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Brain Sciences Jun 2024Neuropathic pain arises from injuries to the nervous system in diseases such as diabetes, infections, toxicity, and traumas. The underlying mechanism of neuropathic pain... (Review)
Review
Neuropathic pain arises from injuries to the nervous system in diseases such as diabetes, infections, toxicity, and traumas. The underlying mechanism of neuropathic pain involves peripheral and central pathological modifications. Peripheral mechanisms entail nerve damage, leading to neuronal hypersensitivity and ectopic action potentials. Central sensitization involves a neuropathological process with increased responsiveness of the nociceptive neurons in the central nervous system (CNS) to their normal or subthreshold input due to persistent stimuli, leading to sustained electrical discharge, synaptic plasticity, and aberrant processing in the CNS. Current treatments, both pharmacological and non-pharmacological, aim to alleviate symptoms but often face challenges due to the complexity of neuropathic pain. Neuromodulation is emerging as an important therapeutic approach for the treatment of neuropathic pain in patients unresponsive to common therapies, by promoting the normalization of neuronal and/or glial activity and by targeting cerebral cortical regions, spinal cord, dorsal root ganglia, and nerve endings. Having a better understanding of the efficacy, adverse events and applicability of neuromodulation through pre-clinical studies is of great importance. Unveiling the mechanisms and characteristics of neuromodulation to manage neuropathic pain is essential to understand how to use it. In the present article, we review the current understanding supporting dorsal root ganglia and spinal cord neuromodulation as a therapeutic approach for neuropathic pain.
PubMed: 38928589
DOI: 10.3390/brainsci14060589 -
International Journal of Molecular... Jun 2024Neuropathic pain, which refers to pain caused by a lesion or disease of the somatosensory system, represents a wide variety of peripheral or central disorders. Treating... (Review)
Review
Neuropathic pain, which refers to pain caused by a lesion or disease of the somatosensory system, represents a wide variety of peripheral or central disorders. Treating neuropathic pain is quite demanding, primarily because of its intricate underlying etiological mechanisms. The central nervous system relies on microglia to maintain balance, as they are associated with serving primary immune responses in the brain next to cell communication. Ferroptosis, driven by phospholipid peroxidation and regulated by iron, is a vital mechanism of cell death regulation. Neuroinflammation can be triggered by ferroptosis in microglia, which contributes to the release of inflammatory cytokines. Conversely, neuroinflammation can induce iron accumulation in microglia, resulting in microglial ferroptosis. Accumulating evidence suggests that neuroinflammation, characterized by glial cell activation and the release of inflammatory substances, significantly exacerbates the development of neuropathic pain. By inhibiting microglial ferroptosis, it may be possible to prevent neuroinflammation and subsequently alleviate neuropathic pain. The activation of the homopentameric α7 subtype of the neuronal nicotinic acetylcholine receptor (α7nAChR) has the potential to suppress microglial activation, transitioning M1 microglia to an M2 phenotype, facilitating the release of anti-inflammatory factors, and ultimately reducing neuropathic pain. Recent years have witnessed a growing recognition of the regulatory role of α7nAChR in ferroptosis, which could be a potential target for treating neuropathic pain. This review summarizes the mechanisms related to α7nAChR and the progress of ferroptosis in neuropathic pain according to recent research. Such an exploration will help to elucidate the relationship between α7nAChR, ferroptosis, and neuroinflammation and provide new insights into neuropathic pain management.
Topics: Ferroptosis; Neuralgia; Humans; Animals; Neuroinflammatory Diseases; Microglia; alpha7 Nicotinic Acetylcholine Receptor; Inflammation
PubMed: 38928421
DOI: 10.3390/ijms25126716 -
International Journal of Molecular... Jun 2024The peripheral nervous system can encounter alterations due to exposure to some of the most commonly used anticancer drugs (platinum drugs, taxanes, vinca alkaloids,... (Review)
Review
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.
