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The rise of cancer immunotherapy has been a milestone in clinical oncology. Above all, immune checkpoint inhibitor treatment (ICI) with monoclonal antibodies targeting programmed cell death protein 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) has improved survival rates for an increasing number of malignancies. However, despite the clinical benefits, ICI-related autoimmunity has become a significant cause of non-relapse-related morbidity and mortality. Neurological immune-related adverse events (irAE-n) are particularly severe toxicities with a high risk for chronic illness, long-term steroid dependency, and early ICI treatment termination. While the clinical characteristics of irAE-n are well described, little is known about underlying immune mechanisms and potential biomarkers. Recently, high frequencies of neuronal autoantibodies in patients with irAE-n have been reported, however, their clinical relevance is unclear. Here, we present a dataset on neuronal autoantibody profiles in ICI-treated cancer patients with and without irAE-n, which was generated to investigate the potential role of neuronal autoantibodies in ICI-induced autoimmunity. Between September 2017 and January 2022 serum samples of 29 cancer patients with irAE-n post-ICI treatment) and 44 cancer control patients without high-grade immune-related adverse events (irAEs, n = 44 pre- and post-ICI treatment) were collected and tested for a large panel of brain-reactive and neuromuscular autoantibodies using indirect immunofluorescence and immunoblot assays. Prevalence of autoantibodies was compared between the groups and correlated with clinical characteristics such as outcome and irAE-n manifestation. These data represent the first systematic comparison of neuronal autoantibody profiles between ICI-treated cancer patients with and without irAE-n, providing valuable information for both researchers and clinicians. In the future, this dataset may be valuable for meta-analyses on the prevalence of neuronal autoantibodies in cancer patients.
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BACKGROUND: Neurologic immune-related adverse events (irAE-n) are rare but severe toxicities of immune checkpoint inhibitor (ICI) treatment. To overcome diagnostic and therapeutic challenges, a better mechanistic understanding of irAE-n is paramount. METHODS: In this observational cohort study, we collected serum and peripheral blood samples from 34 consecutive cancer patients with irAE-n (during acute illness) and 49 cancer control patients without irAE-n (pre- and on-ICI treatment, n = 44 without high-grade irAEs, n = 5 with high-grade nonneurologic irAEs). Patients received either anti-programmed cell death protein (PD)-1 or anti-PD ligand-1 monotherapy or anti-PD-1/anti-cytotoxic T-lymphocyte-associated protein-4 combination therapy. Most common cancers were melanoma, lung cancer, and hepatocellular carcinoma. Peripheral blood immune profiling was performed using 48-marker single-cell mass cytometry and a multiplex cytokine assay. RESULTS: During acute illness, patients with irAE-n presented higher frequencies of cluster of differentiation (CD)8+ effector memory type (EM-)1 and central memory (CM) T cells compared to controls without irAEs. Multiorgan immunotoxicities (neurologic + nonneurologic) were associated with higher CD8+ EM1 T cell counts. While there were no B cell changes in the overall cohort, we detected a marked decrease of IgD- CD11c+ CD21low and IgD- CD24+ CD21high B cells in a subgroup of patients with autoantibody-positive irAE-n. We further identified signatures indicative of enhanced chemotaxis and inflammation in irAE-n patients and discovered C-X-C motif chemokine ligand (CXCL)10 as a promising marker to diagnose high-grade immunotoxicities such as irAE-n. CONCLUSIONS: We demonstrate profound and partly subgroup-specific immune cell dysregulation in irAE-n patients, which may guide future biomarker development and targeted treatment approaches.
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Neoplasias Pulmonares , Melanoma , Humanos , Doença Aguda , Autoimunidade , Ligantes , Estudos RetrospectivosRESUMO
NCS1 (Neuronal calcium sensor protein 1) encodes a highly conserved calcium binding protein abundantly expressed in neurons. It modulates intracellular calcium homeostasis, calcium-dependent signaling pathways as well as neuronal transmission and plasticity. Here, we generated a NCS1 knockout human induced pluripotent stem cell (hiPSC) line using CRISPR-Cas9 genome editing. It shows regular expression of pluripotent markers, normal iPSC morphology and karyotype as well as no detectable off-target effects on top 6 potentially affected genes. This newly generated cell line constitutes a valuable tool for studying the role of NCS1 in the pathophysiology of various neuropsychiatric disorders and non-neurological disease.
