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Identified the cellular process by which Cisplatin chemotherapy causes neuronal damage

  • Once the mechanism has been described by a team from IDIBELL, ICO, HUB, and UAB, new strategies can be designed to alleviate the adverse effects of Cisplatin, one of the most common drugs in chemotherapy.
  • These treatments would allow the optimization of the platinum treatment, prevent the changing to less effective alternatives, and preserve the quality of life of the patients.

Despite the great advances in cancer research in recent years, treatments that can cause very severe adverse effects are still used. This is the case of neuropathy caused by chemotherapy with platinum derivatives, such as Cisplatin and Oxaliplatin. These are widely used drugs that can damage the peripheral nervous system causing a progressive and increasing loss of sensitivity, which may even affect the mobility. The appearance of these adverse effects may force to reduce the dose or change the treatment for a less effective second-line treatment.

To design drugs that alleviate or avoid the adverse effects of Cisplatin, it is important to know the mechanism by which it causes neuropathy. And this is precisely the focus of the study carried out by a team from the Bellvitge Biomedical Research Institute (IDIBELL), the Catalan Institute of Oncology (ICO), the Bellvitge University Hospital (HUB) and the Universitat Autònoma de Barcelona (UAB), in the context of the PhD thesis of Aina Calls, first author of the study, which has shown that Cisplatin induces senescence of peripheral neurons through overexpression of the p21 protein, which would explain the neuropathy.

This discovery represents a paradigm shift in the field, because until now it was believed that oxidative stress and apoptosis cell death caused Cisplatin neuropathy“, says Dr. Jordi Bruna, project leader. The study, published in the Neuro-Oncology journal, shows that neurons respond to Cisplatin damage by generating a series of metabolic changes. These changes induce them to enter in a kind of permanent hibernation, called senescence, which would be causing neuropathic symptoms, and not the direct death of neurons as previously believed.

The study shows the overexpression of the p21 protein induced by the administration of Cisplatin. This is a protein that in response to injury can regulate both, senescence and cellular apoptosis processes. However, the study shows that the pathways involved in apoptosis are not activated. Furthermore, both electron microscopy studies and molecular markers of cellular senescence have confirmed that neurons show morphological characteristics of senescence after treatment with Cisplatin.

Neurons are the paradigm of a highly differentiated cell that cannot replicate, and senescense processes, classically described in replicative cells, are more controversial in non-replicative cells. Therefore, our work contributes to other recent studies that point that senescence processes can be relevant in different neurological pathologies” says Dr. Esther Udina, researcher at the Institut de Neurociències of the UAB (INc-UAB) and co-author of this research.

Until now, clinical trials of neuroprotective treatments aimed to alleviate platinum neuropathy have failed. Dr. Bruna concludes that “this could be because the treatments were focused on preventing neuronal apoptosis,” and adds, “this study provides new targets to alleviate platinum neuropathy. These neuroprotective treatments, administrated with chemotherapy, could prevent the onset of neuropathy, and are less likely to interfere with antitumor efficacy than those aimed to prevent apoptosis”. ” In this way, chemotherapy with Cisplatin would not be limited depending on the appearance of this common adverse effect.

These studies used a mouse model that perfectly mimics the clinical characteristics of the patients. By a cell separation method, each neuron of the dorsal spinal ganglion was individualized and, the genes that were expressed at each moment were studied, with the subsequent validation with protein expression. It is an innovative method that has never been used in this field of research.

Calls A et al. Cisplatin-induced peripheral neuropathy is associated with neuronal senescence-like response. Neuro-Oncology (2020)

Source: https://idibell.cat

 

The SOMA project starts

The SOMA project, led by Prof. Loredana Zollo, of the Università Campus Bio-Medico di Roma (UCBM), and funded by the European Commission within the H2020-FETOPEN-2018-2020 programme (Project Description), gets into the thick of things.

