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Journal of Medicinal Chemistry Jul 2023Chemotherapy-induced peripheral neuropathy (CIPN) is a major unmet medical need with limited treatment options. Despite different mechanisms of action, diverse...
Chemotherapy-induced peripheral neuropathy (CIPN) is a major unmet medical need with limited treatment options. Despite different mechanisms of action, diverse chemotherapeutics can cause CIPN through a converged pathway─an active axon degeneration program that engages the dual leucine zipper kinase (DLK). DLK is a neuronally enriched kinase upstream in the MAPK-JNK cascade, and while it is dormant under physiological conditions, DLK mediates a core mechanism for neuronal injury response under stress conditions, making it an attractive target for treatment of neuronal injury and neurodegenerative diseases. We have developed potent, selective, brain penetrant DLK inhibitors with excellent PK and activity in mouse models of CIPN. Lead compound IACS-52825 () showed strongly effective reversal of mechanical allodynia in a mouse model of CIPN and was advanced into preclinical development.
Topics: Mice; Animals; Neurons; MAP Kinase Signaling System; Brain; Peripheral Nervous System Diseases; Antineoplastic Agents; MAP Kinase Kinase Kinases
PubMed: 37436942
DOI: 10.1021/acs.jmedchem.3c00788 -
European Journal of Neurology Dec 2023Ataxia-telangiectasia (A-T) is a rare, autosomal recessive, multisystem disorder that leads to progressive neurodegeneration with cerebellar ataxia and peripheral...
BACKGROUND AND PURPOSE
Ataxia-telangiectasia (A-T) is a rare, autosomal recessive, multisystem disorder that leads to progressive neurodegeneration with cerebellar ataxia and peripheral polyneuropathy. Cerebellar neurodegeneration is well described in A-T. However, peripheral nervous system involvement is an underdiagnosed but important additional target for supportive and systemic therapies. The aim of this study was to conduct neurophysiological measurements to assess peripheral neurodegeneration and the development of age-dependent neuropathy in A-T.
METHODS
In this prospective study, 42 classical A-T patients were assessed. The motor and sensory nerve conduction of the median and tibial nerves was evaluated. Data were compared to published standard values and a healthy age- and gender-matched control group of 23 participants. Ataxia scores (Klockgether, Scale for the Assessment and Rating of Ataxia) were also assessed.
RESULTS
In A-T, neurophysiological assessment revealed neuropathic changes as early as the first year of life. Subjective symptomatology of neuropathy is rarely described. In the upper extremities, motor neuropathy was predominantly that of a demyelinating type and sensory neuropathy was predominantly that of a mixed type. In the lower extremities, motor and sensory neuropathy was predominantly that of a mixed type. We found significant correlations between age and the development of motor and sensory polyneuropathy in A-T compared with healthy controls (p < 0.001).
CONCLUSIONS
In A-T, polyneuropathy occurs mostly subclinically as early as the first year of life. The current study of a large national A-T cohort demonstrates that development of neuropathy in A-T differs in the upper and lower extremities.
Topics: Humans; Child; Young Adult; Ataxia Telangiectasia; Prospective Studies; Peripheral Nervous System Diseases; Polyneuropathies; Ataxia; Cerebellar Ataxia; Neural Conduction
PubMed: 37540892
DOI: 10.1111/ene.16028 -
Pharmaceutical Biology Dec 2024Diabetic peripheral neuropathy (DPN) results in an enormous burden and reduces the quality of life for patients. Considering there is no specific drug for the management... (Review)
Review
CONTEXT
Diabetic peripheral neuropathy (DPN) results in an enormous burden and reduces the quality of life for patients. Considering there is no specific drug for the management of DPN, traditional Chinese medicine (TCM) has increasingly drawn attention of clinicians and researchers around the world due to its characteristics of multiple targets, active components, and exemplary safety.
OBJECTIVE
To summarize the current status of TCM in the treatment of DPN and provide directions for novel drug development, the clinical effects and potential mechanisms of TCM used in treating DPN were comprehensively reviewed.
METHODS
Existing evidence on TCM interventions for DPN was screened from databases such as PubMed, the Cochrane Neuromuscular Disease Group Specialized Register (CENTRAL), and the Chinese National Knowledge Infrastructure Database (CNKI). The focus was on summarizing and analyzing representative preclinical and clinical TCM studies published before 2023.