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Sistemas CRISPR-Cas , Células-Tronco Pluripotentes Induzidas , Humanos , Sistemas CRISPR-Cas/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Técnicas de Inativação de Genes , Cálcio/metabolismo , Edição de GenesRESUMO
Background: Neurological immune-related adverse events (irAE-n) are severe and potentially fatal toxicities of immune checkpoint inhibitors (ICI). To date, the clinical significance of neuronal autoantibodies in irAE-n is poorly understood. Here, we characterize neuronal autoantibody profiles in patients with irAE-n and compare these with ICI-treated cancer patients without irAE-n. Methods: In this cohort study (DRKS00012668), we consecutively collected clinical data and serum samples of 29 cancer patients with irAE-n (n = 2 pre-ICI, n = 29 post-ICI) and 44 cancer control patients without irAE-n (n = 44 pre- and post-ICI). Using indirect immunofluorescence and immunoblot assays, serum samples were tested for a large panel of neuromuscular and brain-reactive autoantibodies. Results: IrAE-n patients and controls received ICI treatment targeting programmed death protein (PD-)1 (61% and 62%), programmed death ligand (PD-L)1 (18% and 33%) or PD-1 and cytotoxic T-lymphocyte-associated protein (CTLA-)4 (21% and 5%). Most common malignancies were melanoma (both 55%) and lung cancer (11% and 14%). IrAE-n affected the peripheral nervous system (59%), the central nervous system (21%), or both (21%). Prevalence of neuromuscular autoantibodies was 63% in irAE-n patients, which was higher compared to ICI-treated cancer patients without irAE-n (7%, p <.0001). Brain-reactive autoantibodies targeting surface (anti-GABABR, -NMDAR, -myelin), intracellular (anti-GFAP, -Zic4, -septin complex), or unknown antigens were detected in 13 irAE-n patients (45%). In contrast, only 9 of 44 controls (20%) presented brain-reactive autoantibodies before ICI administration. However, seven controls developed de novo brain-reactive autoantibodies after ICI initiation, therefore, prevalence of brain-reactive autoantibodies was comparable between ICI-treated patients with and without irAE-n (p = .36). While there was no clear association between specific brain-reactive autoantibodies and clinical presentation, presence of at least one of six selected neuromuscular autoantibodies (anti-titin, anti-skeletal muscle, anti-heart muscle, anti-LRP4, anti-RyR, anti-AchR) had a sensitivity of 80% (95% CI 0.52-0.96) and a specificity of 88% (95% CI 0.76-0.95) for the diagnosis of myositis, myocarditis, or myasthenia gravis. Conclusion: Neuromuscular autoantibodies may serve as a feasible marker to diagnose and potentially predict life-threatening ICI-induced neuromuscular disease. However, brain-reactive autoantibodies are common in both ICI-treated patients with and without irAE-n, hence, their pathogenic significance remains unclear.
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Doenças do Sistema Imunitário , Neoplasias Pulmonares , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Autoanticorpos , Estudos de CoortesAssuntos
Mpox , Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Cloridrato de Fingolimode/efeitos adversos , Esclerose Múltipla/complicações , Esclerose Múltipla/tratamento farmacológico , Mpox/complicações , Imunossupressores/efeitos adversos , Esclerose Múltipla Recidivante-Remitente/complicações , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológicoRESUMO
Over the past decade, cancer immunotherapy with immune checkpoint inhibitors (ICIs) has significantly improved the outcome of many malignancies. However, with the broad use of ICIs, neurological immune related adverse events (irAE) are increasingly recognized. ICI-induced encephalitis (ICI-iE) is a particularly severe irAE, often leading to treatment termination, long-term sequalae or death. Despite its high morbidity and mortality, data on clinical features and diagnostic criteria are limited. We aimed to define clinical, radiologic and laboratory characteristics of ICI-iE and identify factors that discriminate it from anti-leucine-rich glioma-inactivated (anti-LGI)-1 encephalitis and herpes simplex virus (HSV)-1 encephalitis - two alternative causes of encephalitis - to increase the awareness of ICI-iE and improve its diagnosis and management. To that end, we retrospectively collected 30 cases of ICI-iE that were reported to the Side Effect Registry Immuno-Oncology (SERIO) and 46 cases of anti-LGI1 encephalitis or herpes simplex virus (HSV)-1 encephalitis that presented to a large German neurological referral center (Charité Universitätsmedizin Berlin) between January 2015 and September 2021. Signs and symptoms, imaging and electroencephalogram features, laboratory findings and outcome measures were assessed using standardized case report forms as well as patients' medical records and compared between the groups. The data reported here represents the largest primary cohort of patients with ICI-iE to date and the first comparison with other types of encephalitis. As all three disorders - ICI-iE, HSV-1 encephalitis and anti-LGI1 encephalitis - are rare neurological entities, this dataset can be used as a reference in future clinical studies on ICI-induced neurotoxicity, neurological autoimmune disorders, and central nervous system infections.
