Recent Advances in the Pharmacology of Peripheral Neuropathy

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 12934

Special Issue Editors

UR 20218-NeurIT, Faculties of Medicine and Pharmacy, University of Limoges, 87025 Limoges, France
Interests: pharmacology; pain; peripheral neuropathy; CIPN
UR 20218-NeurIT, Faculties of Medicine and Pharmacy, University of Limoges, 87025 Limoges, France
Interests: CIPN; neuroprotection; microtubule-targeting agents; sensory neurons; mitochondria; tubulin; TRPV1

Special Issue Information

Dear Colleagues,

Peripheral neuropathies encompass a broad array of conditions that involve damage to the peripheral nervous system which affect millions of people worldwide and remain difficult to treat. Peripheral neuropathy can result from inherited causes as well as traumatic injuries, infections, metabolic problems including diabetes, and exposure to chemotherapy. Symptoms vary according to the type of neuropathy and may include sensory symptoms such as numbness, tingling, and pain in the feet and hands, or motor symptoms such as weakness and loss of muscle bulk, particularly in the lower leg and feet muscles. Certain types of neuropathies can affect the autonomic nerves, resulting in impaired sweating, postural hypotension, or insensitivity to pain. Although quite different in their etiologies, they all face the common challenge of a lack of standard treatment. Current options are mainly symptomatic and supportive with medical treatment including physical therapy and if needed, pain medication. Similarly, patients with inherited peripheral neuropathies, such as Charcot–Marie–Tooth disease (CMT), are provided life-long supportive care, but again there are currently no treatments or cures. Therefore, as conventional methods demonstrate limited long-term efficacy, there is a significant need to discover therapies that offer both longitudinal and sustained management of neuropathic symptoms. Furthermore, since different types of neuropathies may respond differently to a given drug, there is a need for studies where predictive factors for response are identified.

This Pharmaceuticals Special Issue invites both reviews and original articles regarding basic, preclinical, and clinical studies relevant as potential therapeutic options for patients with CIPN and inherited peripheral neuropathies.

We look forward to your contribution.

Dr. Claire Demiot
Dr. Amandine Rovini
Guest Editors

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Keywords

  • CIPN
  • inherited neuropathies
  • mechanistic of pain
  • neuroprotection
  • animal models
  • drug discovery

Published Papers (8 papers)