RESULTS
This review identified the ameliorative effects of about 22 single herbal extracts, more than 30 herbal compound prescriptions, and four Chinese patent medicines on DPN in preclinical and clinical research. The latest advances in the mechanism highlight that TCM exerts its beneficial effects on DPN by inhibiting inflammation, oxidative stress and apoptosis, endoplasmic reticulum stress and improving mitochondrial function.
CONCLUSIONS
TCM has shown the power latent capacity in treating DPN. It is proposed that more large-scale and multi-center randomized controlled clinical trials and fundamental experiments should be conducted to further verify these findings.
Topics: Humans; Diabetic Neuropathies; Medicine, Chinese Traditional; Drugs, Chinese Herbal; Animals; Quality of Life; Oxidative Stress; Drug Evaluation, Preclinical
PubMed: 38946248
DOI: 10.1080/13880209.2024.2369301 -
Neurology(R) Neuroimmunology &... Mar 2024Immune-mediated small fiber neuropathy (SFN) is increasingly recognized. Acute-onset SFN (AOSFN) remains poorly described. Herein, we report a series of AOSFN cases in...
BACKGROUND AND OBJECTIVES
Immune-mediated small fiber neuropathy (SFN) is increasingly recognized. Acute-onset SFN (AOSFN) remains poorly described. Herein, we report a series of AOSFN cases in which immune origins are debatable.
METHODS
We included consecutive patients with probable or definite AOSFN. Diagnosis of SFN was based on the NEURODIAB criteria. Acute onset was considered when the maximum intensity and extension of both symptoms and signs were reached within 28 days. We performed the following investigations: clinical examination, neurophysiologic assessment encompassing a nerve conduction study to rule out large fiber neuropathy, laser-evoked potentials (LEPs), warm detection thresholds (WDTs), electrochemical skin conductance (ESC), epidermal nerve fiber density (ENF), and patient serum reactivity against mouse sciatic nerve teased fibers, mouse dorsal root ganglion (DRG) sections, and cultured DRG. The serum reactivity of healthy subjects (n = 10) and diseased controls (n = 12) was also analyzed. Data on baseline characteristics, biological investigations, and disease course were collected.
RESULTS
Twenty patients presenting AOSFN were identified (60% women; median age: 44.2 years [interquartile range: 35.7-56.2]). SFN was definite in 18 patients (90%) and probable in 2 patients. A precipitating event was present in 16 patients (80%). The median duration of the progression phase was 14 days [5-28]. Pain was present in 17 patients (85%). Twelve patients (60%) reported autonomic involvement. The clinical pattern was predominantly non-length-dependent (85%). Diagnosis was confirmed by abnormal LEPs (60%), ENF (55%), WDT (39%), or ESC (31%). CSF analysis was normal in 5 of 5 patients. Antifibroblast growth factor 3 antibodies were positive in 4 of 18 patients (22%) and anticontactin-associated protein-2 antibodies in one patient. In vitro studies showed IgG immunoreactivity against nerve tissue in 14 patients (70%), but not in healthy subjects or diseased controls. Patient serum antibodies bound to unmyelinated fibers, Schwann cells, juxtaparanodes, paranodes, or DRG. Patients' condition improved after a short course of oral corticosteroids (3/3). Thirteen patients (65%) showed partial or complete recovery. Others displayed relapses or a chronic course.
DISCUSSION
AOSFN primarily presents as an acute, non-length-dependent, symmetric painful neuropathy with a variable disease course. An immune-mediated origin has been suggested based on in vitro immunohistochemical studies.
Topics: Adult; Animals; Female; Humans; Male; Mice; Antibodies; Axons; Nerve Fibers; Pain; Peripheral Nervous System Diseases; Small Fiber Neuropathy; Middle Aged
PubMed: 38170952
DOI: 10.1212/NXI.0000000000200195 -
Muscle & Nerve Jan 2024Merosin is a protein complex located in the basement membrane of skeletal muscles and laminin α2-containing regions of the central and peripheral nervous systems....