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Neurotoxic phenomena are among the most common side effects of cytotoxic agents. The development of chemotherapy-induced polyneuropathy (CIPN) is a well-recognized adverse reaction in the peripheral nervous system, while changes of cognitive functions (post-chemotherapy cognitive impairment (PCCI)) are more diffuse and have only recently drawn scientific interest. PCCI in patients most often displays as short-term memory loss, reduced multitasking ability or deficits in language. Not least, due to a lack of preclinical human model systems, the underlying molecular mechanisms are poorly understood, and treatments are missing. We thus investigated whether induced pluripotent stem cell (iPSC)-derived brain organoids can serve as a human model system for the study of chemotherapy induced central nervous system toxicity. We robustly generated mature brain organoids from iPSC-derived neuronal precursor cells (NPC), which showed a typical composition with 1) dividing NPCs forming ventricle like structures 2) matured neurons and 3) supporting glial cells closer to the surface. Furthermore, upon stimulation the brain organoids showed functional signaling. When exposed to increasing concentrations of paclitaxel, a frequently used chemotherapy drug, we observed time dependent neurotoxicity with an EC50 of 153 nM, comparable to a published murine model system. Histological analysis after paclitaxel exposure demonstrated dose dependent apoptosis induction and reduced proliferation in the organoids with further Western blot analyses indicating the degradation of neuronal calcium sensor one protein (NCS-1) and activation of Caspase-3. We could also provide evidence that paclitaxel treatment negatively affects the pool of neuronal and astrocyte precursor cells as well as mature neurons. In summary our data suggests that human iPSC derived brain organoids are a promising preclinical model system to investigate molecular mechanisms underlying PCCI and to develop novel prevention and treatment strategies.
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AIM: Immune checkpoint inhibitor-induced encephalitis (ICI-iE) is a rare but life-threatening toxicity of immune checkpoint inhibitor treatment. We aim to identify the characteristics of ICI-iE and describe factors that discriminate it from herpes simplex virus (HSV)-1 encephalitis and anti-leucine-rich glioma-inactivated 1 (anti-LGI1) encephalitis, as two alternative entities of encephalitis. METHODS: In this retrospective multicentre cohort study, we collected patients with ICI-iE reported to the Side Effect Registry Immuno-Oncology from January 2015 to September 2021 and compared their clinical features and outcome with 46 consecutive patients with HSV-1 or anti-LGI1 encephalitis who were treated at a German neurological referral centre. RESULTS: Thirty cases of ICI-iE, 25 cases of HSV-1 encephalitis and 21 cases of anti-LGI1 encephalitis were included. Clinical presentation of ICI-iE was highly variable and resembled that of HSV-1 encephalitis, while impairment of consciousness (66% vs. 5%, p = .007), confusion (83% vs. 43%; p = .02), disorientation (83% vs. 29%; p = .007) and aphasia (43% vs. 0%; p = .007) were more common in ICI-iE than in anti-LGI1 encephalitis. Antineuronal antibodies (17/18, 94%) and MRI (18/30, 60%) were mostly negative in ICI-iE, but cerebrospinal fluid (CSF) showed pleocytosis and/or elevated protein levels in almost all patients (28/29, 97%). Three patients (10%) died of ICI-iE. Early immunosuppressive treatment was associated with better outcome (r = 0.43). CONCLUSIONS: ICI-iE is a heterogeneous entity without specific clinical features. CSF analysis has the highest diagnostic value, as it reveals inflammatory changes in most patients and enables the exclusion of infection. Early treatment of ICI-iE is essential to prevent sequelae and death.
