AR71, Histamine H3 Receptor Ligand—In Vitro and In Vivo Evaluation (Anti-Inflammatory Activity, Metabolic Stability, Toxicity, and Analgesic Action)
Abstract
:1. Introduction
2. Results and Discussion
2.1. Intrinsic Activity Toward H3R—Assay in HEK Cells Expressing Human Recombinant H3R
2.2. In Silico Docking Studies
2.2.1. Docking Studies to Histamine H3 Receptor
2.2.2. Docking Studies to Histamine H1 and H4 Receptors
2.3. Metabolic Stability of AR71
2.4. Assessment of AR71 Cytotoxicity
2.4.1. Effect of AR71 on the Viability of the Human Astrocyte Cell Line
2.4.2. Effect of AR71 on Human Peripheral Blood Mononuclear Cell Viability (PBMCs)
2.4.3. Effect of AR71 on the Viability of the Human Neuroblastoma Cell Line (SH-SY5Y)
2.4.4. Evaluation of the Growth Rate of Neuroblastoma Cells in the Presence of AR71 with High Content Analysis Image Cytometry
2.5. Assessment of the Neuroprotective Potential of AR71
2.6. Assessment of the Anti-Inflammatory Activity of AR71
2.7. Effects of AR71 on Neuropathic Pain Symptoms in CCI-Exposed Mice
3. Materials and Methods
3.1. Key Reagents
3.2. Cyclic Adenosine Monophosphate (cAMP) Accumulation Assay
3.3. In Silico Studies
3.4. In Vitro Evaluation of AR71 Metabolic Stability
3.5. Cell Cultures
3.6. Cytotoxicity Assessment of AR71
3.6.1. Effect of AR71 on the Viability of Human Astrocytes (MTT Assay)
3.6.2. Effect of AR71 on Human Peripheral Blood Mononuclear Cell (PBMC) Viability
3.6.3. Effect of AR71 on the Viability of the Human Neuroblastoma (SH-SY5Y) Cell Line
3.6.4. Assessment of the Effect of AR71 on the Growth Rate of SH-SY5Y Cells (High Content Analysis Image Cytometry)
3.7. Assessment of Neuroprotective Properties of AR71
3.7.1. Lactate Dehydrogenase Leakage Assay (LDH Assay)
3.7.2. Mitochondrial Membrane Potential (MMP)
3.8. Assessment of Anti-Inflammatory Activity of AR71 (Luminex® Immunoassay)
3.9. Pharmacological Studies In Vivo—Assessment of the Analgesic Activity of AR71
3.9.1. Animals
3.9.2. Chronic Constriction Injury of the Sciatic Nerve (CCI)
3.9.3. Behavioural Tests
3.10. Statistical Analysis
4. Conclusions
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 m/z | Metabolite m/z | Metabolic Pathway |
---|---|---|
AR71 440.31 g/mol | 456.27 (M1) | hydroxylation |
355.30 (M2) | decomposition | |
458.34 (M3) | hydroxylation/reduction | |
438.32 (M4) | dehydrogenation | |
426.28 (M5) | demethylation | |
442.31 (M6) | demethylation/hydroxylation |
Incubation Time | IC50 (μM) | |
---|---|---|
Human Astrocytes | PBM Cells | |
2 h | 41.28 | 70.99 |
24 h | 20.21 | 20.98 |
48 h | 12.53 | 7.48 |
72 h | 9.69 | 4.53 |
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Stasiak, A.; Honkisz-Orzechowska, E.; Gajda, Z.; Wagner, W.; Popiołek-Barczyk, K.; Kuder, K.J.; Latacz, G.; Juszczak, M.; Woźniak, K.; Karcz, T.; et al. AR71, Histamine H3 Receptor Ligand—In Vitro and In Vivo Evaluation (Anti-Inflammatory Activity, Metabolic Stability, Toxicity, and Analgesic Action). Int. J. Mol. Sci. 2024, 25, 8035. https://doi.org/10.3390/ijms25158035
Stasiak A, Honkisz-Orzechowska E, Gajda Z, Wagner W, Popiołek-Barczyk K, Kuder KJ, Latacz G, Juszczak M, Woźniak K, Karcz T, et al. AR71, Histamine H3 Receptor Ligand—In Vitro and In Vivo Evaluation (Anti-Inflammatory Activity, Metabolic Stability, Toxicity, and Analgesic Action). International Journal of Molecular Sciences. 2024; 25(15):8035. https://doi.org/10.3390/ijms25158035
Chicago/Turabian StyleStasiak, Anna, Ewelina Honkisz-Orzechowska, Zbigniew Gajda, Waldemar Wagner, Katarzyna Popiołek-Barczyk, Kamil J. Kuder, Gniewomir Latacz, Michał Juszczak, Katarzyna Woźniak, Tadeusz Karcz, and et al. 2024. "AR71, Histamine H3 Receptor Ligand—In Vitro and In Vivo Evaluation (Anti-Inflammatory Activity, Metabolic Stability, Toxicity, and Analgesic Action)" International Journal of Molecular Sciences 25, no. 15: 8035. https://doi.org/10.3390/ijms25158035