INTRODUCTION/AIMS
Merosin is a protein complex located in the basement membrane of skeletal muscles and laminin α2-containing regions of the central and peripheral nervous systems. However, because of the prominence of muscle-related symptoms, peripheral neuropathy associated with merosin-deficient congenital muscular dystrophy type 1A (MDC1A) has received little clinical attention. This study aimed to present pathological changes in intramuscular nerves of three patients with MDC1A and discuss their relationship with electrophysiological findings to provide new evidence of peripheral nerve involvement in MDC1A.
METHODS
MDC1A was confirmed by clinical features, muscle biopsy, and genetic testing for variants in LAMA2. To clarify peripheral nerve involvement, we statistically evaluated electrophysiological and muscle pathology findings of intramuscular nerves. These findings were compared with those of age-matched boys with Duchenne muscular dystrophy (DMD) as controls with normal nerves. Nerve conduction studies (NCS) were performed before biopsy. Biopsied intramuscular nerves were examined with electron microscopy using g-ratio, which is the ratio of axon diameter to myelinated fiber diameter.
RESULTS
The myelin sheaths were significantly thinner in MDC1A patients than in age-matched DMD patients, with a mean g-ratio of 0.76 ± 0.07 in MDC1A patients and 0.65 ± 0.14 in DMD patients (p < .0001). No neuropathic changes were identified in muscle pathology. Low compound muscle action potential amplitudes, positive sharp waves and fibrillation potentials, and low-amplitude motor unit potentials with increased polyphasia indicated myopathic changes; no neurogenic changes were seen.
DISCUSSION
We postulate that the thin myelin associated with MDC1A reflects the role of merosin in myelin maturation.
Topics: Male; Humans; Myelin Sheath; Muscle, Skeletal; Laminin; Muscular Dystrophy, Duchenne; Peripheral Nervous System Diseases
PubMed: 37933889
DOI: 10.1002/mus.28002 -
Vitamin D Insufficiency as a Risk Factor for Paclitaxel-Induced Peripheral Neuropathy in SWOG S0221.Journal of the National Comprehensive... Nov 2023Prior work suggests that patients with vitamin D insufficiency may have a higher risk of chemotherapy-induced peripheral neuropathy (CIPN) from paclitaxel. The objective... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Prior work suggests that patients with vitamin D insufficiency may have a higher risk of chemotherapy-induced peripheral neuropathy (CIPN) from paclitaxel. The objective of this study was to validate vitamin D insufficiency as a CIPN risk factor.
METHODS
We used data and samples from the prospective phase III SWOG S0221 (ClinicalTrials.gov identifier: NCT00070564) trial that compared paclitaxel-containing chemotherapy regimens for early-stage breast cancer. We quantified pretreatment 25-hydroxy-vitamin D in banked serum samples using a liquid chromatography-tandem mass spectrometry targeted assay. We tested the association between vitamin D insufficiency (≤20 ng/mL) and grade ≥3 sensory CIPN via multiple logistic regression and then adjusted for self-reported race, age, body mass index, and paclitaxel schedule (randomization to weekly or every-2-week dosing). We also tested the direct effect of vitamin D deficiency on mechanical hypersensitivity in mice randomized to a regular or vitamin D-deficient diet.
RESULTS
Of the 1,191 female patients in the analysis, 397 (33.3%) had pretreatment vitamin D insufficiency, and 195 (16.4%) developed grade ≥3 CIPN. Patients with vitamin D insufficiency had a higher incidence of grade ≥3 CIPN than those who had sufficient vitamin D (20.7% vs 14.2%; odds ratio [OR], 1.57; 95% CI, 1.14-2.15; P=.005). The association retained significance after adjusting for age and paclitaxel schedule (adjusted OR, 1.65; 95% CI, 1.18-2.30; P=.003) but not race (adjusted OR, 1.39; 95% CI, 0.98-1.97; P=.066). In the mouse experiments, the vitamin D-deficient diet caused mechanical hypersensitivity and sensitized mice to paclitaxel (both P<.05).
CONCLUSIONS
Pretreatment vitamin D insufficiency is the first validated potentially modifiable predictive biomarker of CIPN from paclitaxel. Prospective trials are needed to determine whether vitamin D supplementation prevents CIPN and improves treatment outcomes in patients with breast and other cancer types.
