scholarly journals Reply to a Comment Paper on the Published Paper by Canta, A. et al: “Calmangafodipir Reduces Sensory Alterations and Prevents Intraepidermal Nerve Fibers Loss in a Mouse Model of Oxaliplatin Induced Peripheral Neurotoxicity”—Antioxidants 2020, 9, 594

Antioxidants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 807
Author(s):  
Annalisa Canta ◽  
Alessia Chiorazzi ◽  
Eleonora Pozzi ◽  
Giulia Fumagalli ◽  
Laura Monza ◽  
...  
Keyword(s):  
Mouse Model ◽  
Nerve Fiber ◽  
Protective Action ◽  
Mechanisms Of Action ◽  
Nerve Fibers ◽  
Peripheral Neurotoxicity ◽  
Published Paper ◽  
Intraepidermal Nerve Fiber

The comments sent by Stehr, Lundstom and Karlsson with reference to our article “Calmangafodipir reduces sensory alterations and prevents intraepidermal nerve fiber loss in a mouse model of oxaliplatin-induced peripheral neurotoxicity“ are very interesting, since they suggest possible mechanisms of action of the compound, which might contribute to its protective action [...]

scholarly journals Calmangafodipir Reduces Sensory Alterations and Prevents Intraepidermal Nerve Fibers Loss in a Mouse Model of Oxaliplatin Induced Peripheral Neurotoxicity

Antioxidants ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 594 ◽  
Author(s):  
Annalisa Canta ◽  
Alessia Chiorazzi ◽  
Eleonora Pozzi ◽  
Giulia Fumagalli ◽  
Laura Monza ◽  
...  
Keyword(s):  
Mouse Model ◽  
Thermal Hyperalgesia ◽  
Nerve Fibers ◽  
Peripheral Neurotoxicity ◽  
Mitochondrial Superoxide ◽  
Key Factor ◽  
Skin Biopsies ◽  
Pre Treatment ◽  
Mitochondrial Superoxide Dismutase ◽  
Intraepidermal Nerve Fiber

Oxaliplatin (OHP) is an antineoplastic compound able to induce peripheral neurotoxicity. Oxidative stress has been suggested to be a key factor in the development of OHP-related peripheral neurotoxicity. Mangafodipir, a contrast agent possessing mitochondrial superoxide dismutase (MnSOD)-mimetic activity, has been tested as a cytoprotector in chemotherapy-induced peripheral neurotoxicity (CIPN). Calmangafodipir (PledOx®) has even better therapeutic activity. We investigated a BALB/c mouse model of OHP-related CIPN and the effects of the pre-treatment of calmangafodipir (2.5, 5, or 10 mg/kg intravenously) on sensory perception, and we performed a pathological study on skin biopsies to assess intraepidermal nerve fiber (IENF) density. At the end of the treatments, OHP alone or in pre-treatment with calmangafodipir 2.5 and 10 mg/kg, induced mechanical allodynia and cold thermal hyperalgesia, but calmangafodipir 5 mg/kg prevented these effects. Accordingly, OHP alone or in pre-treatment with calmangafodipir 2.5 and 10 mg/kg, induced a significant reduction in IENF density, but calmangafodipir 5 mg/kg prevented this reduction. These results confirm a protective effect of calmangafodipir against OHP-induced small fiber neuropathy. Interestingly, these results are in agreement with previous observations suggesting a U-shaped effect of calmangafodipir, with the 10 mg/kg dose less effective than the lower doses.

scholarly journals Intraepidermal Nerve fiber Density in healthy Subjects with Diabetic Family History. ¿Is Neuropathy an early Biomarker? A Pilot study

2021 ◽  
Vol 8 (3) ◽  
pp. 01-08
Author(s):  
Ildefonso Leyva
Keyword(s):  
Pilot Study ◽  
Family History ◽  
Nerve Fiber ◽  
Healthy Subjects ◽  
Nerve Fibers ◽  
Diabetic Patients ◽  
Fiber Density ◽  
Intraepidermal Nerve Fiber Density ◽  
Nerve Fiber Density ◽  
Intraepidermal Nerve Fiber

