Abstract:Mesenchymal stem cells (MSCs) derived exosomes (Exos) are one of the most promising candidate for the treatment of this condition. However, the underlying molecular mechanism remains uncertain. Here we investigated the therapeutic effect of exosomal miR-181c-5p (Exo miR-181c-5p ) on a rat model of neuropathic pain induced by sciatic nerve chronic constriction injury (CCI). In this study NP model was established using the CCI method. NP levels were assessed using PWT and PWL. Microarray analysis and RT-PCR were… Show more
“…43 Transfer of microRNAs between cell types may be brought about by the release and uptake of exosomes. 44 Importantly, altered function of ion channels as a result of the action of primary mediators leads to increased excitability of primary afferent neurons [45][46][47][48][49] and the generation of stimulus-independent spontaneous activity. This incessant spontaneous activity in primary afferents is absolutely crucial for the onset and persistence of pain.…”
Section: Structural Remodeling Of Injured Peripheral Nervesmentioning
Patients with neuropathic pain are heterogeneous in pathophysiology, etiology, and clinical presentation. Signs and symptoms are determined by the nature of the injury and factors such as genetics, sex, prior injury, age, culture, and environment. Basic science has provided general information about pain etiology by studying the consequences of peripheral injury in rodent models. This is associated with the release of inflammatory cytokines, chemokines, and growth factors that sensitize sensory nerve endings, alter gene expression, promote post-translational modification of proteins, and alter ion channel function. This leads to spontaneous activity in primary afferent neurons that is crucial for the onset and persistence of pain and the release of secondary mediators such as colony-stimulating factor 1 from primary afferent terminals. These promote the release of tertiary mediators such as brain-derived neurotrophic factor and interleukin-1β from microglia and astrocytes. Tertiary mediators facilitate the transmission of nociceptive information at the spinal, thalamic, and cortical levels. For the most part, these findings have failed to identify new therapeutic approaches. More recent basic science has better mirrored the clinical situation by addressing the pathophysiology associated with specific types of injury, refinement of methodology, and attention to various contributory factors such as sex. Improved quantification of sensory profiles in each patient and their distribution into defined clusters may improve translation between basic science and clinical practice. If such quantification can be traced back to cellular and molecular aspects of pathophysiology, this may lead to personalized medicine approaches that dictate a rational therapeutic approach for each individual.
“…43 Transfer of microRNAs between cell types may be brought about by the release and uptake of exosomes. 44 Importantly, altered function of ion channels as a result of the action of primary mediators leads to increased excitability of primary afferent neurons [45][46][47][48][49] and the generation of stimulus-independent spontaneous activity. This incessant spontaneous activity in primary afferents is absolutely crucial for the onset and persistence of pain.…”
Section: Structural Remodeling Of Injured Peripheral Nervesmentioning
Patients with neuropathic pain are heterogeneous in pathophysiology, etiology, and clinical presentation. Signs and symptoms are determined by the nature of the injury and factors such as genetics, sex, prior injury, age, culture, and environment. Basic science has provided general information about pain etiology by studying the consequences of peripheral injury in rodent models. This is associated with the release of inflammatory cytokines, chemokines, and growth factors that sensitize sensory nerve endings, alter gene expression, promote post-translational modification of proteins, and alter ion channel function. This leads to spontaneous activity in primary afferent neurons that is crucial for the onset and persistence of pain and the release of secondary mediators such as colony-stimulating factor 1 from primary afferent terminals. These promote the release of tertiary mediators such as brain-derived neurotrophic factor and interleukin-1β from microglia and astrocytes. Tertiary mediators facilitate the transmission of nociceptive information at the spinal, thalamic, and cortical levels. For the most part, these findings have failed to identify new therapeutic approaches. More recent basic science has better mirrored the clinical situation by addressing the pathophysiology associated with specific types of injury, refinement of methodology, and attention to various contributory factors such as sex. Improved quantification of sensory profiles in each patient and their distribution into defined clusters may improve translation between basic science and clinical practice. If such quantification can be traced back to cellular and molecular aspects of pathophysiology, this may lead to personalized medicine approaches that dictate a rational therapeutic approach for each individual.