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Encefalite , Glioma , Herpesvirus Humano 1 , Autoanticorpos , Estudos de Coortes , Encefalite/induzido quimicamente , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Peptídeos e Proteínas de Sinalização Intracelular , Leucina , Estudos RetrospectivosRESUMO
Introduction: Chemotherapy-induced polyneuropathy (CIPN) and post-chemotherapy cognitive impairment (PCCI) are frequent side effects of paclitaxel treatment. CIPN/PCCI are potentially irreversible, reduce quality of life and often lead to treatment limitations, which affect patients' outcome. We previously demonstrated that paclitaxel enhances an interaction of the Neuronal calcium sensor-1 protein (NCS-1) with the Inositol-1,4,5-trisphosphate receptor (InsP3R), which disrupts calcium homeostasis and triggers neuronal cell death via the calcium-dependent protease calpain in dorsal root ganglia neurons and neuronal precursor cells. Prophylactic treatment of rodents with lithium inhibits the NCS1-InsP3R interaction and ameliorates paclitaxel-induced polyneuropathy and cognitive impairment, which is in part supported by limited retrospective clinical data in patients treated with lithium carbonate at the time of chemotherapy. Currently no data are available from a prospective clinical trial to demonstrate its efficacy. Methods and analysis: The PREPARE study will be conducted as a multicenter, randomized, double-blind, placebo-controlled phase-2 trial with parallel group design. N = 84 patients with breast cancer will be randomized 1:1 to either lithium carbonate treatment (targeted serum concentration 0.5-0.8 mmol/l) or placebo with sham dose adjustments as add-on to (nab-) paclitaxel. The primary endpoint is the validated Total Neuropathy Score reduced (TNSr) at 2 weeks after the last (nab-) paclitaxel infusion. The aim is to show that the lithium carbonate group is superior to the placebo group, meaning that the mean TNSr after (nab-) paclitaxel is lower in the lithium carbonate group than in the placebo group. Secondary endpoints include: (1) severity of CIPN, (2) amount and dose of pain medication, (3) cumulative dose of (nab-) paclitaxel, (4) patient-reported symptoms of CIPN, quality of life and symptoms of anxiety and depression, (5) severity of cognitive impairment, (6) hippocampal volume and changes in structural/functional connectivity and (7) serum Neurofilament light chain protein concentrations. Ethics and dissemination: The study protocol was approved by the Berlin ethics committee (reference: 21/232 - IV E 10) and the respective federal agency (Bundesinstitut für Arzneimittel und Medizinprodukte, reference: 61-3910-4044771). The results of the study will be published in peer-reviewed medical journals as well as presented at relevant (inter)national conferences. Clinical trial registration: [https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00027165], identifier [DRKS00027165].
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BACKGROUNDPaclitaxel chemotherapy frequently induces dose-limiting sensory axonal polyneuropathy. Given that sensory symptoms are challenging to assess objectively in clinical practice, an easily accessible biomarker for chemotherapy-induced polyneuropathy (CIPN) holds the potential to improve early diagnosis. Here, we describe neurofilament light chain (NFL), a marker for neuroaxonal damage, as a translational surrogate marker for CIPN.METHODSNFL concentrations were measured in an in vitro model of CIPN, exposing induced pluripotent stem cell-derived sensory neurons (iPSC-DSNs) to paclitaxel. Patients with breast or ovarian cancer undergoing paclitaxel chemotherapy, breast cancer control patients without chemotherapy, and healthy controls were recruited in a cohort study and examined before chemotherapy (V1) and after 28 weeks (V2, after chemotherapy). CIPN was assessed by the validated Total Neuropathy Score reduced (TNSr), which combines patient-reported symptoms with data from clinical examinations. Serum NFL (NFLs) concentrations were measured at both visits with single-molecule array technology.RESULTSNFL was released from iPSC-DSNs upon paclitaxel incubation in a dose- and time-dependent manner and was inversely correlated with iPSC-DSN viability. NFLs strongly increased in paclitaxel-treated patients with CIPN, but not in patients receiving chemotherapy without CIPN or controls, resulting in an 86% sensitivity and 87% specificity. An NFLs increase of +36 pg/mL from baseline was associated with a predicted CIPN probability of more than 0.5.CONCLUSIONNFLs was correlated with CIPN development and severity, which may guide neurotoxic chemotherapy in the future.TRIAL REGISTRATIONClinicalTrials.gov NCT02753036.FUNDINGDeutsche Forschungsgemeinschaft (EXC 257 NeuroCure), BMBF (Center for Stroke Research Berlin, 01 EO 0801), Animalfree Research, EU Horizon 2020 Innovative Medicines Initiative 2 Joint Undertaking (TransBioLine, 821283), Charité 3R - Replace - Reduce - Refine.
