Rodent Models of Diabetic Neuropathy, Role of Calcium Homeostasis in Pain and KB-R7943 as a Potential Therapeutic
Abstract
1. Introduction
2. In Vivo Animal Models of DN: Drug- and Diet-Induced
2.1. Chemically-Induced DN Rodent Models
2.1.1. Streptozotocin (STZ)-Induced Diabetes
2.1.2. Alloxan-Induced Diabetes
2.2. Diet-Induced DN Rodent Models
2.3. Combined Chemically- and Diet-Induced DN Rodent Models
3. Calcium Dyshomeostasis in Diabetic Neuralgia
4. Na+/Ca2+ Exchanger (NCX) in PDN
5. KB-R7943 in the Treatment of PDN
5.1. Other Therapeutic Targets and Drugs for PDN
5.2. Current Challenges and Future Directions
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
DN | diabetic neuropathy |
PDN | painful diabetic neuropathy |
NCX | Na+/Ca2+ exchanger |
NCXrev | NCX reverse mode |
STZ | streptozotocin |
GLUT | glucose transporter |
Ca2+ | calcium |
NMDA | N-methyl-D-aspartate |
AMPA | alpha-amino-3-hydroxy-5-methylisoxazole-4-propionicacid |
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Method | Model | Features of DN | Advantages | Disadvantages | ||
---|---|---|---|---|---|---|
Chemically-induced (type 1 diabetes) | STZ (single high doses or multiple low dose) | Nerve conduction velocity | Behavior | Nerve structure | ||
Rats (single high doses of 35–60 mg/kg/day) [14,17,26,27] | Decreased sensory and motor conduction velocity | Allodynia; hyperalgesia to hypoalgesia | Axonal degeneration; decreased intraepidermal nerve fiber density; reduced corneal nerve fiber length; Schwann cell proliferation; reduced right and left fascicles of phrenic nerve; molecular changes of the peripheral nerves | Low cost; fast induction of diabetes; known duration of diabetes and DN development | High mortality rate; neuropathy phenotype variability; cell/organ toxicity; lack of severe neuropathy changes resembling human pathology; still to elucidate DN pathogenic aspects | |
Mice (single high doses of 100–200 mg/kg/day or multiple low doses of 40–50 mg/kg/day) [15] | Slow sensory and motor conduction velocity | Allodynia; hypoalgesia | Decreased intraepidermal nerve fiber density; decreased size of dorsal root ganglia neuron; molecular changes of the peripheral nerves | Low cost; fast induction of diabetes; known duration of diabetes and DN development | Toxicity and late development of neuropathy in the single high-doses model; lack of severe neuropathy changes resembling human pathology; lack of neuropathy feature of some strains in the multiple low dose | |
Alloxan | ||||||
Rats and mice (single doses of 40–200 mg/kg for rats and 50–200 mg/kg for mice) [14,17,28] | Slow nerve conduction velocity | Allodynia; hyperalgesia; autonomic dysfunction | - | Low cost and affordability; fast induction of diabetes | High mortality rate; narrow diabetic dose; lack of late neuropathy changes; DN insufficient data | |
Diet-induced (prediabetes/metabolic syndrome) | High-energy diet (high-fat, high-sugar, high-fat-high-sugar diets) | |||||
Rats [17,29,30] (fat 25–60% and carbohydrates 10–80% of food content) | Decreased sensory conduction velocity | Allodynia; hypoalgesia | Decreased intraepidermal nerve fiber density and corneal nerve fiber length | Suitable to study insulin resistant and prediabetes related neuropathy | Extended time to DN development compared to drug-induced DN; lack of frank hyperglycemia | |
Mice [26,30,31,32,33] (fat 25–60% and carbohydrates 10–80% of food content) | Decreased sensory and motor conduction velocity | Allodynia; early hyperalgesia, late hypoalgesia | Decreased intraepidermal nerve fiber density | Suitable to study insulin resistant and prediabetes related neuropathy | Extended time to DN development compared to drug-induced DN; lack of frank hyperglycemia | |
Drug and diet combined (type 2 diabetes) | STR (low doses to moderate) + high-energy-diet | |||||
Rats [29,30,34,35] | Slow sensory and motor conduction velocity | Hyper- or hypoalgesia; allodynia | Decreased intraepidermal nerve fiber density; reduction in corneal nerve fiber length; axonal swelling and degeneration; lymphocyte infiltration; Schwann cell damage and demyelination | Shorter time to DN development compared to matched mice; less toxic; gradual development of type 2 diabetes and neuropathy changes | Extended time compared to drug-induced DN development | |
Mice [30,35] | Slow sensory and motor conduction velocity | Hypoalgesia | Decreased intraepidermal nerve fiber density | Less toxic; gradual development of type 2 diabetes and neuropathy changes | Extended time compared to drug-induced DN development |
Feature | NCX1 | NCX2 | NCX3 |
---|---|---|---|
Tissue Distribution | Heart, skeletal muscle, brain | Brain, retina, kidney | Skeletal muscle, brain |
Main Function | Ca2+ extrusion in muscle, heart | Ca2+ regulation in neurons, glial cells | Ca2+ regulation in skeletal muscle |
Pathophysiological Role | Heart failure, arrhythmias | Neurodegenerative diseases, synaptic dysfunction | Muscular disorders, neurodegeneration |
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Ivanova, N.; Hristov, M.; Gateva, P. Rodent Models of Diabetic Neuropathy, Role of Calcium Homeostasis in Pain and KB-R7943 as a Potential Therapeutic. Int. J. Mol. Sci. 2025, 26, 2094. https://doi.org/10.3390/ijms26052094
Ivanova N, Hristov M, Gateva P. Rodent Models of Diabetic Neuropathy, Role of Calcium Homeostasis in Pain and KB-R7943 as a Potential Therapeutic. International Journal of Molecular Sciences. 2025; 26(5):2094. https://doi.org/10.3390/ijms26052094
Chicago/Turabian StyleIvanova, Natasha, Milen Hristov, and Pavlina Gateva. 2025. "Rodent Models of Diabetic Neuropathy, Role of Calcium Homeostasis in Pain and KB-R7943 as a Potential Therapeutic" International Journal of Molecular Sciences 26, no. 5: 2094. https://doi.org/10.3390/ijms26052094
APA StyleIvanova, N., Hristov, M., & Gateva, P. (2025). Rodent Models of Diabetic Neuropathy, Role of Calcium Homeostasis in Pain and KB-R7943 as a Potential Therapeutic. International Journal of Molecular Sciences, 26(5), 2094. https://doi.org/10.3390/ijms26052094