“…In CCI rats, miR-181c-5p from MSC-derived exosomes were found to be significantly downregulated in a timedependent manner. Intrathecal administration of exosomal miR-181c-5p which targets microglia and inhibits the secretion of inflammatory factors alleviated neuropathic pain and the neuroinflammatory response after CCI (Zhang Y. U. et al, 2022).…”
Section: Extracellular Vesicles Regulates Neuropathic Pain Via Mirnamentioning
confidence: 99%
“…EVs generated by cells including neurons, glial cells and immune cells can promote cell-to-cell communication and regulate biological processes after nerve injury (López-Leal et al, 2020). In addition, MSCs including bone marrow MSCs, gingival MSCs, adMSCs, and hucMSCs can release EVs to regulate the pathological progression after nerve injury (Bryk et al, 2022;Zhang Y. U. et al, 2022). EVs derived from different cells contain different signaling molecules and surface antigens as well as different cargos including unique proteins, lipids, and genetic material (Toh et al, 2018).…”
Section: Biogenesis Of Evsmentioning
confidence: 99%
“…, and RNU48 from serum-derived exosomes in patients with complex regional pain syndrome show significant differential expression (McDonald et al, 2014). Carrying miR-181c-5p containing exosomes repress CCI-induced neuropathic pain through inhibition of neuroinflammation (Zhang Y. U. et al, 2022), which provided the therapeutic rationale for studying EVs to treat neuropathic pain.…”
Extracellular vesicles (EVs) including exosomes are vesicular vesicles with phospholipid bilayer implicated in many cellular interactions and have the ability to transfer multiple types of cargo to cells. It has been found that EVs can package various molecules including proteins and nucleic acids (DNA, mRNA, and noncoding RNA). The discovery of EVs as carriers of proteins and various forms of RNA, such as microRNAs (miRNA) and long noncoding RNAs (lncRNA), has raised great interest in the field of drug delivery. Despite the underlying mechanisms of neuropathic pain being unclear, it has been shown that uncontrolled glial cell activation and the neuroinflammation response to noxious stimulation are important in the emergence and maintenance of neuropathic pain. Many studies have demonstrated a role for noncoding RNAs in the pathogenesis of neuropathic pain and EVs may offer possibilities as carriers of noncoding RNAs for potential in neuropathic pain treatment. In this article, the origins and clinical application of EVs and the mechanism of neuropathic pain development are briefly introduced. Furthermore, we demonstrate the therapeutic roles of EVs in neuropathic pain and that this involve vesicular regulation of glial cell activation and neuroinflammation.
“…The latter post-transcriptionally regulate the protein expression of hundreds of genes in a sequence-specific manner [23]. Transfer of microRNAs between cell types may be brought about the release and uptake of exosomes [24].…”
Section: Sensitization and Spontaneous Activity Of Primary Afferentsmentioning
Nerve injury or disease often leads to intractable neuropathic pain. Axons which are severed undergo Wallerian degeneration. This involves the activation of Schwann cells, mast cells, fibroblasts, keratinocytes and epithelial cells and the release of inflammatory cytokines, chemokines and growth factors. These primary mediators sensitize sensory nerve endings, attract macrophages, neutrophils and lymphocytes, alter gene expression, promote post-translational modification of proteins and alter ion channel function. This evokes spontaneous activity in primary afferent neurons that is crucial for the onset and maintenance of pain. In addition, secondary mediators such as colony stimulating factor 1 are generated and released from primary afferent terminals. These promote release of tertiary mediators such as brain-derived neurotrophic factor and interleukin 1b from spinal microglia and astrocytes. Tertiary mediators facilitate the generation and transmission of nociceptive information by facilitating excitatory transmission and attenuating inhibitory transmission in the dorsal horn. Transfer of information between neurons and immune cells is bidirectional. Neurons directly control immune cell function in a process termed neurogenic neuroinflammation. Increased permeability of the blood-brain barrier allows access of immune cells to neurons in central pain pathways. This, together with neurogenic neuroinflammation, increases activity throughout the pain sensory system. This review provides an overview of processes involved in the generation and persistence of peripherally generated neuropathic pain. Attention is drawn to the idea that pain etiology is dependent on the nature of the injury and different processes operate in males compared to females.
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