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Antineoplásicos , Doenças do Sistema Nervoso Periférico , Polineuropatias , Antineoplásicos/efeitos adversos , Biomarcadores , Estudos de Coortes , Humanos , Proteínas de Neurofilamentos , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/diagnóstico , Polineuropatias/induzido quimicamente , Polineuropatias/diagnósticoRESUMO
Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent and potentially irreversible adverse event of cytotoxic chemotherapy. We evaluate whether sensory neurons derived from induced pluripotent stem cells (iPSC-DSN) can serve as human disease model system for chemotherapy induced neurotoxicity. Sensory neurons differentiated from two established induced pluripotent stem cell lines were used (s.c. BIHi005-A https://hpscreg.eu/cell-line/BIHi005-A and BIHi004-B https://hpscreg.eu/cell-line/BIHi004-B, Berlin Institute of Health Stem Cell Core Facility). Cell viability and cytotoxicity assays were performed, comparing susceptibility to four neurotoxic and two non-neurotoxic drugs. RNA sequencing analyses in paclitaxel vs. vehicle (DMSO)-treated sensory neurons were performed. Treatment of iPSC-DSN for 24 h with the neurotoxic drugs paclitaxel, bortezomib, vincristine and cisplatin led to a dose dependent decline of cell viability in clinically relevant IC50 ranges, which was not the case for the non-neurotoxic compounds doxorubicin and 5-fluorouracil. RNA sequencing analyses at 24 h, i.e. before paclitaxel-induced cell death occurred, revealed the differential expression of genes of neuronal injury, cellular stress response, and sterol pathways in response to 1 µM paclitaxel. Neuroprotective effects of lithium chloride co-incubation, which were previously shown in rodent dorsal root ganglia, could be replicated in human iPSC-DSN. Cell lines from the two different donors BIHi005-A and BIHi004-B showed different responses to the neurotoxic treatment in cell viability and cytotoxicity assays.
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Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent, potentially irreversible adverse effect of cytotoxic chemotherapy often leading to a reduction or discontinuation of treatment which negatively impacts patients' prognosis. To date, however, neither predictive biomarkers nor preventive treatments for CIPN are available, which is partially due to a lack of suitable experimental models. We therefore aimed to evaluate whether sensory neurons derived from induced pluripotent stem cells (iPSC-DSN) can serve as human disease model system for CIPN. Treatment of iPSC-DSN for 24 h with the neurotoxic drugs paclitaxel, bortezomib, vincristine and cisplatin led to axonal blebbing and a dose dependent decline of cell viability in clinically relevant IC50 ranges, which was not observed for the non-neurotoxic compounds doxorubicin and 5-fluorouracil. Paclitaxel treatment effects were less pronounced after 24 h but prominent when treatment was applied for 72 h. Global transcriptome analyses performed at 24 h, i.e. before paclitaxel-induced cell death occurred, revealed the differential expression of genes of neuronal injury, cellular stress response, and sterol pathways. We further evaluated if known neuroprotective strategies can be reproduced in iPSC-DSN and observed protective effects of lithium replicating findings from rodent dorsal root ganglia cells. Comparing sensory neurons derived from two different healthy donors, we found preliminary evidence that these cell lines react differentially to neurotoxic drugs as expected from the variable presentation of CIPN in patients. In conclusion, iPSC-DSN are a promising platform to study the pathogenesis of CIPN and to evaluate neuroprotective treatment strategies. In the future, the application of patient-specific iPSC-DSN could open new avenues for personalized medicine with individual risk prediction, choice of chemotherapeutic compounds and preventive treatments.
