-
Autophagy Jan 2024AAV: adeno-associated virus; ATF3: activating transcription factor 3; ATG7: autophagy related 7; AVIL: advillin; cADPR: cyclic ADP ribose; CALC:...
AAV: adeno-associated virus; ATF3: activating transcription factor 3; ATG7: autophagy related 7; AVIL: advillin; cADPR: cyclic ADP ribose; CALC: calcitonin/calcitonin-related polypeptide; CMT: Charcot-Marie-Tooth disease; cKO: conditional knockout; DEG: differentially expressed gene; DRG: dorsal root ganglion; FE-SEM: field emission scanning electron microscopy; IF: immunofluorescence; NCV: nerve conduction velocity; PVALB: parvalbumin; RAG: regeneration-associated gene; ROS: reactive oxygen species; SARM1: sterile alpha and HEAT/Armadillo motif containing 1; : synapsin I.
Topics: Armadillo Domain Proteins; Autophagy; Axons; Calcitonin; Charcot-Marie-Tooth Disease; Cytoskeletal Proteins; Reactive Oxygen Species; Animals; Mice
PubMed: 37561040
DOI: 10.1080/15548627.2023.2244861 -
Pain Aug 2023Pain radiating from the spine into the leg is commonly referred to as "sciatica," "Sciatica" may include various conditions such as radicular pain or painful...
Pain radiating from the spine into the leg is commonly referred to as "sciatica," "Sciatica" may include various conditions such as radicular pain or painful radiculopathy. It may be associated with significant consequences for the person living with the condition, imposing a reduced quality of life and substantial direct and indirect costs. The main challenges associated with a diagnosis of "sciatica" include those related to the inconsistent use of terminology for the diagnostic labels and the identification of neuropathic pain. These challenges hinder collective clinical and scientific understanding regarding these conditions. In this position paper, we describe the outcome of a working group commissioned by the Neuropathic Pain Special Interest Group (NeuPSIG) of the International Association for the Study of Pain (IASP) which was tasked with the following objectives: (1) to revise the use of terminology for classifying spine-related leg pain and (2) to propose a way forward on the identification of neuropathic pain in the context of spine-related leg pain. The panel recommended discouraging the term "sciatica" for use in clinical practice and research without further specification of what it entails. The term "spine-related leg pain" is proposed as an umbrella term to include the case definitions of somatic referred pain and radicular pain with and without radiculopathy. The panel proposed an adaptation of the neuropathic pain grading system in the context of spine-related leg pain to facilitate the identification of neuropathic pain and initiation of specific management in this patient population.
Topics: Humans; Radiculopathy; Leg; Quality of Life; Neuralgia; Sciatica
PubMed: 37235637
DOI: 10.1097/j.pain.0000000000002919 -
JAMA Network Open Aug 2023Chemotherapy-induced peripheral neuropathy (CIPN), one of the most common and severe adverse effects of chemotherapy, is associated with worse quality of life among... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Chemotherapy-induced peripheral neuropathy (CIPN), one of the most common and severe adverse effects of chemotherapy, is associated with worse quality of life among survivors of ovarian cancer. Currently, there is no effective treatment for CIPN.
OBJECTIVE
To evaluate the effect of a 6-month aerobic exercise intervention vs attention-control on CIPN among women treated for ovarian cancer in the Women's Activity and Lifestyle Study in Connecticut (WALC) to provide evidence to inform the guidelines and recommendations for prevention or treatment of CIPN.
DESIGN, SETTING, AND PARTICIPANTS
This prespecified secondary analysis evaluated the Women's Activity and Lifestyle Study in Connecticut (WALC), a multicentered, open-label, population-based, phase 3 randomized clinical trial of an aerobic exercise intervention vs attention control for CIPN in patients who were diagnosed with ovarian cancer. Only WALC participants who received chemotherapy were included in this analysis. Participants were randomized 1:1 to either a 6-month aerobic exercise intervention or to attention control. All analyses were conducted between September 2022 and January 2023.
INTERVENTIONS
The exercise intervention consisted of home-based moderate-intensity aerobic exercise facilitated by weekly telephone counseling from an American College of Sports Medicine/American Cancer Society-certified cancer exercise trainer. Attention control involved weekly health education telephone calls from a WALC staff member.
MAIN OUTCOMES AND MEASURE
Change in CIPN was the primary outcome in this secondary analysis. This outcome was represented by CIPN severity, which was self-measured by participants at baseline and 6 months using the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity scale, with a score range of 0 to 44. A mixed-effects model was used to assess the 6-month change in CIPN between the exercise intervention and attention control arms.