Topics: Humans; Female; Animals; Mice; Paclitaxel; Prospective Studies; Peripheral Nervous System Diseases; Breast Neoplasms; Vitamin D; Risk Factors; Vitamin D Deficiency; Antineoplastic Agents
PubMed: 37935109
DOI: 10.6004/jnccn.2023.7062 -
Cardiovascular Diabetology Sep 2023Diabetic peripheral neuropathy (DPN) has been shown to be independently associated with cardiovascular events and mortality. This study aimed to evaluate changes in left...
Subclinical left ventricular deformation and microvascular dysfunction in T2DM patients with and without peripheral neuropathy: assessed by 3.0 T cardiac magnetic resonance imaging.
BACKGROUND
Diabetic peripheral neuropathy (DPN) has been shown to be independently associated with cardiovascular events and mortality. This study aimed to evaluate changes in left ventricular (LV) microvascular perfusion and myocardial deformation in type 2 diabetes mellitus (T2DM) patients with and without DPN, as well as to investigate the association between myocardial perfusion and LV deformation.
METHODS
Between October 2015 and July 2022, one hundred and twenty-three T2DM patients without DPN, fifty-four patients with DPN and sixty age‑ and sex‑matched controls who underwent cardiovascular magnetic resonance imaging were retrospectively analyzed. LV myocardial perfusion parameters at rest, including upslope, time to maximum signal intensity (TTM), max signal intensity (max SI), and myocardial strains, including global radial, circumferential and longitudinal strain (GRS, GCS and GLS, respectively), were calculated and compared among the groups with One‑way analysis of variance. Univariable and multivariable linear regression analyses were performed to explore the independent factors influencing LV myocardial perfusion indices and LV strains in diabetes.
RESULTS
The LV GLS, upslope and max SI were significantly deteriorated from controls, through patients without DPN, to patients with DPN (all P < 0.001). Compared with controls, TTM was increased and LV GRS and GCS were decreased in both patient groups (all P < 0.05). Multivariable regression analyses considering covariates showed that DPN was independently associated with reduced upslope, max SI and LV GLS (β = - 0.360, - 2.503 and 1.113, p = 0.021, 0.031 and 0.010, respectively). When the perfusion indices upslope and max SI were included in the multivariable analysis for LV deformation, DPN and upslope (β = 1.057 and - 0.870, p = 0.020 and 0.018, respectively) were significantly associated with LV GLS.
CONCLUSION
In patients with T2DM, there was more severe LV microvascular and myocardial dysfunction in patients with complicated DPN, and deteriorated subclinical LV systolic dysfunction was associated with impaired myocardial circulation.
Topics: Humans; Diabetes Mellitus, Type 2; Retrospective Studies; Heart; Peripheral Nervous System Diseases; Magnetic Resonance Imaging
PubMed: 37735418
DOI: 10.1186/s12933-023-01981-7 -
Cell Reports Nov 2023Schwann cells respond to acute axon damage by transiently transdifferentiating into specialized repair cells that restore sensorimotor function. However, the molecular...
Schwann cells respond to acute axon damage by transiently transdifferentiating into specialized repair cells that restore sensorimotor function. However, the molecular systems controlling repair cell formation and function are not well defined, and consequently, it is unclear whether this form of cellular plasticity has a role in peripheral neuropathies. Here, we identify Mitf as a transcriptional sensor of axon damage under the control of Nrg-ErbB-PI3K-PI5K-mTorc2 signaling. Mitf regulates a core transcriptional program for generating functional repair Schwann cells following injury and during peripheral neuropathies caused by CMT4J and CMT4D. In the absence of Mitf, core genes for epithelial-to-mesenchymal transition, metabolism, and dedifferentiation are misexpressed, and nerve repair is disrupted. Our findings demonstrate that Schwann cells monitor axonal health using a phosphoinositide signaling system that controls Mitf nuclear localization, which is critical for activating cellular plasticity and counteracting neural disease.
Topics: Humans; Peripheral Nervous System Diseases; Schwann Cells; Axons; Signal Transduction; Cell Plasticity; Nerve Regeneration; Peripheral Nerve Injuries; Sciatic Nerve
PubMed: 38007688
DOI: 10.1016/j.celrep.2023.113282 -
Journal of Cancer Research and Clinical... Aug 2023Chemotherapy induced peripheral neuropathy (CIPN) is a debilitating condition that is a direct consequence of receiving cancer treatment. The molecular aetiology of CIPN...