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Antineoplásicos/toxicidade , Axônios/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células Receptoras Sensoriais/efeitos dos fármacos , Axônios/patologia , Linhagem Celular , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Células Receptoras Sensoriais/patologia , Imagem com Lapso de Tempo/métodosRESUMO
The 26S proteasome inhibitor bortezomib is currently used to treat multiple myeloma but also is effective in the treatment of antibody-mediated autoimmune disorders. One clinical concern is bortezomib's toxicity towards the (central) nervous system. We used standardized neuropsychological testing to assess cognitive function in six patients with myasthenia gravis and systemic lupus erythematodes before and after treatment with a mean cumulative dose of 9.4 mg m-2 bortezomib. In addition, cognitive performance was measured in adult C57Bl/6 mice after treatment with a human equivalent cumulative dose of 15.6 mg m-2. Bortezomib concentrations were analysed in the human CSF as well as the brain tissue and serum of adult C57Bl/6 mice at various time points after the injection of 1.3 mg m-2 bortezomib with liquid chromatography-tandem mass spectrometry. Neither patients nor mice showed signs of cognitive impairment after bortezomib therapy. Bortezomib concentrations in the human CSF and murine brain tissue reached only 5-7% of serum concentrations with comparable concentrations measured in the hippocampus and the neocortex. Five-fold higher concentrations were needed to damage neuronal cells in vitro. In conclusion, penetration of the intact blood-brain barrier by bortezomib is low. Overall, our data show that bortezomib is a safe medication in terms of central nervous system toxicity.
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OBJECTIVE: Critical illness polyneuropathy (CIP) is a common complication of severe systemic illness treated in intensive care medicine. Ischemic stroke leads to an acute critical injury of the brain with hemiparesis, immunosuppression and subsequent infections, all of which require extended medical treatment. Stroke-induced sarcopenia further contributes to poor rehabilitation and is characterized by muscle wasting and denervation in the paralytic, but also the unaffected limbs. Therefore, we asked whether stroke leads to an additional CIP-like neurodegeneration. RESULTS: Focal brain ischemia was induced in adult mice by 60-min middle cerebral artery occlusion (MCAo) following reperfusion and led to functional deficits and marked hemispheric brain atrophy. Nerve conduction function and muscle potentials were measured in the ipsilateral sciatic nerve and gastrocnemius and quadriceps muscle with electroneurography/-myography on days 10, 22, 44 after stroke. An additional crush-injury to the sciatic nerve was included in two sham mice as positive control (sham +). We found no differences in nerve conduction function nor spontaneous electromyographic activity between MCAo and sham animals. Sham + mice developed marked reduction of the motor action potential amplitudes and conduction velocities with pathologic spontaneous activity. In conclusion, we found no peripheral nerve dysfunction/degeneration as signs of a CIP-like phenotype after MCAo.
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Isquemia Encefálica , Doenças do Sistema Nervoso Periférico , Acidente Vascular Cerebral , Animais , Isquemia Encefálica/complicações , Estado Terminal , Camundongos , Condução NervosaRESUMO
BACKGROUND: Neurotoxicity is a frequent side effect of cytotoxic chemotherapy and affects a large number of patients. Despite the high medical need, few research efforts have addressed the impact of cytotoxic agents on cognition (ie, postchemotherapy cognitive impairment; PCCI). One unsolved question is whether individual cytotoxic drugs have differential effects on cognition. We thus examine the current state of research regarding PCCI. Neurological symptoms after targeted therapies and immunotherapies are not part of this review. METHODS: A literature search was conducted in the PubMed database, and 1215 articles were reviewed for predefined inclusion and exclusion criteria. Thirty articles were included in the systematic review. RESULTS: Twenty-five of the included studies report significant cognitive impairment. Of these, 21 studies investigated patients with breast cancer. Patients mainly received combinations of 5-fluorouracil, epirubicin, cyclophosphamide, doxorubicin, and taxanes (FEC/FEC-T). Five studies found no significant cognitive impairment in chemotherapy patients. Of these, 2 studies investigated patients with colon cancer receiving 5-fluorouracil and oxaliplatin (FOLFOX). Independent risk factors for PCCI were patient age, mood alterations, cognitive reserve, and the presence of apolipoprotein E e4 alleles. CONCLUSIONS: There is evidence that certain chemotherapy regimens cause PCCI more frequently than others as evidenced by 21 out of 23 studies in breast cancer patients (mainly FEC-T), whereas 2 out of 3 studies with colon cancer patients (FOLFOX) did not observe significant changes. Further studies are needed defining patient cohorts by treatment protocol in addition to cancer type to elucidate the effects of individual cytotoxic drugs on cognitive functions.