Objective: Evaluate the intraepidermal nerve fiber density in healthy subjects with diabetic family history compared with diabetic patients and controls. Introduction: Neuropathy is the most prevalent chronic complication of diabetes, presenting various symptoms that interfere with daily living activities, psychosocially disability, and reducing life quality. The skin biopsy is recognized as a minimally invasive procedure that allows morphometric quantification of intraepidermal nerve fibers and has made possible the study of peripheral neuropathies involving thin fibers that traditional methods cannot diagnose. Methods: Analytical cross-sectional observational pilot study with seven patients per group including healthy, diabetic, and healthy with diabetic family history subjects. For the statistical analysis, we used the R package, R software version 3.3.2, with a confidence level of 95%. The research was performed with ANOVA and Kruskal-Wallis test to test the primary objective. Results: The density of intraepidermal nerve fibers is similar between the group with diabetic family history 6.8 ± 2.1 (3.5 - 10.1) and diabetic patients 6.3 ± 2.9 (3.5 - 7.05) while the control group reported a density in parameters of normality of 10± 1.2 (8.2 - 10.1) with a p= 0.01 between the three groups. The decrease of intraepidermal nerve fibers showed a tendency to decrease with increasing age and BMI with a ratio coefficient for age of r= -0.342, 95% CI (-0.67 - 0.106), p= 0.129; and for BMI of r= -0.36, 95% CI (-0.685 - 0.0847), p= 0.109. Conclusion: Intraepidermal nerve fiber density is decreased in subjects with a family history of diabetes mellitus type 2 and even more so in diabetics, with no statistical difference.

scholarly journals Intraepidermal Nerve Fiber Analysis in Human Patients and Animal Models of Peripheral Neuropathy: A Comparative Review

2019 ◽  
Vol 48 (1) ◽  
pp. 59-70 ◽  
Author(s):  
Lisa M. Mangus ◽  
Deepa B. Rao ◽  
Gigi J. Ebenezer
Keyword(s):  
Peripheral Neuropathy ◽  
Animal Models ◽  
Skin Biopsy ◽  
Nerve Fiber ◽  
Sensory Nerve ◽  
Nerve Fibers ◽  
Fiber Analysis ◽  
Comparative Review ◽  
Nerve Fiber Analysis ◽  
Intraepidermal Nerve Fiber

Analysis of intraepidermal nerve fibers (IENFs) in skin biopsy samples has become a standard clinical tool for diagnosing peripheral neuropathies in human patients. Compared to sural nerve biopsy, skin biopsy is safer, less invasive, and can be performed repeatedly to facilitate longitudinal assessment. Intraepidermal nerve fiber analysis is also more sensitive than conventional nerve histology or electrophysiological tests for detecting damage to small-diameter sensory nerve fibers. The techniques used for IENF analysis in humans have been adapted for large and small animal models and successfully used in studies of diabetic neuropathy, chemotherapy-induced peripheral neuropathy, HIV-associated sensory neuropathy, among others. Although IENF analysis has yet to become a routine end point in nonclinical safety testing, it has the potential to serve as a highly relevant indicator of sensory nerve fiber status in neurotoxicity studies, as well as development of neuroprotective and neuroregenerative therapies. Recently, there is also interest in the evaluation of IENF via skin biopsy as a biomarker of small fiber neuropathy in the regulatory setting. This article provides an overview of the anatomic and pathophysiologic principles behind IENF analysis, its use as a diagnostic tool in humans, and applications in animal models with focus on comparative methodology and considerations for study design.

scholarly journals Advantages of an Automated Method Compared With Manual Methods for the Quantification of Intraepidermal Nerve Fiber in Skin Biopsy

2021 ◽  
Author(s):  
Marta Francisca Corrà ◽  
Mafalda Sousa ◽  
Inês Reis ◽  
Fabiana Tanganelli ◽  
Nuno Vila-Chã ◽  
...  
Keyword(s):  
Skin Biopsy ◽  
Nerve Fiber ◽  
High Reliability ◽  
Nerve Fibers ◽  
Fiber Density ◽  
Automated Method ◽  
Manual Counting ◽  
Intraepidermal Nerve Fiber Density ◽  
Lower Variability ◽  
Intraepidermal Nerve Fiber

