Comprehensive Assessment of Cannabidiol and HU308 in Acute and Chronic Colitis Models: Efficacy, Safety, and Mechanistic Innovations
Abstract
:1. Introduction
2. Materials and Methods
2.1. Animal Care and Use
2.2. Dextran Sodium Sulphate Solution Preparation
2.3. Induction of Colitis
2.3.1. Acute Colitis
2.3.2. Chronic Colitis
2.4. Experimental Design and Pharmacological Treatments
2.4.1. Experimental Design
2.4.2. Pharmacological Treatments for Acute Colitis
2.4.3. Pharmacological Treatments for Chronic Colitis
2.5. Assessment of Colitis Clinical Markers
2.5.1. Disease Activity Index Score
2.5.2. Pain Behaviours
2.6. Random Blood Glucose
2.7. Euthanasia and Tissue Collection
2.7.1. Colon Length
2.7.2. Organ to Body Weight Percentage
2.7.3. Myeloperoxidase Activity
2.8. Determination of Pro-Inflammatory and Anti-Inflammatory Cytokines in Colon Tissues
2.9. Colon Histopathology
2.10. Plasma and Colon GLP-1 Measurement
2.11. Complete Blood Count and Plasma Biochemistry
2.12. Statistical Analysis
3. Results
3.1. Results of Acute Studies
3.1.1. Impact of CBD and HU308 Treatments on DSS-Induced Clinical Scores
CBD and HU308 Reduced DAI Scores
HU308 Maintained Healthy Body Weight
CBD and HU308 Reduced Diarrhoeal Scores
CBD and HU308 Reduced Faecal Blood Scores
CBD and HU308 Reduced Grimace Scores
3.1.2. Impact of CBD and HU308 Treatments on Colon Length, MPO Activity, Plasma GLP-1 Levels, and Spleen Metrics
CBD and HU308 Increased Colon Length
CBD and HU308 Reduced Colonic MPO Activity
CBD and HU308 Regulated Colon and Plasma GLP-1 Levels
CBD and HU308 Demonstrated a Beneficial Role in Spleen Metrics
CBD and HU308 Reduced MPO Activity in the Spleen
3.1.3. Inflammatory Cytokine Levels in DSS-Induced Colitis with CBD and HU308 Treatment
CBD and HU308 Reduced Interleukin-6 (IL-6)
CBD and HU308 Reduced Interleukin-1 Beta (IL-1β)
CBD and HU308 Had No Effect on Interleukin-10 (IL-10)
CBD and HU308 Reduced Monocyte Chemoattractant Protein-1 (MCP-1)
CBD and HU308 Reduced Tumour Necrosis Factor-Alpha (TNF-α)
3.1.4. Safety Profile of CBD and HU308
3.2. Results of Chronic Studies
3.2.1. Impact of HU308 Treatment on DSS-Induced Colitis Clinical Markers
HU308 Group Maintained Healthy Body Weight Throughout the Study
HU308 Reduced Diarrhoeal Scores
HU308 Reduced Faecal Blood Scores
HU308 Reduced DAI Scores
3.2.2. Impact of HU308 Treatments on Colon Length, MPO Activity, Plasma GLP-1 Levels, and Spleen Metrics in DSS-Induced Chronic Colitis
HU308 Increased Colon Length
HU308 Reduced MPO Activity in the Colon
HU308 Regulated Colonic and Plasma GLP-1 Levels
HU308 Reduced Relative Spleen Weight
HU308 Reduced MPO Activity in the Spleen
HU308 Normalized Colon Histopathological Score
3.2.3. HU308 Reduced Pro-Inflammatory Cytokine Levels in DSS-Induced Colitis
3.2.4. Impact of HU308 Treatment on Haematology and Liver and Kidney Function
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Clinical Colitis Scores | 0 | 1 | 2 | 3 |
---|---|---|---|---|
Body weight loss score | <5% | 5–10% | 11–15% | 16–20% |
Diarrhoeal score/stool consistency | Normal | Mild-soft, but still formed | Very soft/Sticky | Loose/diarrhoea |
Faecal blood score/rectal bleeding | Normal colour stool/no rectal bleeding | Positive hemoccult—slight (brown colour)/slight blood spotting in the anus | Positive hemoccult—darker (reddish)/significant presence of blood in the anus | Visible trace of blood/rectal bleeding |
Pain Features/Scores | 0 | 1 | 2 |
---|---|---|---|
Orbital tightening | Not present | Closing of eyelid, narrowing of orbital area | Complete closure of eye with tightened orbital |
Nose bulge | Not present | Slight bulging on the bridge of nose | Completely bulged nose |
Cheek bulge | Not present | Slight bulging of the cheek | Completely bulged |
Ear position | Normal position | Ears moving towards the back | Folded ear forming a pointed shape |
Whisker change | Normal whisker position | Whiskers pulled back/front | Clumping of whiskers |
