Impact of Dose, Sex, and Strain on Oxaliplatin-Induced Peripheral Neuropathy in Mice

Chemotherapy-induced peripheral neuropathy (CIPN) is a common, dose limiting, and long-lasting side effect of chemotherapy treatment. Unfortunately, no treatment has proven efficacious for this side effect. Rodent models play a crucial role in the discovery of new mechanisms underlying the initiation, progression, and recovery of CIPN and the potential discovery of new therapeutics. However, there is limited consistency in the dose, the sex, age, and genetic background of the animal used in these studies and the outcome measures used in evaluation of CIPN rely primarily on noxious and reflexive measures. The main objective of this study was to provide a comprehensive and systematic characterization of oxaliplatin-induced peripheral neuropathy in mice by using a battery of behavioral, sensory, electrophysiological, and morphometric measures in both sexes of the two widely used strains of mice, C57BL/6J and BALB/cJ. Mice received intraperitoneal injections of 3 or 30 mg/kg cumulative doses of oxaliplatin over the course of 2 weeks. Both doses induced long-term and time-dependent mechanical and cold hypersensitivity. Our results show that 30 mg/kg oxaliplatin reduced the locomotor activity in C57BL/6J mice, and C57BL/6J females showed anxiety-like behavior one-week post completion of treatment. In the same dose group, BALB/cJ males and females sustained a larger decrease in sucrose preference than either male or female C57BL/6J mice. Both strains failed to show significant changes in burrowing and nesting behaviors. Two clinically relevant assessments of changes to the peripheral nerve fibers, nerve conduction and intraepidermal nerve fiber density (IENFD) were evaluated. Only BALB/cJ females showed significant reduction in the nerve conduction amplitude 1 week after 30 mg/kg oxaliplatin regimen. Moreover, this dose of the chemo agent reduced the IENF density in both sexes and strains. Our findings suggest that mouse strain, sex, and assay type should be carefully considered when assessing the effects of oxaliplatin and potential therapeutic interventions.

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Loss of intraepidermal nerve fiber density during SIV peripheral neuropathy is mediated by monocyte activation and elevated monocyte chemotactic proteins

Journal of Neuroinflammation ◽

10.1186/s12974-015-0456-8 ◽

2015 ◽

Vol 12 (1) ◽

Cited By ~ 9

Author(s):

Jessica R. Lakritz ◽

Jake A. Robinson ◽

Michael J. Polydefkis ◽

Andrew D. Miller ◽

Tricia H. Burdo

Keyword(s):

Peripheral Neuropathy ◽

Nerve Fiber ◽

Monocyte Activation ◽

Fiber Density ◽

Intraepidermal Nerve Fiber Density ◽

Nerve Fiber Density ◽

Intraepidermal Nerve Fiber

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Autonomic and peripheral neuropathy with reduced intraepidermal nerve fiber density can be observed in patients with gastrointestinal dysmotility

Clinical Case Reports ◽

10.1002/ccr3.2575 ◽

2019 ◽

Vol 8 (1) ◽

pp. 142-148 ◽

Cited By ~ 3

Author(s):

Bodil Ohlsson ◽

Lars B. Dahlin ◽

Elisabet Englund ◽

Béla Veress

Keyword(s):

Peripheral Neuropathy ◽

Nerve Fiber ◽

Fiber Density ◽

Gastrointestinal Dysmotility ◽

Intraepidermal Nerve Fiber Density ◽

Nerve Fiber Density ◽

Intraepidermal Nerve Fiber

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

Neuroscience and Neurological Surgery ◽

10.31579/2578-8868/169 ◽

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.

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Intraepidermal nerve fiber density and nerve conduction study parameters correlate with clinical staging of diabetic polyneuropathy

Diabetes Research and Clinical Practice ◽

10.1016/j.diabres.2012.09.026 ◽

2013 ◽

Vol 99 (1) ◽

pp. 24-29 ◽

Cited By ~ 18

Author(s):

Aiko Arimura ◽

Takahisa Deguchi ◽

Kazuhiro Sugimoto ◽

Tadashi Uto ◽

Tomonori Nakamura ◽

...

Keyword(s):

Nerve Fiber ◽

Nerve Conduction Study ◽

Nerve Conduction ◽

Diabetic Polyneuropathy ◽

Clinical Staging ◽

Fiber Density ◽

Intraepidermal Nerve Fiber Density ◽

Nerve Fiber Density ◽

Intraepidermal Nerve Fiber

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Metanx Alleviates Multiple Manifestations of Peripheral Neuropathy and Increases Intraepidermal Nerve Fiber Density in Zucker Diabetic Fatty Rats

Diabetes ◽

10.2337/db11-1524 ◽

2012 ◽

Vol 61 (8) ◽

pp. 2126-2133 ◽

Cited By ~ 25

Author(s):

H. Shevalye ◽

P. Watcho ◽

R. Stavniichuk ◽

E. Dyukova ◽

S. Lupachyk ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Nerve Fiber ◽

Fiber Density ◽

Intraepidermal Nerve Fiber Density ◽

Zucker Diabetic Fatty Rats ◽

Nerve Fiber Density ◽

Intraepidermal Nerve Fiber

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Treatment of Streptozotocin-Induced Diabetic Rats with Alogliptin: Effect on Vascular and Neural Complications

Experimental Diabetes Research ◽

10.1155/2011/810469 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 18

Author(s):

Eric P. Davidson ◽

Lawrence J. Coppey ◽

Brian Dake ◽

Mark A. Yorek

Keyword(s):

Conduction Velocity ◽

Nerve Conduction ◽

Nerve Conduction Velocity ◽

Sensory Nerve ◽

Diabetic Rats ◽

Fiber Density ◽

Dpp Iv ◽

Intraepidermal Nerve Fiber Density ◽

Calcitonin Gene ◽

Nerve Fiber Density

We sought to determine the effect of dipeptidyl peptidase IV (DPP-IV) inhibition on streptozotocin diabetes-induced vascular and neural dysfunction. After 4 weeks of untreated diabetes, rats were treated for 12 weeks with Alogliptin (DPP-IV inhibitor). Diabetes caused a slowing of motor and sensory nerve conduction velocity, thermal hypoalgesia, reduction in intraepidermal nerve fiber density in the hindpaw, and impairment in vascular relaxation to acetylcholine and calcitonin gene-related peptide in epineurial arterioles. Treatment significantly improved motor nerve conduction velocity and thermal response latency. Sensory nerve conduction velocity was marginally improved with treatment of diabetic rats, and treatment did not improve the decrease in intraepidermal nerve fiber density. Vascular relaxation by epineurial arterioles to calcitonin gene-related peptide but not acetylcholine was significantly improved with treatment. These studies suggest that some but not all vascular and neural complications associated with type 1 diabetes can be improved with the inhibition of DPP-IV activity.

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