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Research

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12 pages, 2171 KiB  
Article
Netazepide, an Antagonist of Cholecystokinin Type 2 Receptor, Prevents Vincristine-Induced Sensory Neuropathy in Mice
by Amandine Bernard, Mohamad Mroué, Sylvie Bourthoumieu, Malcolm Boyce, Laurence Richard, Franck Sturtz, Claire Demiot and Aurore Danigo
Pharmaceuticals 2024, 17(2), 144; https://doi.org/10.3390/ph17020144 - 23 Jan 2024
Viewed by 881
Abstract
Among the vinca-alkaloid class, vincristine is a potent chemotherapeutic agent with significant neurotoxic effects and is employed to address a wide spectrum of cancer types. Recently, the therapeutic potential of the cholecystokinin type 2 receptor (CCK2R) as a target for vincristine-induced peripheral neuropathy [...] Read more.
Among the vinca-alkaloid class, vincristine is a potent chemotherapeutic agent with significant neurotoxic effects and is employed to address a wide spectrum of cancer types. Recently, the therapeutic potential of the cholecystokinin type 2 receptor (CCK2R) as a target for vincristine-induced peripheral neuropathy (VIPN) was demonstrated. In this study, the impact of preventive CCK2R blockade using netazepide (Trio Medicines Ltd., London, UK) was investigated in a mouse model of vincristine-induced peripheral neuropathy. Netazepide is a highly selective CCK2R antagonist under development for the treatment of patients with gastric neuroendocrine tumors caused by hypergastrinemia secondary to chronic autoimmune atrophic gastritis. Vincristine-induced peripheral neuropathy was induced by intraperitoneal injections of vincristine at 100 µg/kg/d for 7 days (D0 to D7). Netazepide (2 mg/kg/d or 5 mg/kg/d, per os) was administered one day before vincristine treatment until D7. Vincristine induced a high tactile allodynia from D1 to D7. VIPN was characterized by dorsal root ganglion neuron (DRG) and intraepidermal nerve fiber (IENF) loss, and enlargement and loss of myelinated axons in the sciatic nerve. Netazepide completely prevented the painful symptoms and nerve injuries induced by vincristine. In conclusion, the fact that netazepide protected against vincristine-induced peripheral neuropathy in a mouse model strongly supports the assessment of its therapeutic potential in patients receiving such chemotherapy. Full article
(This article belongs to the Special Issue Recent Advances in the Pharmacology of Peripheral Neuropathy)
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19 pages, 4459 KiB  
Article
The Antinociceptive Responses of MTDZ to Paclitaxel−Induced Peripheral Neuropathy and Acute Nociception in Mice: Behavioral, Pharmacological, and Biochemical Approaches
by Ketlyn P. da Motta, Carolina C. Martins, Vanessa M. Macedo, Beatriz F. dos Santos, Nelson Luís De C. Domingues, Cristiane Luchese and Ethel A. Wilhelm
Pharmaceuticals 2023, 16(9), 1217; https://doi.org/10.3390/ph16091217 - 29 Aug 2023
Viewed by 684
Abstract
The efficacy of 5-((4-methoxyphenyl)thio)benzo[c][1,2,5] thiodiazole (MTDZ) in mitigating paclitaxel (PTX)-induced peripheral neuropathy was investigated in male and female Swiss mice. The study examined the effects of MTDZ on various pathways, including transient receptor potential cation channel subfamily V member 1 (TRPV1), glutamatergic, nitrergic, [...] Read more.
The efficacy of 5-((4-methoxyphenyl)thio)benzo[c][1,2,5] thiodiazole (MTDZ) in mitigating paclitaxel (PTX)-induced peripheral neuropathy was investigated in male and female Swiss mice. The study examined the effects of MTDZ on various pathways, including transient receptor potential cation channel subfamily V member 1 (TRPV1), glutamatergic, nitrergic, guanylate cyclase (cGMP), serotonergic, and opioidergic. Mice received intraperitoneal PTX (2 mg/kg) or vehicle on days 1, 2, and 3, followed by oral MTDZ (1 mg/kg) or vehicle from days 3 to 14. Mechanical and thermal sensitivities were assessed using Von Frey and hot plate tests on days 8, 11, and 14. The open field test evaluated locomotion and exploration on day 12. On day 15, nitrite and nitrate (NOx) levels and Ca2+−ATPase activity in the cerebral cortex and spinal cord were measured after