RESULTS
Of the 134 participants (all females; mean [SD] age, 57.5 [8.3] years) included in the analysis, 69 were in the exercise intervention arm and 65 were in the attention control arm. The mean (SD) time since diagnosis was 1.7 (1.0) years. The mean (SD) baseline CIPN scores were 8.1 (5.6) in the exercise intervention arm and 8.8 (7.9) in the attention control arm (P = .56). At 6 months, the self-reported CIPN score was reduced by 1.3 (95% CI, -2.3 to -0.2) points in the exercise intervention arm compared with an increase of 0.4 (95% CI, -0.8 to 1.5) points in the attention control arm. The between-group difference was -1.6 (95% CI, -3.1 to -0.2) points. The point estimate was larger among the 127 patients with CIPN symptoms at enrollment (-2.0; 95% CI, -3.6 to -0.5 points).
CONCLUSIONS AND RELEVANCE
Findings of this secondary analysis of the WALC trial indicate that a 6-month aerobic exercise intervention vs attention control significantly improved self-reported CIPN among patients who were treated for ovarian cancer. While replication of the findings in other studies is warranted, incorporating referrals to exercise programs into standard oncology care could reduce CIPN symptoms and increase quality of life in patients with ovarian cancer.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02107066.
Topics: United States; Humans; Female; Middle Aged; Quality of Life; Exercise; Ovarian Neoplasms; Peripheral Nervous System Diseases; Antineoplastic Agents
PubMed: 37526937
DOI: 10.1001/jamanetworkopen.2023.26463 -
Nutrients Aug 2023Alpha-lipoic acid (ALA) was found to improve the symptoms in patients with diabetic sensorimotor peripheral neuropathy (DSPN) by reducing oxidative stress and... (Meta-Analysis)
Meta-Analysis Review
Alpha-lipoic acid (ALA) was found to improve the symptoms in patients with diabetic sensorimotor peripheral neuropathy (DSPN) by reducing oxidative stress and ameliorating microcirculation. Our meta-analysis is aimed at evaluating the effects of oral-administered ALA versus a placebo in patients with DSPN and determining the optimal dosage for this treatment. We systematically reviewed randomized controlled trials (RCTs) in the PubMed, Embase, and Cochrane databases to determine the efficacy of oral ALA for patients with DSPN. The primary outcome was total symptoms' score (TSS), and secondary outcomes were the neurological disability score (NDS), neuropathy impaired score (NIS), NIS-lower limb (NIS-LL), vibration perception threshold (VPT), nerve conduction study (NCS) results, and global satisfaction. A subgroup analysis of the ALA dosage (600, 1200, and 1800 mg/day) was also conducted. Ten RCTs (1242 patients) were included. ALA treatment produced favorable results for TSS (a dose-related trend was observed), NDS, and the global satisfaction score. For VAS, VPT, NIS-LL, and NCS results, ALA did not produce favorable results. ALA treatment had favorable effects on DSPN by reducing sensory symptoms, and it resulted in a dose-dependent response relative to the placebo for TSS and the global satisfaction score. The use of ALA to prevent neurological symptoms should be further researched.
Topics: Humans; Diabetic Neuropathies; Thioctic Acid; Administration, Oral; Databases, Factual; Lower Extremity; Diabetes Mellitus
PubMed: 37630823
DOI: 10.3390/nu15163634 -
Diabetes Research and Clinical Practice Dec 2023Diabetic peripheral neuropathy (DPN) is found in around one third of people with diabetes, but remains inadequately diagnosed and treated. Its management includes three... (Review)
Review
Diabetic peripheral neuropathy (DPN) is found in around one third of people with diabetes, but remains inadequately diagnosed and treated. Its management includes three cornerstones: 1) causal treatment with lifestyle modification, intensive diabetes therapy aimed at near-normoglycemia, and multifactorial cardiovascular risk intervention, 2) pathogenesis-oriented pharmacotherapy, and 3) symptomatic pain relief. Since symptomatic analgesic monotherapy only relieves the pain without targeting the underlying neuropathy and both has limited efficacy and is associated with adverse events, there is an unmet need for additional approaches derived from the pathogenetic concepts of DPN. Preclinical studies have suggested that diabetic neuropathy can be prevented or improved through the use of various agents that interfere with the pathophysiology of the underlying condition. Some of these encouraging findings could be translated successfully into the clinical setting. Efficacy and excellent safety were demonstrated in several meta-analyses (α-lipoic acid) and randomized clinical trials (benfotiamine, actovegin, epalrestat) in the treatment of symptomatic DPN. The NATHAN 1 trial demonstrated an improvement of neuropathic signs (deficits, impairments) after four years in asymptomatic DPN. These compounds are currently authorized for treatment of DPN in several countries. Long-term pivotal clinical trials should further establish their value as mono- and combination therapies in DPN.
Topics: Humans; Combined Modality Therapy; Diabetes Mellitus; Diabetic Neuropathies; Pain; Thioctic Acid
PubMed: 38245327
DOI: 10.1016/j.diabres.2023.110764 -
Brain : a Journal of Neurology Nov 2023Valid, responsive blood biomarkers specific to peripheral nerve damage would improve management of peripheral nervous system (PNS) diseases. Neurofilament light chain...
