Pharmacology & Therapeutics最新文献

{"title":"Ion channel dysregulation and cellular adaptations to alpha-synuclein in stressful pacemakers of the parkinsonian brainstem","authors":"Wei-Hua Chiu ,&nbsp;Nadine Wattad ,&nbsp;Joshua A. Goldberg","doi":"10.1016/j.pharmthera.2024.108683","DOIUrl":"10.1016/j.pharmthera.2024.108683","url":null,"abstract":"<div><p>Parkinson's disease (PD) is diagnosed by its cardinal motor symptoms that are associated with the loss of dopamine neurons in the substantia nigra pars compacta (SNc). However, PD patients suffer from various non-motor symptoms years before diagnosis. These prodromal symptoms are thought to be associated with the appearance of Lewy body pathologies (LBP) in brainstem regions such as the dorsal motor nucleus of the vagus (DMV), the locus coeruleus (LC) and others. The neurons in these regions that are vulnerable to LBP are all slow autonomous pacemaker neurons that exhibit elevated oxidative stress due to their perpetual influx of Ca²⁺ ions. Aggregation of toxic α-Synuclein (aSyn) – the main constituent of LBP – during the long prodromal period challenges these vulnerable neurons, presumably altering their biophysics and physiology. In contrast to pathophysiology of late stage parkinsonism which is well-documented, little is known about the pathophysiology of the brainstem during prodromal PD.</p><p>In this review, we discuss ion channel dysregulation associated with aSyn aggregation in brainstem pacemaker neurons and their cellular responses to them. While toxic aSyn elevates oxidative stress in SNc and LC pacemaker neurons and exacerbates their phenotype, DMV neurons mount an adaptive response that mitigates the oxidative stress. Ion channel dysregulation and cellular adaptations may be the drivers of the prodromal symptoms of PD. For example, selective targeting of toxic aSyn to DMV pacemakers, elevates the surface density of K⁺ channels, which slows their firing rate, resulting in reduced parasympathetic tone to the gastrointestinal tract, which resembles the prodromal PD symptoms of dysphagia and constipation. The divergent responses of SNc &amp; LC vs. DMV pacemaker neurons may explain why the latter outlive the former despite presenting LBPs earlier. Elucidation the brainstem pathophysiology of prodromal PD could pave the way for physiological biomarkers, earlier diagnosis and novel neuroprotective therapies for PD.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"260 ","pages":"Article 108683"},"PeriodicalIF":12.0,"publicationDate":"2024-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141475618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Matrikines in the skin: Origin, effects, and therapeutic potential","authors":"Jonathan P. Sirois,&nbsp;Andrea Heinz","doi":"10.1016/j.pharmthera.2024.108682","DOIUrl":"10.1016/j.pharmthera.2024.108682","url":null,"abstract":"<div><p>The extracellular matrix (ECM) represents a complex multi-component environment that has a decisive influence on the biomechanical properties of tissues and organs. Depending on the tissue, ECM components are subject to a homeostasis of synthesis and degradation, a subtle interplay that is influenced by external factors and the intrinsic aging process and is often disturbed in pathologies. Upon proteolytic cleavage of ECM proteins, small bioactive peptides termed matrikines can be formed. These bioactive peptides play a crucial role in cell signaling and contribute to the dynamic regulation of both physiological and pathological processes such as tissue remodeling and repair as well as inflammatory responses. In the skin, matrikines exert an influence for instance on cell adhesion, migration, and proliferation as well as vasodilation, angiogenesis and protein expression. Due to their manifold functions, matrikines represent promising leads for developing new therapeutic options for the treatment of skin diseases. This review article gives a comprehensive overview on matrikines in the skin, including their origin in the dermal ECM, their biological effects and therapeutic potential for the treatment of skin pathologies such as melanoma, chronic wounds and inflammatory skin diseases or for their use in anti-aging cosmeceuticals.