PURPOSE
Chemotherapy induced peripheral neuropathy (CIPN) is a debilitating condition that is a direct consequence of receiving cancer treatment. The molecular aetiology of CIPN is not well understood, and it is theorised that there may be a genetic component. Genetic polymorphisms in Glutathione-S Transferase (GST) genes, including GSTT1, GSTM1 and GSTP1, encode for enzymes known to metabolise drugs used in chemotherapy, and have been theorised to be associated with CIPN. This study aimed to investigate four markers in these genes for an association in a mixed cancer cohort in relation to CIPN (n = 172).
METHODS
CIPN was measured using the neuropathy item from the Patient Reported Outcome Common Terminology Criteria for Adverse Event (PRO-CTCAE) assessment. Genotyping for all samples was performed using PCR for the GSTM1 and GSTT1 null variants and restriction fragment length polymorphisms for the GSTP1 and GSTM1 polymorphisms.
RESULTS
No associations were found for the GST gene markers in relation to CIPN within our study, or CIPN severity. Longitudinal stratification of the CIPN phenotypes to examine links for neuropathy, identified nominally significant protective associations with the GSTM* null allele (p-value = 0.038, OR = 0.55) and the presence of pain at month 2 of treatment, as well as a risk factor for pain related month 2 of treatment for individuals with the GSTT1*null allele (p-value = 0.030, OR = 1.64). Higher severity of pain in patients with CIPN persisted at each time-point compared to those without CIPN.
CONCLUSION
No significant results for an association between CIPN with polymorphisms in GSTM1, GSTT1 and GSTP1 were identified. However, associations for the GSTM1¬-null and GSTT1-null polymorphisms with pain at month 2 following chemotherapy were identified.
Topics: Humans; Genetic Predisposition to Disease; Case-Control Studies; Polymorphism, Genetic; Glutathione Transferase; Glutathione S-Transferase pi; Risk Factors; Pain; Peripheral Nervous System Diseases; Antineoplastic Agents; Genotype
PubMed: 36939926
DOI: 10.1007/s00432-023-04677-3 -
Neurological Sciences : Official... Dec 2023Small fiber neuropathy [SFN] is a common peripheral neurologic disorder with a vast array of implicated etiologies. It has previously been proposed that some forms of...
INTRODUCTION
Small fiber neuropathy [SFN] is a common peripheral neurologic disorder with a vast array of implicated etiologies. It has previously been proposed that some forms of immune-mediated small fiber neuropathy are driven by vasculitis, though antinuclear cytoplasmic antibodies [ANCA] antibodies have not commonly been reported in association with SFN, thus far. We present this case series to discuss the observation of a possible novel association between ANCA and SFN.
METHODS
This is a retrospective case series of 6 patients with SFN and ANCA positivity, with and without systemic manifestations. Patients included were diagnosed with SFN by skin biopsy or autonomic function testing and were seropositive for ANCA by ELISA.
RESULTS
Six patients are outlined, including 4 females and 2 males. Antigen specific antibodies were MPO alone in 4 cases, PR3 alone in 1 case and both MPO and PR3 in 1 case. Systemic vasculitis was noted in 2 patients. Five patients received immunosuppression. Three patients experienced partial improvement, while symptoms stabilized in 3 patients.
DISCUSSION
This is the first series of patients with suspected immune-mediated SFN and ANCA antibody positivity, raising the possibility of ANCA mediated isolated SFN. This is in contradistinction to the more typical ANCA-mediated peripheral neuropathy manifestations of mononeuropathy multiplex or axonal sensorimotor neuropathy. We cannot unequivocally prove ANCA-associated vasculitis [AAV] causality in these cases; however, the stabilization in SFN symptomatology and associated improvement in ANCA antibody titer, after AAV treatment, may be indicative of an association.
Topics: Male; Female; Humans; Antibodies, Antineutrophil Cytoplasmic; Small Fiber Neuropathy; Retrospective Studies; Vasculitis; Enzyme-Linked Immunosorbent Assay; Peroxidase
PubMed: 37453951
DOI: 10.1007/s10072-023-06954-y