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The microtubule-stabilizing agent paclitaxel frequently leads to chemotherapy-induced peripheral neuropathy (CIN), which further increases the burden of disease and often necessitates treatment limitations. The pathophysiology of CIN appears to involve both "upstream" effects including altered intracellular calcium signaling and activation of calcium dependent proteases such as calpain as well as subsequent "downstream" neuro-inflammatory reactions with cytokine release and macrophage infiltration of dorsal root ganglia. In this study, we aimed to investigate whether these processes are linked by the pro-inflammatory cytokine interleukin-6 (IL-6). We observed that paclitaxel exposure induced IL-6 synthesis in cultured sensory neurons from postnatal Wistar rats, which could be prevented by co-treatment with a calpain inhibitor. This suggests a calcium dependent process. We demonstrate that adult C57BL/6 mice deficient in IL-6 are protected from developing functional and histological changes of paclitaxel-induced neuropathy. Furthermore, pretreatment with an IL-6-neutralizing antibody resulted in the prevention of paclitaxel-induced neuropathy in C57BL/6 mice. Electrophysiological data from our preclinical model was adequately reflected by measurements of patients undergoing paclitaxel therapy for ovarian cancer. In this cohort, measured Il-6 levels correlated with the severity of neuropathy. Our findings demonstrate that IL-6 plays a pivotal role in the pathophysiology of paclitaxel-induced neuropathy per se and that pharmacological or genetic interference with this signaling pathway prevents the development of this potentially debilitating adverse effect. These findings provide a rationale for a clinical trial with IL-6 neutralizing antibodies to prevent dose-limiting neurotoxic adverse effects of paclitaxel chemotherapy.
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Interleucina-6/metabolismo , Doenças do Sistema Nervoso/induzido quimicamente , Doenças do Sistema Nervoso/metabolismo , Paclitaxel/efeitos adversos , Transdução de Sinais , Animais , Animais Recém-Nascidos , Anticorpos Neutralizantes/farmacologia , Estudos de Coortes , Feminino , Gânglios Espinais/patologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Modelos Biológicos , Paclitaxel/farmacologia , Ratos , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/patologia , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: It was previously reported that high salt dietary conditions can drive autoimmunity and worsen severity and symptoms of autoimmune diseases. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a common autoimmune condition of the peripheral nervous system which leads to progressive paralysis and sensory deficits due to a demyelination and secondary axonal loss of peripheral nerves. We used a previously described model with a knockout of CD86 in non-obese diabetic mice (CD86-/- NOD), which results in the spontaneous development of an autoimmune peripheral neuropathy similar to CIDP and investigated the influence of a high salt diet on functional impairment, electrophysiological parameters, demyelination and neuroinflammation in these mice. METHODS: At seven weeks of age, asymptomatic female CD86-/- NOD mice were randomly assigned to a normal or high salt diet containing 4% sodium chloride in food and 1% in water. The diet was continued for a total of 30â¯weeks. RESULTS: Mice on the high salt diet showed a delayed onset of clinical symptoms and an ameliorated disease course with a reduced decline of locomotor function. Furthermore, electrophysiological parameters of neuropathy and demyelination were attenuated in mice on the high salt diet, which was confirmed with histological analysis. Additionally, we observed a reduced immune cell infiltration of sciatic nerves in mice which had received the high salt diet. CONCLUSIONS: We demonstrate beneficial effects of high salt diet regarding disease progression, functional, electrophysiological and histological parameters in a transgenic mouse model of spontaneous autoimmune neuropathy.