Movement/gait | Normal activity | Moves slowly | Moves only when provoked |
Body position/hunching | Normal position | Slight tuck to abdomen | Fully hunched |
Score | Severity of Inflammation | Crypt Damage | Goblet Cell Loss | Ulceration |
---|---|---|---|---|
0 | Absent | intact crypts | absent | absent |
1 | Increased presence of inflammatory cells in lamina propria | Loss of the basal one-third | <10% | |
2 | Also infiltrates submucosa | Loss of the basal two-thirds | Decreased by 10–50% | |
3 | Transmural | Loss of entire crypt | Decreased by > 50% | Present |
Treatment Groups | Healthy Control | Colitis Vehicle | 2.5 mg/kg HU308 | 10 mg/kg HU308 |
---|---|---|---|---|
WBC (109/L) | 6.2 ± 0.6 | 6.8 ± 2.0 | 4.0 ± 0.3 | 6.6 ± 1.1 |
Lymphocytes (109/L) | 2.9 ± 1.2 | 5.2 ± 1.7 | 1.2 ± 1.1 | 5.2 ± 1.1 |
Monocytes (109/L) | 0.1 ± 0.03 | 0.3 ± 0.1 | 0.1 ± 0.05 | 0.3 ± 0.03 |
Granulocytes (109/L) | 3.2 ± 1.0 | 1.3 ± 0.3 | 2.6 ± 1.0 | 1.1 ± 0.1 |
RBC (1012/L) | 9.2 ± 0.1 | 9.6 ± 0.2 | 9.4 ± 0.2 | 9.4 ± 0.2 |
Haemoglobin (g/L) | 134.7 ± 2.3 | 135.4 ± 1.8 | 137.3 ± 4.3 | 135.38 ± 2.6 |
Haematocrit (%) | 41.9 ± 0.6 | 43.4 ± 1.0 | 42.7 ± 1.0 | 42.6 ± 0.7 |
Mean corpuscular volume (fL) | 45.6 ± 0.2 | 45.2 ± 0.3 | 45.3 ± 0.4 | 45.4 ± 0.1 |
Mean corpuscular haemoglobin (pg) | 14.6 ± 0.1 | 14.5 ± 0.1 | 14.5 ± 0.2 | 14.4 ± 0.1 |
Mean corpuscular haemoglobin concentration (g/L) | 320.8 ± 2.6 | 321.4 ± 2.4 | 321.0 ± 2.9 | 317.3 ± 1.5 |
Red cell distribution width (%) | 11.8 ± 0.2 | 11.6 ± 0.3 | 11.8 ± 0.2 | 12.1 ± 0.1 |
Platelets (109/L) | 1017.3 ± 65.1 | 917.4 ± 118.0 | 1054.0 ± 49 | 966.3 ± 17.2 |
Mean platelet volume (fL) | 4.9 ± 0.02 | 5.2 ± 0.1 | 5.4 ± 0.3 | 5.2 ± 0.1 |
Platelet distribution width | 16.3 ± 0.01 | 16.4 ± 0.1 | 16.6 ± 0.6 | 16.2 ± 0.1 |
Procalcitonin (%) | 0.5 ± 0.01 | 0.5 ± 0.1 | 0.5 ± 0.02 | 0.5 ± 0.02 |
Treatment Groups | Healthy Control | Colitis Control | 2.5 mg/kg HU308 |
---|---|---|---|
WBC (109/L) | 5.6 ± 0.8 | 6.8 ± 0.8 | 4.4 ± 0.4 * |
Lymphocytes (109/L) | 2.5 ± 1.2 | 2.4 ± 1.1 | 0.1 ± 0.04 * |
Monocytes (109/L) | 0.2 ± 0.04 | 0.2± 0.1 | 0.1 ± 0.02 |
Granulocytes (109/L) | 3.0 ± 1.0 | 4.2 ± 1.1 | 4.2 ± 0.4 |
RBC (1012/L) | 9.2 ± 0.1 | 8.9 ± 0.1 | 8.7 ± 0.2 |
Haemoglobin (g/L) | 135.3 ± 2.2 | 131.3 ± 1.3 | 128.5 ± 2.7 |
Haematocrit (%) | 42.3 ± 0.7 | 41.0 ± 0.3 | 39.8 ± 0.8 |
Mean corpuscular volume (fL) | 45.8 ± 0.2 | 46.1 ± 0.3 | 45.8 ± 0.2 |
Mean corpuscular haemoglobin (pg) | 14.6 ± 0.1 | 14.7 ± 0.1 | 14.7 ± 0.1 |
Mean corpuscular haemoglobin concentration (g/L) | 319.3 ± 2.9 | 319.5 ± 2.4 | 322.8 ± 1.9 |
Red cell distribution width (%) | 11.7 ± 0.2 | 12.3 ± 0.3 | 12.5 ± 0.3 |
Platelets (109/L) | 1034.3 ± 62.2 | 980.0 ± 45.8 | 958.2 ± 26.6 |
Mean platelet volume (fL) | 4.9 ± 0.04 | 4.9 ± 0.9 | 5.0 ± 0.07 |
Platelet distribution width | 16.3 ± 0.05 | 16.1 ± 0.05 | 16.1 ± 0.06 |
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Thapa, D.; Patil, M.; Warne, L.N.; Carlessi, R.; Falasca, M. Comprehensive Assessment of Cannabidiol and HU308 in Acute and Chronic Colitis Models: Efficacy, Safety, and Mechanistic Innovations. Cells 2024, 13, 2013. https://doi.org/10.3390/cells13232013
Thapa D, Patil M, Warne LN, Carlessi R, Falasca M. Comprehensive Assessment of Cannabidiol and HU308 in Acute and Chronic Colitis Models: Efficacy, Safety, and Mechanistic Innovations. Cells. 2024; 13(23):2013. https://doi.org/10.3390/cells13232013
Chicago/Turabian StyleThapa, Dinesh, Mohan Patil, Leon N Warne, Rodrigo Carlessi, and Marco Falasca. 2024. "Comprehensive Assessment of Cannabidiol and HU308 in Acute and Chronic Colitis Models: Efficacy, Safety, and Mechanistic Innovations" Cells 13, no. 23: 2013. https://doi.org/10.3390/cells13232013
APA StyleThapa, D., Patil, M., Warne, L. N., Carlessi, R., & Falasca, M. (2024). Comprehensive Assessment of Cannabidiol and HU308 in Acute and Chronic Colitis Models: Efficacy, Safety, and Mechanistic Innovations. Cells, 13(23), 2013. https://doi.org/10.3390/cells13232013