The Bifunctional Dimer Caffeine-Indan Attenuates α-Synuclein Misfolding, Neurodegeneration and Behavioral Deficits after Chronic Stimulation of Adenosine A1 Receptors

• Published in: International journal of molecular sciences 2024-08, Vol.25 (17), p.9386
• Main Authors: Jakova, Elisabet, Aigbogun, Omozojie P, Moutaoufik, Mohamed Taha, Allen, Kevin J H, Munir, Omer, Brown, Devin, Taghibiglou, Changiz, Babu, Mohan, Phenix, Chris P, Krol, Ed S, Cayabyab, Francisco S
• Format: Article
• Language: English
• Subjects: 1-aminoindan; Adenosine; adenosine A1 receptor; alpha-Synuclein - metabolism; Animals; Anxiety; Behavior; Behavior, Animal - drug effects; Biodistribution; Caffeine; Caffeine - pharmacology; dimer; Drug dosages; Male; Metabolism; Molecular Docking Simulation; N6-cyclopentyladenosine; Neurodegeneration; Neuroprotective Agents - pharmacology; Parkinson Disease - drug therapy; Parkinson Disease - metabolism; Parkinson Disease - pathology; Positron-Emission Tomography - methods; Protein Folding - drug effects; Rats; Receptor, Adenosine A1 - metabolism; α-synucleinopathy
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25179386

We previously found that chronic adenosine A1 receptor stimulation with N -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, behavioral abnormalities, and neurodegeneration in our rodent model. Behavioral tests and histological stains assessed neuroprotective effects of the dimer compound. A rapid synthesis of the F-labeled 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 F-labeled 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.