Local Colonic Administration of a Serine Protease Inhibitor Improves Post-Inflammatory Visceral Hypersensitivity in Rats
Abstract
:1. Introduction
2. Materials and Methods
2.1. Animals
2.2. Experimental Design
2.3. Materials and Reagents
2.4. Induction of Colitis
2.5. Intracolonic Drug Administration
2.6. Colonic Mechanosensitivity
2.7. Colonic Compliance
2.8. Inflammatory Parameters
2.8.1. Colonoscopy
2.8.2. Macroscopic Score
2.8.3. Microscopic Score
2.8.4. Myeloperoxidase Activity
2.9. Proteolytic Activities on Fecal and Colonic Samples
2.10. Pharmacokinetic Experiments
2.11. Data Presentation and Statistical Analysis
3. Results
3.1. TNBS-Induced Colitis Resolves Spontaneously after 10–14 Days
3.2. Colonic Trypsin-Like Activity Is Increased in Post-Colitis Rats
3.3. Fecal Trypsin-Like Activity Does Not Differ between Post-Colitis Rats and Controls
3.4. The Serine Protease Inhibitor UAMC-00050 Inhibits Trypsin-Like Enzymes In Vitro
3.5. Colonically Administered UAMC-00050 Is Not Detectable in Plasma after 30 Min
3.6. Intracolonic Administration of UAMC-00050 Alters Trypsin-Like Activity in the Colon of Post-Colitis Animals
3.7. Intracolonic Administration of UAMC-00050 Decreases Visceral Hypersensitivity in Post-Colitis Rats
3.8. Intracolonic Administration of UAMC-00050 Increases Colonic Compliance
3.9. Intracolonic Administration of UAMC-00050 Increases MPO Activity in the Distal Colon Without Affecting Other Inflammatory Parameters
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Compound | Retention Time (min) | Precursor Ion (m/z) | Product Ion (m/z) | Fragmentor Voltage (V) | Collision Energy (eV) |
---|---|---|---|---|---|
UAMC-00050 | 6.3 | 659.2 | 91.2 | 185 | 60 |
267.3 | 185 | 40 | |||
250.2 | 185 | 35 | |||
Nordazepam-D5 | 7.0 | 276.0 | 140.0 | 100 | 35 |
Group | Drug | N | Day 3 | Day of VMR | |||
---|---|---|---|---|---|---|---|
Colonoscopy | Colonoscopy | Macroscopy | Microscopy | MPO Activity | |||
Control | Vehicle | 8 | 0.0 ± 0.0 | 0.0 ± 0.0 | 0.0 ± 0.0 | 0.5 ± 0.3 | 0.3 ± 0.1 |
5.0 mg/kg | 8 | 0.0 ± 0.0 | 0.0 ± 0.0 | 0.0 ± 0.0 | 0.8 ± 0.4 | 0.6 ± 0.2 # | |
Post-colitis | Vehicle | 8 | 6.3 ± 0.6 * | 0.0 ± 00 | 0.0 ± 0.0 | 0.6 ± 0.4 | 0.3 ± 0.2 |
0.1 mg/kg | 8 | 7.5 ± 0.5 * | 0.0 ± 0.0 | 0.0 ± 0.0 | 0.4 ± 0.4 | 2.0 ± 0.7 # | |
1.0 mg/kg | 8 | 7.4 ± 0.6 * | 0.0 ± 0.0 | 0.0 ± 0.0 | 0.8 ± 0.4 | 2.0 ± 0.5 # | |
2.5 mg/kg | 8 | 7.1 ± 0.5 * | 0.0 ± 0.0 | 0.0 ± 0.0 | 0.5 ± 0.4 | 2.1 ± 0.5 # | |
5.0 mg/kg | 8 | 6.9 ± 0.5 * | 0.0 ± 0.0 | 0.0 ± 0.0 | 0.6 ± 0.4 | 1.7 ± 0.5 # |
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Hanning, N.; De bruyn, M.; Ceuleers, H.; Boogaerts, T.; Berg, M.; Smet, A.; De Schepper, H.U.; Joossens, J.; van Nuijs, A.L.N.; De Man, J.G.; et al. Local Colonic Administration of a Serine Protease Inhibitor Improves Post-Inflammatory Visceral Hypersensitivity in Rats. Pharmaceutics 2021, 13, 811. https://doi.org/10.3390/pharmaceutics13060811
Hanning N, De bruyn M, Ceuleers H, Boogaerts T, Berg M, Smet A, De Schepper HU, Joossens J, van Nuijs ALN, De Man JG, et al. Local Colonic Administration of a Serine Protease Inhibitor Improves Post-Inflammatory Visceral Hypersensitivity in Rats. Pharmaceutics. 2021; 13(6):811. https://doi.org/10.3390/pharmaceutics13060811
Chicago/Turabian StyleHanning, Nikita, Michelle De bruyn, Hannah Ceuleers, Tim Boogaerts, Maya Berg, Annemieke Smet, Heiko U. De Schepper, Jurgen Joossens, Alexander L. N. van Nuijs, Joris G. De Man, and et al. 2021. "Local Colonic Administration of a Serine Protease Inhibitor Improves Post-Inflammatory Visceral Hypersensitivity in Rats" Pharmaceutics 13, no. 6: 811. https://doi.org/10.3390/pharmaceutics13060811
APA StyleHanning, N., De bruyn, M., Ceuleers, H., Boogaerts, T., Berg, M., Smet, A., De Schepper, H. U., Joossens, J., van Nuijs, A. L. N., De Man, J. G., Augustyns, K., De Meester, I., & De Winter, B. Y. (2021). Local Colonic Administration of a Serine Protease Inhibitor Improves Post-Inflammatory Visceral Hypersensitivity in Rats. Pharmaceutics, 13(6), 811. https://doi.org/10.3390/pharmaceutics13060811