Topics: Humans; Antineoplastic Agents; Peripheral Nervous System Diseases; Ion Channels; Animals; Neurotoxicity Syndromes; Membrane Transport Proteins; Neoplasms
PubMed: 38928257
DOI: 10.3390/ijms25126552 -
International Journal of Molecular... Jun 2024Gap injuries to the peripheral nervous system result in pain and loss of function, without any particularly effective therapeutic options. Within this context,... (Review)
Review
Gap injuries to the peripheral nervous system result in pain and loss of function, without any particularly effective therapeutic options. Within this context, mesenchymal stem cell (MSC)-derived exosomes have emerged as a potential therapeutic option. Thus, the focus of this study was to review currently available data on MSC-derived exosome-mounted scaffolds in peripheral nerve regeneration in order to identify the most promising scaffolds and exosome sources currently in the field of peripheral nerve regeneration. We conducted a systematic review following PRISMA 2020 guidelines. Exosome origins varied (adipose-derived MSCs, bone marrow MSCs, gingival MSC, induced pluripotent stem cells and a purified exosome product) similarly to the materials (Matrigel, alginate and silicone, acellular nerve graft [ANG], chitosan, chitin, hydrogel and fibrin glue). The compound muscle action potential (CMAP), sciatic functional index (SFI), gastrocnemius wet weight and histological analyses were used as main outcome measures. Overall, exosome-mounted scaffolds showed better regeneration than scaffolds alone. Functionally, both exosome-enriched chitin and ANG showed a significant improvement over time in the sciatica functional index, CMAP and wet weight. The best histological outcomes were found in the exosome-enriched ANG scaffold with a high increase in the axonal diameter and muscle cross-section area. Further studies are needed to confirm the efficacy of exosome-mounted scaffolds in peripheral nerve regeneration.
Topics: Exosomes; Nerve Regeneration; Mesenchymal Stem Cells; Humans; Animals; Tissue Scaffolds; Peripheral Nerve Injuries; Mesenchymal Stem Cell Transplantation
PubMed: 38928194
DOI: 10.3390/ijms25126489 -
International Journal of Molecular... Jun 2024The exact mechanism by which diabetic neuropathy develops is still not fully known, despite our advances in medical knowledge. Progressing neuropathy may occur with a... (Review)
Review
The exact mechanism by which diabetic neuropathy develops is still not fully known, despite our advances in medical knowledge. Progressing neuropathy may occur with a persistently favorable metabolic status in some patients with diabetes mellitus, while, in others, though seldom, a persistently unfavorable metabolic status is not associated with significant neuropathy. This might be significantly due to genetic differences. While recent years have brought compelling progress in the understanding of the pathogenetic background-in particular, accelerated progress is being made in understanding molecular biological mechanisms-some aspects are still not fully understood. A comparatively small amount of information is accessible on this matter; therefore, by summarizing the available data, in this review, we aim to provide a clearer picture of the current state of knowledge, identify gaps in the previous studies, and possibly suggest directions for future studies. This could help in developing more personalized approaches to the prevention and treatment of diabetic neuropathy, while also taking into account individual genetic profiles.
Topics: Humans; Diabetic Neuropathies; Genetic Predisposition to Disease; Genetic Variation; Animals
PubMed: 38928135
DOI: 10.3390/ijms25126429 -
International Journal of Molecular... Jun 2024Mutations in the gene are associated with autosomal recessive spastic ataxia of Charlevoix-Saguenay disease (ARSACS) or complex clinical phenotypes of...
Mutations in the gene are associated with autosomal recessive spastic ataxia of Charlevoix-Saguenay disease (ARSACS) or complex clinical phenotypes of Charcot-Marie-Tooth disease (CMT). This study aimed to identify mutations in a Korean CMT cohort with cerebellar ataxia and spasticity by whole exome sequencing (WES). As a result, eight pathogenic mutations in four families were identified as the underlying causes of these complex phenotypes. The prevalence of CMT families with mutations was determined to be 0.3%. All the patients showed sensory, motor, and gait disturbances with increased deep tendon reflexes. Lower limb magnetic resonance imaging (MRI) was performed in four patients and all had fatty replacements. Of note, they all had similar fatty infiltrations between the proximal and distal lower limb muscles, different from the neuromuscular imaging feature in most CMT patients without mutations who had distal dominant fatty involvement. Therefore, these findings were considered a characteristic feature in CMT patients with mutations. Although further studies with more cases are needed, our results highlight lower extremity MRI findings in CMT patients with mutations and broaden the clinical spectrum. We suggest screening for in recessive CMT patients with complex phenotypes of ataxia and spasticity.
Topics: Humans; Male; Charcot-Marie-Tooth Disease; Female; Mutation; Adult; Republic of Korea; Muscle Spasticity; Heterozygote; Cohort Studies; Middle Aged; Magnetic Resonance Imaging; Heat-Shock Proteins; Pedigree; Exome Sequencing; Cerebellar Ataxia; Phenotype; Adolescent; Young Adult
PubMed: 38928084
DOI: 10.3390/ijms25126378 -
International Journal of Molecular... Jun 2024Congenital insensitivity to pain is a rare human condition in which affected individuals do not experience pain throughout their lives. This study aimed to identify the...