euthanizing the animals. MTDZ administration reversed the heightened mechanical and thermal sensitivities induced by PTX in male and female mice without affecting locomotion or exploration. MTDZ also modulated multiple pathways, including glutamatergic, NO/L−arginine/cGMP, serotonergic (5−HT1A/1B), opioid, and TRPV1 pathways. Additionally, MTDZ reduced NOx levels and modulated Ca2+−ATPase activity. In conclusion, MTDZ effectively alleviated PTX−induced peripheral neuropathy and demonstrated multi-targeted modulation of pain-related pathways. Its ability to modulate multiple pathways, reduce NOx levels, and modulate Ca2+−ATPase activity makes it a potential pharmacological candidate for peripheral neuropathy, acute nociceptive, and inflammatory conditions. Further research is needed to explore its therapeutic potential in these areas. Full article
(This article belongs to the Special Issue Recent Advances in the Pharmacology of Peripheral Neuropathy)
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12 pages, 2999 KiB  
Article
Amlexanox: Readthrough Induction and Nonsense-Mediated mRNA Decay Inhibition in a Charcot–Marie–Tooth Model of hiPSCs-Derived Neuronal Cells Harboring a Nonsense Mutation in GDAP1 Gene
by Nesrine Benslimane, Federica Miressi, Camille Loret, Laurence Richard, Angélique Nizou, Ioanna Pyromali, Pierre-Antoine Faye, Frédéric Favreau, Fabrice Lejeune and Anne-Sophie Lia
Pharmaceuticals 2023, 16(7), 1034; https://doi.org/10.3390/ph16071034 - 21 Jul 2023
Cited by 1 | Viewed by 1295
Abstract
Nonsense mutations are involved in multiple peripheral neuropathies. These mutations induce the presence of a premature termination codon (PTC) at the mRNA level. As a result, a dysfunctional or truncated protein is synthesized, or even absent linked to nonsense-mediated mRNA degradation (NMD) system [...] Read more.
Nonsense mutations are involved in multiple peripheral neuropathies. These mutations induce the presence of a premature termination codon (PTC) at the mRNA level. As a result, a dysfunctional or truncated protein is synthesized, or even absent linked to nonsense-mediated mRNA degradation (NMD) system activation. Readthrough molecules or NMD inhibitors could be innovative therapies in these hereditary neuropathies, particularly molecules harboring the dual activity as amlexanox. Charcot–Marie–Tooth (CMT) is the most common inherited pathology of the peripheral nervous system, affecting 1 in 2500 people worldwide. Nonsense mutations in the GDAP1 gene have been associated with a severe form of CMT, prompting us to investigate the effect of readthrough and NMD inhibitor molecules. Although not clearly defined, GDAP1 could be involved in mitochondrial functions, such as mitophagy. We focused on the homozygous c.581C>G (p.Ser194*) mutation inducing CMT2H using patient human induced pluripotent stem cell (hiPSC)-derived neuronal cells. Treatment during 20 h with 100 µM of amlexanox on this cell model stabilized GDAP1 mRNAs carrying UGA-PTC and induced a restoration of the mitochondrial morphology. These results highlight the potential of readthrough molecules associated to NMD inhibitors for the treatment of genetic alterations in CMT, opening the way for future investigations and a potential therapy. Full article
(This article belongs to the Special Issue Recent Advances in the Pharmacology of Peripheral Neuropathy)
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15 pages, 2115 KiB  
Article
Kaurenoic Acid Reduces Ongoing Chronic Constriction Injury-Induced Neuropathic Pain: Nitric Oxide Silencing of Dorsal Root Ganglia Neurons
by Tiago H. Zaninelli, Sandra S. Mizokami, Mariana M. Bertozzi, Telma Saraiva-Santos, Felipe A. Pinho-Ribeiro, Gabriele Inácio de Oliveira, Renata Streck, Eduardo J. A. Araújo, Nilton S. Arakawa, Sergio M. Borghi, Rubia Casagrande and Waldiceu A. Verri
Pharmaceuticals 2023, 16(3), 343; https://doi.org/10.3390/ph16030343 - 23 Feb 2023
Cited by 2 | Viewed by 1521
Abstract
Kaurenoic acid (KA) is a diterpene extracted from Sphagneticola trilobata (L.) Pruski. KA presents analgesic properties. However, the analgesic activity and mechanisms of action of KA in neuropathic pain have not been investigated so far; thus, we addressed these points in the present [...] Read more.