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"260 ","pages":"Article 108682"},"PeriodicalIF":12.0,"publicationDate":"2024-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0163725824001025/pdfft?md5=90797462ec730c14de8ea807d03266ab&pid=1-s2.0-S0163725824001025-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141449186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioactive lipids in the skin barrier mediate its functionality in health and disease","authors":"Anna Nicolaou ,&nbsp;Alexandra C. Kendall","doi":"10.1016/j.pharmthera.2024.108681","DOIUrl":"10.1016/j.pharmthera.2024.108681","url":null,"abstract":"<div><p>Our skin protects us from external threats including ultraviolet radiation, pathogens and chemicals, and prevents excessive trans-epidermal water loss. These varied activities are reliant on a vast array of lipids, many of which are unique to skin, and that support physical, microbiological and immunological barriers. The cutaneous physical barrier is dependent on a specific lipid matrix that surrounds terminally-differentiated keratinocytes in the <em>stratum corneum</em>. Sebum- and keratinocyte-derived lipids cover the skin's surface and support and regulate the skin microbiota. Meanwhile, lipids signal between resident and infiltrating cutaneous immune cells, driving inflammation and its resolution in response to pathogens and other threats. Lipids of particular importance include ceramides, which are crucial for <em>stratum corneum</em> lipid matrix formation and therefore physical barrier functionality, fatty acids, which contribute to the acidic pH of the skin surface and regulate the microbiota, as well as the <em>stratum corneum</em> lipid matrix, and bioactive metabolites of these fatty acids, involved in cell signalling, inflammation, and numerous other cutaneous processes. These diverse and complex lipids maintain homeostasis in healthy skin, and are implicated in many cutaneous diseases, as well as unrelated systemic conditions with skin manifestations, and processes such as ageing. Lipids also contribute to the gut-skin axis, signalling between the two barrier sites. Therefore, skin lipids provide a valuable resource for exploration of healthy cutaneous processes, local and systemic disease development and progression, and accessible biomarker discovery for systemic disease, as well as an opportunity to fully understand the relationship between the host and the skin microbiota. Investigation of skin lipids could provide diagnostic and prognostic biomarkers, and help identify new targets for interventions. Development and improvement of existing <em>in vitro</em> and <em>in silico</em> approaches to explore the cutaneous lipidome, as well as advances in skin lipidomics technologies, will facilitate ongoing progress in skin lipid research.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"260 ","pages":"Article 108681"},"PeriodicalIF":12.0,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0163725824001013/pdfft?md5=49cdd94ea59a7ad08886d87e4af148c3&pid=1-s2.0-S0163725824001013-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141425976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"UFMylation: An integral post-translational modification for the regulation of proteostasis and cellular functions","authors":"Xiaohui Wang ,&nbsp;Xiaowei Lv ,&nbsp;Jingjing Ma ,&nbsp;Guoqiang Xu","doi":"10.1016/j.pharmthera.2024.108680","DOIUrl":"10.1016/j.pharmthera.2024.108680","url":null,"abstract":"<div><p>Ubiquitin-fold modifier 1 (UFM1) is covalently conjugated to protein substrates via a cascade of enzymatic reactions, a process known as UFMylation. UFMylation orchestrates an array of vital biological functions, including maintaining endoplasmic reticulum (ER) homeostasis, facilitating protein biogenesis, promoting cellular differentiation, regulating DNA damage response, and participating in cancer-associated signaling pathways. UFMylation has rapidly evolved into one of the forefront research areas within the last few years, yet much remains to be uncovered. In this review, first, UFMylation and its cellular functions associated with diseases are briefly introduced. Then, we summarize the proteomic approaches for identifying UFMylation substrates and explore the impact of UFMylation on gene transcription, protein translation, and maintenance of ER homeostasis. Next, we highlight the intricate regulation between UFMylation and two protein degradation pathways, the ubiquitin-proteasome system and the autophagy-lysosome pathway, and explore the potential of UFMylation system as a drug target. Finally, we discuss emerging perspectives in the UFMylation field. This review may provide valuable insights for drug discovery targeting the UFMylation system.