CMT patients. However, no convincing evidence for a similar recommendation could be found for all other drugs.InterpretationIt is important that patients with CMT are not denied effective treatments that may prolong life expectancy for cancer or improve their health status if affected by non‐oncological diseases. Accurate monitoring of peripheral nerve function in CMT patients treated with any neurotoxic agent remains mandatory to detect the earliest signs of neuropathy worsening and atypical clinical courses. Neurologists monitoring CMT patients as part of their normal care package or for natural history studies should keep detailed records of exposures to neurotoxic medications and support reporting of accelerated neuropathy progression if observed.
Stefanie Stoller, Scott Capozza, Paola Alberti, Maryam Lustberg, and Ian R. Kleckner
Springer Science and Business Media LLC
Eleonora Pozzi, Elisa Ballarini, Virginia Rodriguez-Menendez, Annalisa Canta, Alessia Chiorazzi, Laura Monza, Mario Bossi, Paola Alberti, Alessio Malacrida, Cristina Meregalli,et al.
MDPI AG
Chemotherapy-induced peripheral neurotoxicity is one of the most common dose-limiting toxicities of several widely used anticancer drugs such as platinum derivatives (cisplatin) and taxanes (paclitaxel). Several molecular mechanisms related to the onset of neurotoxicity have already been proposed, most of them having the sensory neurons of the dorsal root ganglia (DRG) and the peripheral nerve fibers as principal targets. In this study we explore chemotherapy-induced peripheral neurotoxicity beyond the neuronocentric view, investigating the changes induced by paclitaxel (PTX) and cisplatin (CDDP) on satellite glial cells (SGC) in the DRG and their crosstalk. Rats were chronically treated with PTX (10 mg/Kg, 1qwx4) or CDDP (2 mg/Kg 2qwx4) or respective vehicles. Morpho-functional analyses were performed to verify the features of drug-induced peripheral neurotoxicity. Qualitative and quantitative immunohistochemistry, 3D immunofluorescence, immunoblotting, and transmission electron microscopy analyses were also performed to detect alterations in SGCs and their interconnections. We demonstrated that PTX, but not CDDP, produces a strong activation of SGCs in the DRG, by altering their interconnections and their physical contact with sensory neurons. SGCs may act as principal actors in PTX-induced peripheral neurotoxicity, paving the way for the identification of new druggable targets for the treatment and prevention of chemotherapy-induced peripheral neurotoxicity.