Valid, responsive blood biomarkers specific to peripheral nerve damage would improve management of peripheral nervous system (PNS) diseases. Neurofilament light chain (NfL) is sensitive for detecting axonal pathology but is not specific to PNS damage, as it is expressed throughout the PNS and CNS. Peripherin, another intermediate filament protein, is almost exclusively expressed in peripheral nerve axons. We postulated that peripherin would be a promising blood biomarker of PNS axonal damage. We demonstrated that peripherin is distributed in sciatic nerve, and to a lesser extent spinal cord tissue lysates, but not in brain or extra-neural tissues. In the spinal cord, anti-peripherin antibody bound only to the primary cells of the periphery (anterior horn cells, motor axons and primary afferent sensory axons). In vitro models of antibody-mediated axonal and demyelinating nerve injury showed marked elevation of peripherin levels only in axonal damage and only a minimal rise in demyelination. We developed an immunoassay using single molecule array technology for the detection of serum peripherin as a biomarker for PNS axonal damage. We examined longitudinal serum peripherin and NfL concentrations in individuals with Guillain-Barré syndrome (GBS, n = 45, 179 time points), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, n = 35, 70 time points), multiple sclerosis (n = 30), dementia (as non-inflammatory CNS controls, n = 30) and healthy individuals (n = 24). Peak peripherin levels were higher in GBS than all other groups (median 18.75 pg/ml versus < 6.98 pg/ml, P < 0.0001). Peak NfL was highest in GBS (median 220.8 pg/ml) and lowest in healthy controls (median 5.6 pg/ml), but NfL did not distinguish between CIDP (17.3 pg/ml), multiple sclerosis (21.5 pg/ml) and dementia (29.9 pg/ml). While peak NfL levels were higher with older age (rho = +0.39, P < 0.0001), peak peripherin levels did not vary with age. In GBS, local regression analysis of serial peripherin in the majority of individuals with three or more time points of data (16/25) displayed a rise-and-fall pattern with the highest value within the first week of initial assessment. Similar analysis of serial NfL concentrations showed a later peak at 16 days. Group analysis of serum peripherin and NfL levels in GBS and CIDP patients were not significantly associated with clinical data, but in some individuals with GBS, peripherin levels appeared to better reflect clinical outcome measure improvement. Serum peripherin is a promising new, dynamic and specific biomarker of acute PNS axonal damage.
Topics: Humans; Peripherins; Intermediate Filaments; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Guillain-Barre Syndrome; Axons; Biomarkers; Dementia; Multiple Sclerosis
PubMed: 37435933
DOI: 10.1093/brain/awad234 -
Proceedings of the National Academy of... Aug 2023Small molecules directly targeting the voltage-gated sodium channel (VGSC) Na1.7 have not been clinically successful. We reported that preventing the addition of a small...
Small molecules directly targeting the voltage-gated sodium channel (VGSC) Na1.7 have not been clinically successful. We reported that preventing the addition of a small ubiquitin-like modifier onto the Na1.7-interacting cytosolic collapsin response mediator protein 2 (CRMP2) blocked Na1.7 function and was antinociceptive in rodent models of neuropathic pain. Here, we discovered a CRMP2 regulatory sequence (CRS) unique to Na1.7 that is essential for this regulatory coupling. CRMP2 preferentially bound to the Na1.7 CRS over other Na isoforms. Substitution of the Na1.7 CRS with the homologous domains from the other eight VGSC isoforms decreased Na1.7 currents. A cell-penetrant decoy peptide corresponding to the Na1.7-CRS reduced Na1.7 currents and trafficking, decreased presynaptic Na1.7 expression, reduced spinal CGRP release, and reversed nerve injury-induced mechanical allodynia. Importantly, the Na1.7-CRS peptide did not produce motor impairment, nor did it alter physiological pain sensation, which is essential for survival. As a proof-of-concept for a Na1.7 -targeted gene therapy, we packaged a plasmid encoding the Na1.7-CRS in an AAV virus. Treatment with this virus reduced Na1.7 function in both rodent and rhesus macaque sensory neurons. This gene therapy reversed and prevented mechanical allodynia in a model of nerve injury and reversed mechanical and cold allodynia in a model of chemotherapy-induced peripheral neuropathy. These findings support the conclusion that the CRS domain is a targetable region for the treatment of chronic neuropathic pain.
