The Bifunctional Dimer Caffeine-Indan Attenuates α-Synuclein Misfolding, Neurodegeneration and Behavioral Deficits after Chronic Stimulation of Adenosine A1 Receptors
Abstract
:1. Background
2. Results
2.1. Caffeine-Indan Dimer Decreased the Behavioral Deficits after Chronic A1R Stimulation
2.2. Molecular Docking Revealed Potential Binding of C8–6–I to α-Syn and Adenosine Receptors
2.3. C8–6–I Decreased CPA-Induced α-Synuclein Expression and Aggregation in Substantia Nigra and Hippocampus
2.4. C8–6–I Decreased CPA-Induced Neurodegeneration in Substantia Nigra and Hippocampus
2.5. 18F-Labeled C8–6–I and Its Potential Therapeutic Use for In Vivo Studies
2.6. 18F-Labeled C8–6–I In Vivo Metabolism and Distribution in the Major Organs Including the Brain
2.7. In Vivo PET/CT Imaging in CD-1 Mice
3. Discussion
4. Methods
4.1. In Vivo Animal Protocol
4.2. Reagents
4.3. Behavior Tests
4.3.1. Y-Maze
4.3.2. Open Field Test
4.3.3. Forced Swim Test
4.4. Structural Modeling and Molecular Docking
4.5. Immunohistochemistry
4.6. Thioflavin-S
4.7. Fluoro-Jade C
4.8. Radiochemistry
4.9. Micro-PET/CT Imaging
4.10. In Vivo Metabolic Stability and Biodistribution
4.11. Statistical Analyses
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Organ | 5 min | 10 min | 20 min | 40 min | 60 min |
---|---|---|---|---|---|
Blood | 0.76 ± 0.040 | 0.78 ± 0.14 | 0.67 ± 0.19 | 0.48 ± 0.029 | 0.39 ± 0.11 |
Liver | 5.12 ± 1.65 | 6.91 ± 2.02 | 6.64 ± 1.44 | 4.76 ± 0.54 | 5.74 ± 1.12 |
Small intestine | 8.56 ± 2.02 | 11.18 ± 3.11 | 13.02 ± 1.24 | 9.35 ± 1.82 | 12.33 ± 0.81 |
Kidney | 16.26 ± 1.82 | 11.86 ± 1.74 | 11.02 ± 0.48 | 8.65 ± 1.21 | 4.27 ± 0.37 |
Spleen | 6.54 ± 0.88 | 5.49 ± 1.05 | 5.71 ± 0.69 | 5.80 ± 0.83 | 3.79 ± 0.33 |
Lung | 7.03 ± 1.24 | 5.51 ± 0.44 | 5.52 ± 0.72 | 3.00 ± 1.40 | 1.42 ± 0.22 |
Heart | 2.34 ± 0.26 | 1.77 ± 0.17 | 1.14 ± 0.040 | 1.01 ± 0.16 | 0.49 ± 0.018 |
Large intestine | 2.98 ± 0.94 | 3.06 ± 0.73 | 2.83 ± 0.068 | 2.69 ± 0.26 | 2.50 ± 0.93 |
Bone | 1.00 ± 0.18 | 1.24 ± 0.44 | 1.18 ± 0.005 | 1.04 ± 0.27 | 1.20 ± 0.34 |
Brain | 0.17 ± 0.014 | 0.14 ± 0.027 | 0.10 ± 0.013 | 0.10 ± 0.011 | 0.05 ± 0.005 |
Time (min) | Flow Rate (mL/min) | Mobile Phase A (%) | Mobile Phase B (%) |
---|---|---|---|
0.00 | 5 | 90 | 10 |
3.00 | 5 | 90 | 10 |
7.00 | 5 | 60 | 40 |
10.00 | 5 | 40 | 60 |
15.00 | 5 | 10 | 90 |
17.00 | 5 | 10 | 90 |
18.00 | 5 | 90 | 10 |
21.00 | 5 | 90 | 10 |
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Jakova, E.; Aigbogun, O.P.; Moutaoufik, M.T.; Allen, K.J.H.; Munir, O.; Brown, D.; Taghibiglou, C.; Babu, M.; Phenix, C.P.; Krol, E.S.; et al. The Bifunctional Dimer Caffeine-Indan Attenuates α-Synuclein Misfolding, Neurodegeneration and Behavioral Deficits after Chronic Stimulation of Adenosine A1 Receptors. Int. J. Mol. Sci. 2024, 25, 9386. https://doi.org/10.3390/ijms25179386
Jakova E, Aigbogun OP, Moutaoufik MT, Allen KJH, Munir O, Brown D, Taghibiglou C, Babu M, Phenix CP, Krol ES, et al. The Bifunctional Dimer Caffeine-Indan Attenuates α-Synuclein Misfolding, Neurodegeneration and Behavioral Deficits after Chronic Stimulation of Adenosine A1 Receptors. International Journal of Molecular Sciences. 2024; 25(17):9386. https://doi.org/10.3390/ijms25179386
Chicago/Turabian StyleJakova, Elisabet, Omozojie P. Aigbogun, Mohamed Taha Moutaoufik, Kevin J. H. Allen, Omer Munir, Devin Brown, Changiz Taghibiglou, Mohan Babu, Chris P. Phenix, Ed S. Krol, and et al. 2024. "The Bifunctional Dimer Caffeine-Indan Attenuates α-Synuclein Misfolding, Neurodegeneration and Behavioral Deficits after Chronic Stimulation of Adenosine A1 Receptors" International Journal of Molecular Sciences 25, no. 17: 9386. https://doi.org/10.3390/ijms25179386