A highly challenging study in the field of upper limb neuroprostheses: SOMA aims at developing novel low-invasive bidirectional interface based on ultrasound probes and algorithms enabling the decoding of muscular activity and the sensing of close-to-natural somatic sensations.

The first meeting between the 7 partners involved in the SOMA project took place on October 28th. An international network of partners collaborates to the project: Fraunhofer-Institut für Biomedizinische Technik will develop the ultrasound (US) probes, University College of London will develop the miniaturized electronics, Imperial College London will investigate the myoelectric control based on US recording of the prosthesis, Università di Napoli “Federico II” will develop an in vitro model of the muscles and of the somatosensory system for the experimental validation of the US interfaces, Universidad Autònoma de Barcelona will perform tests of biocompatibility and functionality on animal models, and Össur, a world leader company in the development of prostheses, will contribute to the development of the new SOMA prosthesis.

The team of partners is coordinated by UCBM, who will also develop the instrumented hand prosthesis, the algorithms for encoding somatic sensations and the techniques for stimulating the PNS through ultrasound probes. The UAB team, led by Prof. Xavier Navarro, will lead the validation of the new interface system in vivo.

The virtual kick-off meeting defined the first actions to achieve the ambitious objectives of the project: the prostheses will be able to feel and route back to the amputee tactile and thermal sensations, and also pain. To this purpose, SOMA will take advantage of the most advanced technology in the field of tissue engineering and neurocomputational modeling, integrated in a synergistic way with the most advanced technologies, hardware and software, in the field of neuroprostheses and implantable devices.
 

NEUROGRAPH project

 

 

A graphene EcoG Microtransistorsfabricated by ICN2 and CNM groups of the graphcat consortium similar to the ones that will be used in the Neurograph project, . Image credit: Nature Materials, media.springernature.com

 

The Direcció General de Recerca de la Generalitat de Catalunya resolved, on December 19th 2019, to provide co-funding from the FEDER funds to the emerging technologies consortium GRAPHCAT.

Within GRAPHCAT, the Group NPiR in cooperation with the Group of Vascular Pharmacology of the UAB, takes part in the subproject NEUROGRAPH: Monitoring Cortical Depolarization in Neurointensive Care using Graphene EcoG Microtransistors.

The UAB team will explore models of brain lesion by ischemia and attempt to validate the application of CSD detection for predicting spreading of brain damage. In addition, novel therapeutic agents will be investigated in order to construct a close-loop system of detection-treatment to reduce the extension of the ischemic brain area.

The UAB Neurograph team is leaded by Drs. Jaume del Valle, Francesc Jiménez and Xavier Navarro.

Project funded to develop a new treatment to stop ALS

The project lead by Rubén López-Vales, from the Group NPiR, entitled "A new treatment to stop the progression of amyotrophic lateral sclerosis (ALS)", will investigate the contribution of a new family of lipids to modulate neuroinflammation in mice with ALS, looking for a new therapy that will be more effective than the current ones. The objective is to stop the progression of ALS and find new biomarkers that predict their evolution.

The project has been selected, after a rigorous selection process with the participation of more than 250 experts, and will receive a maximum of 500,000 euros, which will be provided by the "La Caixa" Foundation and the Luzón Foundation.

Group of Neuroplasticity and Regeneration

The research activities of the Group focus on the study of physiopathological mechanisms of neural lesions, neuropathic pain and neurodegeneration, and on the application of novel therapeutic strategies for regenerating traumatic and degenerative lesions of the nervous system.

The members of the group have combined expertise in microsurgery, neurophysiology, rehabilitation, morphology, cell culture, cellular and molecular neurobiology, bioelectronics and immunology.

The group has established cooperative research in clinical neurosciences, particularly on new nerve repair therapies with the Hospital Clinic of Barcelona, in modulation of neural plasticity after brain and spinal cord lesions with the Institute Guttmann of Neurorehabilitation, and in motoneuron diseases and neuropathies with the Hospital of Bellvitge.

Which are the research lines of the group?

What can the group offer?