PreprintArticleVersion 1Preserved in Portico This version is not peer-reviewed
The Bifunctional Dimer Caffeine-Indan Attenuates α-Synuclein Misfolding, Neurodegeneration and Behavioural Deficits After Chronic Stimulation of Adenosine A1 Receptors
Version 1
: Received: 12 June 2024 / Approved: 13 June 2024 / Online: 13 June 2024 (08:06:38 CEST)
How to cite:
Jakova, E.; Aigbogun, O. P.; Moutaoufik, M. T.; Allen, K. J.; Munir, O.; Brown, D.; Taghibiglou, C.; Babu, M.; Phenix, C. P.; Krol, E. S.; Cayabyab, F. S. The Bifunctional Dimer Caffeine-Indan Attenuates α-Synuclein Misfolding, Neurodegeneration and Behavioural Deficits After Chronic Stimulation of Adenosine A1 Receptors. Preprints2024, 2024060901. https://doi.org/10.20944/preprints202406.0901.v1
Jakova, E.; Aigbogun, O. P.; Moutaoufik, M. T.; Allen, K. J.; Munir, O.; Brown, D.; Taghibiglou, C.; Babu, M.; Phenix, C. P.; Krol, E. S.; Cayabyab, F. S. The Bifunctional Dimer Caffeine-Indan Attenuates α-Synuclein Misfolding, Neurodegeneration and Behavioural Deficits After Chronic Stimulation of Adenosine A1 Receptors. Preprints 2024, 2024060901. https://doi.org/10.20944/preprints202406.0901.v1
Jakova, E.; Aigbogun, O. P.; Moutaoufik, M. T.; Allen, K. J.; Munir, O.; Brown, D.; Taghibiglou, C.; Babu, M.; Phenix, C. P.; Krol, E. S.; Cayabyab, F. S. The Bifunctional Dimer Caffeine-Indan Attenuates α-Synuclein Misfolding, Neurodegeneration and Behavioural Deficits After Chronic Stimulation of Adenosine A1 Receptors. Preprints2024, 2024060901. https://doi.org/10.20944/preprints202406.0901.v1
APA Style
Jakova, E., Aigbogun, O. P., Moutaoufik, M. T., Allen, K. J., Munir, O., Brown, D., Taghibiglou, C., Babu, M., Phenix, C. P., Krol, E. S., & Cayabyab, F. S. (2024). The Bifunctional Dimer Caffeine-Indan Attenuates α-Synuclein Misfolding, Neurodegeneration and Behavioural Deficits After Chronic Stimulation of Adenosine A1 Receptors. Preprints. https://doi.org/10.20944/preprints202406.0901.v1
Chicago/Turabian Style
Jakova, E., Ed S. Krol and Francisco Sandoval Cayabyab. 2024 "The Bifunctional Dimer Caffeine-Indan Attenuates α-Synuclein Misfolding, Neurodegeneration and Behavioural Deficits After Chronic Stimulation of Adenosine A1 Receptors" Preprints. https://doi.org/10.20944/preprints202406.0901.v1
Abstract
We previously found that chronic adenosine A1 receptor stimulation with N6-Cyclopentyladenosine increased α-synuclein misfolding and neurodegeneration in a novel α-synucleinopathy model, a hallmark of Parkinson’s disease. Here, we aimed to synthesize a dimer caffeine-indan linked by a 6-carbon chain to cross the blood-brain barrier and tested its ability to bind α-synuclein, reducing misfolding, behavioural abnormalities, and neurodegeneration in our rodent model. Behavioural tests and histological stains assessed neuroprotective effects of the dimer compound. A rapid synthesis of the 18F-labelled analogue enabled Positron Emission Tomography and Computed Tomography imaging for biodistribution measurement. Molecular docking analysis showed that the dimer binds to α-synuclein N- and C-termini and the non-amyloid-β-component (NAC) domain, similar to 1-aminoindan, and this binding promotes a neuroprotective α-synuclein “loop” conformation. The dimer also binds to the orthosteric binding site for adenosine within the adenosine A1 receptor. Immunohistochemistry and confocal imaging showed the dimer abolished α-synuclein upregulation and aggregation in the substantia nigra and hippocampus, and the dimer mitigated cognitive deficits, anxiety, despair, and motor abnormalities. The 18F-labelled dimer remained stable post-injection and distributed in various organs, notably in the brain, suggesting its potential as a Positron Emission Tomography tracer for α-synuclein and adenosine A1 receptor in Parkinson’s disease therapy.
Medicine and Pharmacology, Neuroscience and Neurology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
,
,
,
,