Topics: Animals; Hyperalgesia; Chronic Pain; Macaca mulatta; Neuralgia; NAV1.7 Voltage-Gated Sodium Channel; Ganglia, Spinal; NAV1.8 Voltage-Gated Sodium Channel
PubMed: 37498871
DOI: 10.1073/pnas.2217800120 -
Antioxidants & Redox Signaling Dec 2023The remarkable geometry of the axon exposes it to unique challenges for survival and maintenance. Axonal degeneration is a feature of peripheral neuropathies, glaucoma,... (Review)
Review
The remarkable geometry of the axon exposes it to unique challenges for survival and maintenance. Axonal degeneration is a feature of peripheral neuropathies, glaucoma, and traumatic brain injury, and an early event in neurodegenerative diseases. Since the discovery of Wallerian degeneration (WD), a molecular program that hijacks nicotinamide adenine dinucleotide (NAD) metabolism for axonal self-destruction, the complex roles of NAD in axonal viability and disease have become research priority. The discoveries of the protective Wallerian degeneration slow (Wld) and of sterile alpha and TIR motif containing 1 (SARM1) activation as the main instructive signal for WD have shed new light on the regulatory role of NAD in axonal degeneration in a growing number of neurological diseases. SARM1 has been characterized as a NAD hydrolase and sensor of NAD metabolism. The discovery of regulators of nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) proteostasis in axons, the allosteric regulation of SARM1 by NAD and NMN, and the existence of clinically relevant windows of action of these signals has opened new opportunities for therapeutic interventions, including SARM1 inhibitors and modulators of NAD metabolism. Events upstream and downstream of SARM1 remain unclear. Furthermore, manipulating NAD metabolism, an overdetermined process crucial in cell survival, for preventing the degeneration of the injured axon may be difficult and potentially toxic. There is a need for clarification of the distinct roles of NAD metabolism in axonal maintenance as contrasted to WD. There is also a need to better understand the role of NAD metabolism in axonal endangerment in neuropathies, diseases of the white matter, and the early stages of neurodegenerative diseases of the central nervous system. 39, 1167-1184.
Topics: Humans; Wallerian Degeneration; NAD; Peripheral Nervous System Diseases; Axons; Neurodegenerative Diseases
PubMed: 37503611
DOI: 10.1089/ars.2023.0350 -
Diabetes Research and Clinical Practice Dec 2023This article summarizes the latest epidemiology of diabetic autonomic neuropathy (DAN), and provides a brief overview on epidemiology, current outcomes measures for... (Review)
Review
This article summarizes the latest epidemiology of diabetic autonomic neuropathy (DAN), and provides a brief overview on epidemiology, current outcomes measures for screening and diagnosis in research and clinical settings, the latest evidence on effective management, and novel perspectives on the impacts of social determinants of health in development and management of DAN. Among the various forms of diabetic neuropathy, distal symmetric polyneuropathy and diabetic autonomic neuropathies, particularly cardiovascular autonomic neuropathy, are by far the most studied. However, emerging data highlight the impact of other forms of autonomic neuropathies such as gastrointestinal and urogenital autonomic neuropathies, on healthcare and patients' reported outcomes [1].
Topics: Humans; Diabetic Neuropathies
PubMed: 38245325
DOI: 10.1016/j.diabres.2023.110762 -
Post-transcriptional microRNA repression of PMP22 dose in severe Charcot-Marie-Tooth disease type 1.Brain : a Journal of Neurology Oct 2023Copy number variation (CNV) may lead to pathological traits, and Charcot-Marie-Tooth disease type 1A (CMT1A), the commonest inherited peripheral neuropathy, is due to a...
Copy number variation (CNV) may lead to pathological traits, and Charcot-Marie-Tooth disease type 1A (CMT1A), the commonest inherited peripheral neuropathy, is due to a genomic duplication encompassing the dosage-sensitive PMP22 gene. MicroRNAs act as repressors on post-transcriptional regulation of gene expression and in rodent models of CMT1A, overexpression of one such microRNA (miR-29a) has been shown to reduce the PMP22 transcript and protein level. Here we present genomic and functional evidence, for the first time in a human CNV-associated phenotype, of the 3' untranslated region (3'-UTR)-mediated role of microRNA repression on gene expression. The proband of the family presented with an early-onset, severe sensorimotor demyelinating neuropathy and harboured a novel de novo deletion in the PMP22 3'-UTR. The deletion is predicted to include the miR-29a seed binding site and transcript analysis of dermal myelinated nerve fibres using a novel platform, revealed a marked increase in PMP22 transcript levels. Functional evidence from Schwann cell lines harbouring the wild-type and mutant 3'-UTR showed significantly increased reporter assay activity in the latter, which was not ameliorated by overexpression of a miR-29a mimic. This shows the importance of miR-29a in regulating PMP22 expression and opens an avenue for therapeutic drug development.
Topics: Humans; Charcot-Marie-Tooth Disease; MicroRNAs; DNA Copy Number Variations; Myelin Proteins; Gene Expression
PubMed: 37337674
DOI: 10.1093/brain/awad203