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Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/patologia , Cloreto de Sódio na Dieta/farmacologia , Animais , Feminino , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Distribuição AleatóriaRESUMO
Paclitaxel is a cytotoxic drug which frequently causes sensory peripheral neuropathy in patients. Increasing evidence suggests that altered intracellular calcium (Ca2+) signals play an important role in the pathogenesis of this condition. In the present study, we examined the interplay between Ca2+ release channels in the endoplasmic reticulum (ER) and Ca2+ permeable channels in the plasma membrane in the context of paclitaxel mediated neurotoxicity. We observed that in small to medium size dorsal root ganglia neurons (DRGN) the inositol-trisphosphate receptor (InsP3R) type 1 was often concentrated in the periphery of cells, which is in contrast to homogenous ER distribution. G protein-coupled designer receptors were used to further elucidate phosphoinositide mediated Ca2+ signaling: This approach showed strong InsP3 mediated Ca2+ signals close to the plasma membrane, which can be amplified by Ca2+ entry through TRPV4 channels. In addition, our results support a physical interaction and partial colocalization of InsP3R1 and TRPV4 channels. In the context of paclitaxel-induced neurotoxicity, blocking Ca2+ influx through TRPV4 channels reduced cell death in cultured DRGN. Pretreatment of mice with the pharmacological TRPV4 inhibitor HC067047 prior to paclitaxel injections prevented electrophysiological and behavioral changes associated with paclitaxel-induced neuropathy. In summary, these results underline the relevance of TRPV4 signaling for the pathogenesis of paclitaxel-induced neuropathy and suggest novel preventive strategies.
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Antineoplásicos Fitogênicos/toxicidade , Síndromes Neurotóxicas/prevenção & controle , Paclitaxel/toxicidade , Canais de Cátion TRPV/antagonistas & inibidores , Animais , Canais de Cálcio/efeitos dos fármacos , Canais de Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Gânglios Espinais/patologia , Imuno-Histoquímica , Receptores de Inositol 1,4,5-Trifosfato/genética , Camundongos Endogâmicos C57BL , Síndromes Neurotóxicas/patologia , Ratos , Ratos Wistar , TransfecçãoRESUMO
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disorder, which causes progressive sensory and motor deficits and often results in severe disability. Knockout of the co-stimulatory protein CD86 in mice of the non-obese diabetic background (NoD.129S4-Cd86 tm1Shr /JbsJ) results in the development of a spontaneous autoimmune peripheral polyneuropathy (SAPP). We used this previously described transgenic model to study the effects of the sphingosine-1-phosphate receptor agonist fingolimod on SAPP symptoms, functional and electrophysiological characteristics. Compared to two control strains, knockout of CD86 in NOD mice (CD86-/- NOD) resulted in progressive paralysis with distinct locomotor deficits due to a severe sensory-motor axonal-demyelinating polyneuropathy as assessed by electrophysiological measurements. We started fingolimod treatment when CD86-/- NOD mice showed signs of unilateral hind limb weakness and continued at a dose of 1 mg/kg/day for eight weeks. We did not observe any beneficial effects of fingolimod regarding disease progression. In addition, fingolimod did not influence the functional outcome of CD86-/- NOD mice compared to vehicle treatment nor any of the electrophysiological characteristics. In summary, we show that fingolimod treatment has no beneficial effects in autoimmune polyneuropathy, which is in line with recent clinical data obtained in CIDP patients.
Assuntos
Doenças Autoimunes/tratamento farmacológico , Antígeno B7-2/fisiologia , Modelos Animais de Doenças , Cloridrato de Fingolimode/farmacologia , Imunossupressores/farmacologia , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Polineuropatias/tratamento farmacológico , Animais , Doenças Autoimunes/patologia , Feminino , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Doenças do Sistema Nervoso Periférico/patologia , Polineuropatias/patologia , Resultado do TratamentoRESUMO
Suramin is a trypan blue analogon originally developed to treat protozoan infections, which was found to have diverse antitumor effects. One of the most severe side effects in clinical trials was the development of a peripheral sensory-motor polyneuropathy. In this study, we aimed to investigate suramin-induced neuropathy with a focus on calcium (Ca2+) homeostasis as a potential pathomechanism. Adult C57Bl/6 mice treated with a single injection of 250 mg/kg bodyweight suramin developed locomotor and sensory deficits, which were confirmed by electrophysiological measurements showing a predominantly sensory axonal-demyelinating polyneuropathy. In a next step, we used cultured dorsal root ganglia neurons (DRGN) as an in vitro cell model to further investigate underlying pathomechanisms. Cell viability of DRGN was significantly decreased after 24-hour suramin treatment with a calculated IC50 of 283 µM. We detected a suramin-induced Ca2+ influx into DRGN from the extracellular space, which could be reduced with the voltage-gated calcium channel (VGCC) inhibitor nimodipine. Co-incubation of suramin and nimodipine partially improved cell viability of DRGN after suramin exposure. In summary, we describe suramin-induced neurotoxic effects on DRGN as well as potentially neuroprotective agents targeting intracellular Ca2+ dyshomeostasis.