Abstract Intraepidermal nerve fiber density (IENFD) measurements in skin biopsy are performed manually by 1–3 operators. To improve diagnostic accuracy and applicability in clinical practice, we developed an automated method for fast IENFD determination with low operator-dependency. Sixty skin biopsy specimens were stained with the axonal marker PGP9.5 and imaged using a widefield fluorescence microscope. IENFD was first determined manually by 3 independent observers. Subsequently, images were processed in their Z-max projection and the intradermal line was delineated automatically. IENFD was calculated automatically (fluorescent images automated counting [FIAC]) and compared with manual counting on the same fluorescence images (fluorescent images manual counting [FIMC]), and with classical manual counting (CMC) data. A FIMC showed lower variability among observers compared with CMC (interclass correlation [ICC] = 0.996 vs 0.950). FIMC and FIAC showed high reliability (ICC = 0.999). A moderate-to-high (ICC = 0.705) was observed between CMC and FIAC counting. The algorithm process took on average 15 seconds to perform FIAC counting, compared with 10 minutes for FIMC counting. This automated method rapidly and reliably detects small nerve fibers in skin biopsies with clear advantages over the classical manual technique.

scholarly journals Comment on “Calmangafodipir Reduces Sensory Alterations and Prevents Intraepidermal Nerve Fibers Loss in a Mouse Model of Oxaliplatin Induced Peripheral Neurotoxicity” Antioxidants 2020, 9, 594

Antioxidants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 802
Author(s):  
Jan Eric Stehr ◽  
Ingemar Lundström ◽  
Jan Olof G. Karlsson
Keyword(s):  
Mouse Model ◽  
Nerve Fibers ◽  
Peripheral Neurotoxicity

We have with enthusiasm read the article “Calmangafodipir Reduces Sensory Alterations and Prevents Intraepidermal Nerve Fibers Loss in a Mouse Model of Oxaliplatin Induced Peripheral Neurotoxicity” written by Annalisa Canta, Guido Cavaletti and co-workers and published in Antioxidants [...]

scholarly journals Sex-related differences in response to masseteric injections of glutamate and nerve growth factor in healthy human participants

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Abdelrahman M. Alhilou ◽  
Akiko Shimada ◽  
Camilla I. Svensson ◽  
Peter Svensson ◽  
Malin Ernberg ◽  
...  
Keyword(s):  
Nmda Receptors ◽  
Nerve Fiber ◽  
Masseter Muscle ◽  
Pain Sensitivity ◽  
Nerve Fibers ◽  
Receptor Expression ◽  
Healthy Human ◽  
Neurophysiological Mechanisms ◽  
Human Participants ◽  
Positive Correlations

AbstractThe neurophysiological mechanisms underlying NGF-induced masseter muscle sensitization and sex-related differences in its effect are not well understood in humans. Therefore, this longitudinal cohort study aimed to investigate the effect of NGF injection on the density and expression of substance P, NMDA-receptors and NGF by the nerve fibers in the human masseter muscle, to correlate expression with pain characteristics, and to determine any possible sex-related differences in these effects of NGF. The magnitude of NGF-induced mechanical sensitization and pain during oral function was significantly greater in women than in men (P < 0.050). Significant positive correlations were found between nerve fiber expression of NMDA-receptors and peak pain intensity (rs = 0.620, P = 0.048), and expression of NMDA-receptors by putative nociceptors and change in temporal summation pain after glutamate injection (rs = 0.561, P = 0.003). In women, there was a significant inverse relationship between the degree of NGF-induced mechanical sensitization and the change in nerve fiber expression of NMDA-receptors alone (rs = − 0.659, P = 0.013), and in combination with NGF (rs = − 0.764, P = 0.001). In conclusion, women displayed a greater magnitude of NGF-induced mechanical sensitization that also was associated with nerve fibers expression of NMDA-receptors, when compared to men. The present findings suggest that, in women, increased peripheral NMDA-receptor expression could be associated with masseter muscle pain sensitivity.