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"260 ","pages":"Article 108680"},"PeriodicalIF":12.0,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141327077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic insights into medulloblastoma relapse","authors":"Kendell Peterson ,&nbsp;Maria Turos-Cabal ,&nbsp;April D. Salvador ,&nbsp;Isabel Palomo-Caturla ,&nbsp;Ashley J. Howell ,&nbsp;Megan E. Vieira ,&nbsp;Sean M. Greiner ,&nbsp;Thibaut Barnoud ,&nbsp;Jezabel Rodriguez-Blanco","doi":"10.1016/j.pharmthera.2024.108673","DOIUrl":"10.1016/j.pharmthera.2024.108673","url":null,"abstract":"<div><p>Pediatric brain tumors are the leading cause of cancer-related deaths in children, with medulloblastoma (MB) being the most common type. A better understanding of these malignancies has led to their classification into four major molecular subgroups. This classification not only facilitates the stratification of clinical trials, but also the development of more effective therapies. Despite recent progress, approximately 30% of children diagnosed with MB experience tumor relapse. Recurrent disease in MB is often metastatic and responds poorly to current therapies. As a result, only a small subset of patients with recurrent MB survive beyond one year. Due to its dismal prognosis, novel therapeutic strategies aimed at preventing or managing recurrent disease are urgently needed. In this review, we summarize recent advances in our understanding of the molecular mechanisms behind treatment failure in MB, as well as those characterizing recurrent cases. We also propose avenues for how these findings can be used to better inform personalized medicine approaches for the treatment of newly diagnosed and recurrent MB. Lastly, we discuss the treatments currently being evaluated for MB patients, with special emphasis on those targeting MB by subgroup at diagnosis and relapse.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"260 ","pages":"Article 108673"},"PeriodicalIF":12.0,"publicationDate":"2024-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0163725824000937/pdfft?md5=4beb186973f7f1f12b001d2538e954b9&pid=1-s2.0-S0163725824000937-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141299659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mithramycin and its analogs: Molecular features and antitumor action","authors":"José Portugal","doi":"10.1016/j.pharmthera.2024.108672","DOIUrl":"10.1016/j.pharmthera.2024.108672","url":null,"abstract":"<div><p>The antitumor antibiotic mithramycin A (MTA) binds to G/C-rich DNA sequences in the presence of dications. MTA inhibits transcription regulated by the Sp1 transcription factor, often enhanced during tumor development. It shows antitumor activity, but its clinical use was discontinued due to toxic side effects. However, recent observations have led to its use being reconsidered. The MTA biosynthetic pathways have been modified to produce mithramycin analogs (mithralogs) that encompass lower toxicity and improved pharmacological activity. Some mithralogs reduce gene expression in human ovarian and prostate tumors, among other types of cancer. They down-regulate gene expression in various cellular processes, including Sp1-responsive genes that control tumor development. Moreover, MTA and several mithralogs, such as EC-8042 (DIG-MSK) and EC-8105, effectively treat Ewing sarcoma by inhibiting transcription controlled by the oncogenic EWS-FLI1 transcription factor.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"260 ","pages":"Article 108672"},"PeriodicalIF":13.5,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141260627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent advances in the reciprocal regulation of m6A modification with non-coding RNAs and its therapeutic application in acute myeloid leukemia","authors":"Jiawang Yang ,&nbsp;Feng Liang ,&nbsp;Fenglin Zhang ,&nbsp;Hailong Zhao ,&nbsp;Qihai Gong ,&nbsp;Ning Gao","doi":"10.1016/j.pharmthera.2024.108671","DOIUrl":"10.1016/j.pharmthera.2024.108671","url":null,"abstract":"<div><p>N⁶-methyladenosine (m⁶A) is one of the most common modifications of RNA in eukaryotic cells and is involved in mRNA metabolism, including stability, translation, maturation, splicing, and export. m⁶A also participates in the modification of multiple types of non-coding RNAs, such as microRNAs, long non-coding RNAs, and circular RNAs, thereby affecting their metabolism and functions. Increasing evidence has revealed that m⁶A regulators, such as