Kaurenoic acid (KA) is a diterpene extracted from Sphagneticola trilobata (L.) Pruski. KA presents analgesic properties. However, the analgesic activity and mechanisms of action of KA in neuropathic pain have not been investigated so far; thus, we addressed these points in the present study. A mouse model of neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. Acute (at the 7th-day post-CCI surgery) and prolonged (from 7–14th days post-CCI surgery) KA post-treatment inhibited CCI-induced mechanical hyperalgesia at all evaluated time points, as per the electronic version of von Frey filaments. The underlying mechanism of KA was dependent on activating the NO/cGMP/PKG/ATP-sensitive potassium channel signaling pathway since L-NAME, ODQ, KT5823, and glibenclamide abolished KA analgesia. KA reduced the activation of primary afferent sensory neurons, as observed by a reduction in CCI-triggered colocalization of pNF-κB and NeuN in DRG neurons. KA treatment also increased the expression of neuronal nitric oxide synthase (nNOS) at the protein level as well as the intracellular levels of NO in DRG neurons. Therefore, our results provide evidence that KA inhibits CCI neuropathic pain by activating a neuronal analgesic mechanism that depends on nNOS production of NO to silence the nociceptive signaling that generates analgesia. Full article
(This article belongs to the Special Issue Recent Advances in the Pharmacology of Peripheral Neuropathy)
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13 pages, 2154 KiB  
Article
Segmental Upregulation of ASIC1 Channels in the Formalin Acute Pain Mouse Model
by María Natalia Gobetto, Libia Catalina Salinas Castellanos, Natalia Estefanía Contreras, Alejandro Omar Sodero, Damián Alejandro Cambiagno, Georgina Oriana Mingolo Malnati, Mayra Micaela Montes, Osvaldo Daniel Uchitel and Carina Weissmann
Pharmaceuticals 2022, 15(12), 1539; https://doi.org/10.3390/ph15121539 - 12 Dec 2022
Cited by 1 | Viewed by 1625
Abstract
Background: Hindpaw injection of formalin in rodents is used to assess acute persistent pain. The response to formalin is biphasic. The initial response (first minutes) is thought to be linked to inflammatory, peripheral mechanisms, while the latter (around 30 min after the injection), [...] Read more.
Background: Hindpaw injection of formalin in rodents is used to assess acute persistent pain. The response to formalin is biphasic. The initial response (first minutes) is thought to be linked to inflammatory, peripheral mechanisms, while the latter (around 30 min after the injection), is linked to central mechanisms. This model is useful to analyze the effect of drugs at one or both phases, and the involvement of ion channels in the response. Acid-sensing ion channels (ASICs) regulate synaptic activities and play important roles in pain conditions. Recently, psalmotoxin-1 (Pctx-1), a toxin that inhibits ASIC1a-constituted channels, and antisense ASIC1a-RNA, intrathecal administered in mice were shown to affect both phases of the test. Methods: The mouse formalin test was performed on C57/BL6 7- to 9-week-old mice. Behavioral tests were conducted and tissue was extracted to detect proteins (ASIC1 and pERK) and ASIC1-mRNA and mir485-5p levels. Results: The injection of formalin was accompanied by an increase in ASIC1 levels. This was detected at the contralateral anterior cingulate cortex (ACC) compared to the ipsilateral side, and both sides of the ACC of vehicle-injected animals. At the spinal cord and dorsal root ganglia, ASIC1 levels followed a gradient stronger at lumbar (L) 3 and decreased towards L5. Gender differences were detected at the ACC; with female mice showing higher ASIC1a levels at the ACC. No significant changes in ASIC1-mRNA levels were detected. Evidence suggests ASIC1 upregulation depends on regulatory microRNAs. Conclusion: This work highlights the important role of ASIC1 in pain and the potential role of pharmacological therapies aimed at this channel. Full article
(This article belongs to the Special Issue Recent Advances in the Pharmacology of Peripheral Neuropathy)
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Review