scholarly journals PK/PD Modeling of the PDE7 Inhibitor—GRMS-55 in a Mouse Model of Autoimmune Hepatitis

Pharmaceutics ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 597
Author(s):  
Artur Świerczek ◽  
Hanna Plutecka ◽  
Marietta Ślusarczyk ◽  
Grażyna Chłoń-Rzepa ◽  
Elżbieta Wyska
Keyword(s):  
Mouse Model ◽  
Autoimmune Hepatitis ◽  
Disease Progression ◽  
Hepatoprotective Activity ◽  
Mechanisms Of Action ◽  
Progression Model ◽  
Adrenoceptor Agonist ◽  
Tnf Α ◽  
Disease Progression Model ◽  
Time Courses

This study aimed to assess the efficacy and explore the mechanisms of action of a potent phosphodiesterase (PDE)7A and a moderate PDE4B inhibitor GRMS-55 in a mouse model of autoimmune hepatitis (AIH). The concentrations of GRMS-55 and relevant biomarkers were measured in the serum of BALB/c mice with concanavalin A (ConA)-induced hepatitis administered with GRMS-55 at two dose levels. A semi-mechanistic PK/PD/disease progression model describing the time courses of measured biomarkers was developed. The emetogenicity as a potential side effect of the studied compound was evaluated in the α2-adrenoceptor agonist-induced anesthesia model. The results indicate that liver damage observed in mice challenged with ConA was mainly mediated by TNF-α and IFN-γ. GRMS-55 decreased the levels of pro-inflammatory mediators and the transaminase activities in the serum of mice with AIH. The anti-inflammatory properties of GRMS-55, resulting mainly from PDE7A inhibition, led to a high hepatoprotective activity in mice with AIH, which was mediated by an inhibition of pro-inflammatory signaling. GRMS-55 did not induce the emetic-like behavior. The developed PK/PD/disease progression model may be used in future studies to assess the potency and explore the mechanisms of action of new investigational compounds for the treatment of AIH.

scholarly journals Early loss of peptidergic intraepidermal nerve fibers in an STZ-induced mouse model of insensate diabetic neuropathy

Pain ◽  
2008 ◽  
Vol 140 (1) ◽  
pp. 35-47 ◽  
Author(s):  
Megan S. Johnson ◽  
Janelle M. Ryals ◽  
Douglas E. Wright
Keyword(s):  
Mouse Model ◽  
Diabetic Neuropathy ◽  
Nerve Fibers ◽  
Early Loss

Electron Microscopical and Immunohistochemical Studies on the Induction of "Qi" Employing Needling Manipulation

1992 ◽  
Vol 20 (01) ◽  
pp. 25-35 ◽  
Author(s):  
Michio Kimura ◽  
Kazuo Tohya ◽  
Kyo-ichi Kuroiwa ◽  
Hirohisa Oda ◽  
E. Christo Gorawski ◽  
...  
Keyword(s):  
Mast Cells ◽  
Nerve Fiber ◽  
Functional Relationship ◽  
Nerve Fibers ◽  
Elastic Fibers ◽  
Electron Microscopical Analysis ◽  
Calcitonin Gene ◽  
Transparent Materials ◽  
Electron Microscopical ◽  
Immunohistochemical Studies

During a sparrow-pecking and twisting-needle manipulation to the acupoints BL 23, 24 and 25 for an induction of "Qi", it was found that some transparent materials were binding to the needles after removed from the volunteer's skin. Electron-microscopical analysis of the transparent materials revealed that they corresponded to the injured fascia made up of collagen fibers, elastic fibers, fibroblasts, adipocytes and mast cells. Rarely were nerve fiber-like structures observed in the materials. Immunohistochemically, calcitonin gene-related peptide-positive nerve fibers could be demonstrated in the acupoint BL 24 associated fascia. A possible functional relationship between the needle manipulation and the induction of Qi-sensation is discussed along with the acupoint tissue constitution.

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