writers, erasers, and readers, perform m⁶A-dependent modification of ncRNAs, thus affecting cancer progression. Moreover, ncRNAs modulate m⁶A regulators to affect cancer development and progression. In this review, we summarize recent advances in understanding m⁶A modification and ncRNAs and provide insights into the interaction between m⁶A modification and ncRNAs in cancer. We also discuss the potential clinical applications of the mechanisms underlying the interplay between m⁶A modifications and ncRNAs in acute myeloid leukemia (AML). Therefore, clarifying the mutual regulation between m⁶A modifications and ncRNAs is of great significance to identify novel therapeutic targets for AML and has great clinical application prospects.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"259 ","pages":"Article 108671"},"PeriodicalIF":13.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141236466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intercellular pathways of cancer treatment-related cardiotoxicity and their therapeutic implications: the paradigm of radiotherapy","authors":"Stella Logotheti ,&nbsp;Athanasia Pavlopoulou ,&nbsp;Hamid Khoshfekr Rudsari ,&nbsp;Anne-Marie Galow ,&nbsp;Yağmur Kafalı ,&nbsp;Efthymios Kyrodimos ,&nbsp;Aris I. Giotakis ,&nbsp;Stephan Marquardt ,&nbsp;Anastasia Velalopoulou ,&nbsp;Ioannis I. Verginadis ,&nbsp;Constantinos Koumenis ,&nbsp;Thorsten Stiewe ,&nbsp;Jerome Zoidakis ,&nbsp;Ilangko Balasingham ,&nbsp;Robert David ,&nbsp;Alexandros G. Georgakilas","doi":"10.1016/j.pharmthera.2024.108670","DOIUrl":"10.1016/j.pharmthera.2024.108670","url":null,"abstract":"<div><p>Advances in cancer therapeutics have improved patient survival rates. However, cancer survivors may suffer from adverse events either at the time of therapy or later in life. Cardiovascular diseases (CVD) represent a clinically important, but mechanistically understudied complication, which interfere with the continuation of best-possible care, induce life-threatening risks, and/or lead to long-term morbidity. These concerns are exacerbated by the fact that targeted therapies and immunotherapies are frequently combined with radiotherapy, which induces durable inflammatory and immunogenic responses, thereby providing a fertile ground for the development of CVDs. Stressed and dying irradiated cells produce ‘danger’ signals including, but not limited to, major histocompatibility complexes, cell-adhesion molecules, proinflammatory cytokines, and damage-associated molecular patterns. These factors activate intercellular signaling pathways which have potentially detrimental effects on the heart tissue homeostasis. Herein, we present the clinical crosstalk between cancer and heart diseases, describe how it is potentiated by cancer therapies, and highlight the multifactorial nature of the underlying mechanisms. We particularly focus on radiotherapy, as a case known to often induce cardiovascular complications even decades after treatment. We provide evidence that the secretome of irradiated tumors entails factors that exert systemic, remote effects on the cardiac tissue, potentially predisposing it to CVDs. We suggest how diverse disciplines can utilize pertinent state-of-the-art methods in feasible experimental workflows, to shed light on the molecular mechanisms of radiotherapy-related cardiotoxicity at the organismal level and untangle the desirable immunogenic properties of cancer therapies from their detrimental effects on heart tissue. Results of such highly collaborative efforts hold promise to be translated to next-generation regimens that maximize tumor control, minimize cardiovascular complications, and support quality of life in cancer survivors.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"260 ","pages":"Article 108670"},"PeriodicalIF":12.0,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141185940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The endocrine FGFs axis: A systemic anti-fibrotic response that could prevent pulmonary fibrogenesis?","authors":"Mada Ghanem ,&nbsp;Gabrielle Archer ,&nbsp;Bruno Crestani ,&nbsp;Arnaud A. Mailleux","doi":"10.1016/j.pharmthera.2024.108669","DOIUrl":"10.1016/j.pharmthera.2024.108669","url":null,"abstract":"<div><p>Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease for which therapeutic options are limited, with an unmet need to identify new therapeutic targets. IPF is thought to be the consequence of repeated microlesions of the alveolar epithelium, leading to aberrant