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29 pages, 7108 KiB  
Review
Readthrough Activators and Nonsense-Mediated mRNA Decay Inhibitor Molecules: Real Potential in Many Genetic Diseases Harboring Premature Termination Codons
by Nesrine Benslimane, Camille Loret, Pauline Chazelas, Frédéric Favreau, Pierre-Antoine Faye, Fabrice Lejeune and Anne-Sophie Lia
Pharmaceuticals 2024, 17(3), 314; https://doi.org/10.3390/ph17030314 - 28 Feb 2024
Viewed by 741
Abstract
Nonsense mutations that generate a premature termination codon (PTC) can induce both the accelerated degradation of mutated mRNA compared with the wild type version of the mRNA or the production of a truncated protein. One of the considered therapeutic strategies to bypass PTCs [...] Read more.
Nonsense mutations that generate a premature termination codon (PTC) can induce both the accelerated degradation of mutated mRNA compared with the wild type version of the mRNA or the production of a truncated protein. One of the considered therapeutic strategies to bypass PTCs is their “readthrough” based on small-molecule drugs. These molecules promote the incorporation of a near-cognate tRNA at the PTC position through the native polypeptide chain. In this review, we detailed the various existing strategies organized according to pharmacological molecule types through their different mechanisms. The positive results that followed readthrough molecule testing in multiple neuromuscular disorder models indicate the potential of this approach in peripheral neuropathies. Full article
(This article belongs to the Special Issue Recent Advances in the Pharmacology of Peripheral Neuropathy)
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19 pages, 325 KiB  
Review
A Review of Recent Pharmacological Advances in the Management of Diabetes-Associated Peripheral Neuropathy
by Osman Syed, Predrag Jancic and Nebojsa Nick Knezevic
Pharmaceuticals 2023, 16(6), 801; https://doi.org/10.3390/ph16060801 - 29 May 2023
Cited by 1 | Viewed by 2376
Abstract
Diabetic peripheral neuropathy is a common complication of longstanding diabetes mellitus. These neuropathies can present in various forms, and with the increasing prevalence of diabetes mellitus, a subsequent increase in peripheral neuropathy cases has been noted. Peripheral neuropathy has a significant societal and [...] Read more.
Diabetic peripheral neuropathy is a common complication of longstanding diabetes mellitus. These neuropathies can present in various forms, and with the increasing prevalence of diabetes mellitus, a subsequent increase in peripheral neuropathy cases has been noted. Peripheral neuropathy has a significant societal and economic burden, with patients requiring concomitant medication and often experiencing a decline in their quality of life. There is currently a wide variety of pharmacological interventions, including serotonin norepinephrine reuptake inhibitors, gapentanoids, sodium channel blockers, and tricyclic antidepressants. These medications will be discussed, as well as their respective efficacies. Recent advances in the treatment of diabetes mellitus with incretin system-modulating drugs, specifically glucagon-like peptide-1 agonists, have been promising, and their potential implication in the treatment of peripheral diabetic neuropathy is discussed in this review. Full article
(This article belongs to the Special Issue Recent Advances in the Pharmacology of Peripheral Neuropathy)
14 pages, 1606 KiB  
Review
Peripheral Neuropathy in Systemic Autoimmune Rheumatic Diseases—Diagnosis and Treatment
by Jean Marcos De Souza, Thiago Junqueira Trevisan, Samara Rosa Sepresse, Ana Carolina Londe, Marcondes Cavalcante França Júnior and Simone Appenzeller
Pharmaceuticals 2023, 16(4), 587; https://doi.org/10.3390/ph16040587 - 14 Apr 2023
Cited by 2 | Viewed by 2956
Abstract
Peripheral neuropathy (PN) is frequently observed in systemic rheumatic diseases and is a challenge in clinical practice. We aimed to review the evidence on the subject and proposed a comprehensive approach to these patients, facilitating diagnosis and management. We searched the MEDLINE database [...] Read more.
Peripheral neuropathy (PN) is frequently observed in systemic rheumatic diseases and is a challenge in clinical practice. We aimed to review the evidence on the subject and proposed a comprehensive approach to these patients, facilitating diagnosis and management. We searched the MEDLINE database for the terms (and its respective Medical Subject Headings (MeSH) terms): “peripheral neuropathy” AND “rheumatic diseases” OR “systemic lupus erythematosus”, “rheumatoid arthritis”, “Sjogren syndrome”, and “vasculitis” from 2000 to 2023. This literature review focuses on the diagnostic workup of PNs related to systemic lupus erythematosus, Sjögren’s syndrome, rheumatoid arthritis, and systemic vasculitis. For every type of PN, we provide a pragmatic flowchart for diagnosis and also describe evidence-based strategies of treatment. Full article
(This article belongs to the Special Issue Recent Advances in the Pharmacology of Peripheral Neuropathy)
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