Congenital insensitivity to pain is a rare human condition in which affected individuals do not experience pain throughout their lives. This study aimed to identify the molecular etiology of congenital insensitivity to pain in two Thai patients. Clinical, radiographic, histopathologic, immunohistochemical, and molecular studies were performed. Patients were found to have congenital insensitivity to pain, self-mutilation, acro-osteolysis, cornea scars, reduced temperature sensation, tooth agenesis, root maldevelopment, and underdeveloped maxilla and mandible. The skin biopsies revealed fewer axons, decreased vimentin expression, and absent neurofilament expression, indicating lack of dermal nerves. Whole exome and Sanger sequencing identified a rare homozygous variant c.4039C>T; p.Arg1347Cys in the plakin domain of , a cytolinker protein. This p.Arg1347Cys variant is in the spectrin repeat 9 region of the plakin domain, a region not previously found to harbor pathogenic missense variants in other plectinopathies. The substitution with a cysteine is expected to decrease the stability of the spectrin repeat 9 unit of the plakin domain. Whole mount in situ hybridization and an immunohistochemical study suggested that is important for the development of maxilla and mandible, cornea, and distal phalanges. Additionally, the presence of dental anomalies in these patients further supports the potential involvement of in tooth development. This is the first report showing the association between the variant and congenital insensitivity to pain in humans.
Topics: Humans; Homozygote; Male; Plectin; Female; Pain Insensitivity, Congenital; Child; Pedigree; Mutation, Missense; Exome Sequencing
PubMed: 38928066
DOI: 10.3390/ijms25126358 -
Bioengineering (Basel, Switzerland) Jun 2024Muscular dystrophies present diagnostic challenges, requiring accurate classification for effective diagnosis and treatment. This study investigates the efficacy of deep...
Muscular dystrophies present diagnostic challenges, requiring accurate classification for effective diagnosis and treatment. This study investigates the efficacy of deep learning methodologies in classifying these disorders using skeletal muscle MRI scans. Specifically, we assess the performance of the Swin Transformer (SwinT) architecture against traditional convolutional neural networks (CNNs) in distinguishing between healthy individuals, Becker muscular dystrophy (BMD), and limb-girdle muscular Dystrophy type 2 (LGMD2) patients. Moreover, 3T MRI scans from a retrospective dataset of 75 scans (from 54 subjects) were utilized, with multiparametric protocols capturing various MRI contrasts, including T1-weighted and Dixon sequences. The dataset included 17 scans from healthy volunteers, 27 from BMD patients, and 31 from LGMD2 patients. SwinT and CNNs were trained and validated using a subset of the dataset, with the performance evaluated based on accuracy and F-score. Results indicate the superior accuracy of SwinT (0.96), particularly when employing fat fraction (FF) images as input; it served as a valuable parameter for enhancing classification accuracy. Despite limitations, including a modest cohort size, this study provides valuable insights into the application of AI-driven approaches for precise neuromuscular disorder classification, with potential implications for improving patient care.
PubMed: 38927816
DOI: 10.3390/bioengineering11060580 -
Genes Jun 2024Neurodegenerative diseases are a heterogeneous group of age-related disorders that are characterised by the gradual degeneration or death of neurons in the central or...
Neurodegenerative diseases are a heterogeneous group of age-related disorders that are characterised by the gradual degeneration or death of neurons in the central or peripheral nervous system [...].
Topics: Neurodegenerative Diseases; Humans; Phenotype; Genotype
PubMed: 38927722
DOI: 10.3390/genes15060786 -
Genes Jun 2024Extracellular vesicles (EVs) are "micro-shuttles" that play a role as mediators of intercellular communication. Cells release EVs into the extracellular environment in... (Review)
Review
Extracellular vesicles (EVs) are "micro-shuttles" that play a role as mediators of intercellular communication. Cells release EVs into the extracellular environment in both physiological and pathological conditions and are involved in intercellular communication, due to their ability to transfer proteins, lipids, and nucleic acids, and in the modulation of the immune system and neuroinflammation. Because EVs can penetrate the blood-brain barrier and move from the central nervous system to the peripheral circulation, and vice versa, recent studies have shown a substantial role for EVs in several neurological diseases, including multiple sclerosis (MS). MS is a demyelinating disease where the main event is caused by T and B cells triggering an autoimmune reaction against myelin constituents. Recent research has elucidate the potential involvement of extracellular vesicles (EVs) in the pathophysiology of MS, although, to date, their potential role both as agents and therapeutic targets in MS is not fully defined. We present in this review a summary and comprehensive examination of EVs' involvement in the pathophysiology of multiple sclerosis, exploring their potential applications as biomarkers and indicators of therapy response.
Topics: Humans; Multiple Sclerosis; Extracellular Vesicles; Biomarkers; Animals; Blood-Brain Barrier
PubMed: 38927708
DOI: 10.3390/genes15060772