epithelial-mesenchymal communication and the accumulation of extracellular matrix proteins. The reactivation of developmental pathways, such as Fibroblast Growth Factors (FGFs), is a well-described mechanism during lung fibrogenesis. Secreted FGFs with local paracrine effects can either exert an anti-fibrotic or a pro-fibrotic action during this pathological process through their FGF receptors (FGFRs) and heparan sulfate residues as co-receptors. Among FGFs, endocrine FGFs (FGF29, FGF21, and FGF23) play a central role in the control of metabolism and tissue homeostasis. They are characterized by a low affinity for heparan sulfate, present in the cell vicinity, allowing them to have endocrine activity. Nevertheless, their interaction with FGFRs requires the presence of mandatory co-receptors, alpha and beta Klotho proteins (KLA and KLB). Endocrine FGFs are of growing interest for their anti-fibrotic action during liver, kidney, or myocardial fibrosis. Innovative therapies based on FGF19 or FGF21 analogs are currently being studied in humans during liver fibrosis. Recent data report a similar anti-fibrotic action of endocrine FGFs in the lung, suggesting a systemic regulation of the pulmonary fibrotic process. In this review, we summarize the current knowledge on the protective effect of endocrine FGFs during the fibrotic processes, with a focus on pulmonary fibrosis.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"259 ","pages":"Article 108669"},"PeriodicalIF":13.5,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0163725824000895/pdfft?md5=2fa70f5ca438378a85096562c85402d7&pid=1-s2.0-S0163725824000895-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141144135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurobiological mechanisms of botulinum neurotoxin-induced analgesia for neuropathic pain","authors":"Ana Bagues ,&nbsp;Jiaxin Hu ,&nbsp;Ishraq Alshanqiti ,&nbsp;Man-Kyo Chung","doi":"10.1016/j.pharmthera.2024.108668","DOIUrl":"10.1016/j.pharmthera.2024.108668","url":null,"abstract":"<div><p>Botulinum neurotoxins (BoNTs) are a family of neurotoxins produced by <em>Clostridia</em> and other bacteria that induce botulism. BoNTs are internalized into nerve terminals at the site of injection and cleave soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins to inhibit the vesicular release of neurotransmitters. BoNTs have been approved for multiple therapeutic applications, including the treatment of migraines. They have also shown efficacies for treating neuropathic pain, such as diabetic neuropathy, and postherpetic and trigeminal neuralgia. However, the mechanisms underlying BoNT-induced analgesia are not well understood. Peripherally administered BoNT is taken up by the nerve terminals and reduces the release of glutamate, calcitonin gene-related peptide, and substance P, which decreases neurogenic inflammation in the periphery. BoNT is retrogradely transported to sensory ganglia and central terminals in a microtubule-dependent manner. BoNTs decrease the expression of pronociceptive genes (ion channels or cytokines) from sensory ganglia and the release of neurotransmitters and neuropeptides from primary afferent central terminals, which likely leads to decreased central sensitization in the dorsal horn of the spinal cord or trigeminal nucleus. BoNT-induced analgesia is abolished after capsaicin-induced denervation of transient receptor potential vanilloid 1 (TRPV1)-expressing afferents or the knockout of substance P or the neurokinin-1 receptor. Although peripheral administration of BoNT leads to changes in the central nervous system (e.g., decreased phosphorylation of glutamate receptors in second-order neurons, reduced activation of microglia, contralateral localization, and cortical reorganization), whether such changes are secondary to changes in primary afferents or directly mediated by trans-synaptic, transcytotic, or the hematogenous transport of BoNT is controversial. To enhance their therapeutic potential, BoNTs engineered for specific targeting of nociceptive pathways have been developed to treat chronic pain. Further mechanistic studies on BoNT-induced analgesia can enhance the application of native or engineered BoNTs for neuropathic pain treatment with improved safety and efficacy.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"259 ","pages":"Article 108668"},"PeriodicalIF":13.5,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141086347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}