Michael Campos

Introduction. Parkinson’s Disease is the result of progressive degeneration of the dopaminergic neurons in the Substantia Nigra.¹ Cardinal features include resting tremor, bradykinesia, rigidity, and a variety of other motor and non-motor symptoms.² The key molecular pathogenic mechanisms include neuroinflammation and oxidative stress, mitochondrial dysfunction, alpha-synuclein misfolding and aggregation, and impairment of protein clearance.² The cytoplasmic inclusions of alpha-synuclein aggregates, known as Lewy bodies, are the cytologic hallmark of PD.¹ Epidemiological studies demonstrate that caffeine consumption is associated with a significantly lower risk of PD, however, the underlying mechanism is unclear.^3,5 A recent study found that Adenosine A2A Receptors modulate alpha-synuclein aggregation and toxicity.³ A 2016 clinical trial found that higher caffeine consumption was associated with a lower rate of starting L-Dopa treatment.⁴ Together, these studies suggest that the neuroprotective effect may be due to caffeine’s action as an Adenosine A2A antagonist. Methods. SH-SY5Y cells overexpressing alpha-synuclein and rat primary neuronal cultures were exposed to extracellular alpha-synuclein. Cell viability was determined using a Propidium Iodide and Syto-13 uptake assay. Chemiluminescent detection analyzed NMDA receptor subunits NMDAR1 and NMDAR2B immunoreactivity, and a Bimolecular Fluorescence Complementation assay was used to evaluate alpha-synuclein dimerization.³ 79 newly diagnosed PD patients were followed for 4 years. Caffeine Consumption, UPDRS, L-dopa Equivalent Daily Dose, NMS-Quest, and the time from PD diagnosis to the need for L-dopa treatment were recorded at baseline, 2 years, and 4 years.⁴ Results. Alpha-synuclein impairment of long term potentiation in cells was rescued through an NMDA receptor-dependent mechanism, and cell death was prevented by selective A2AR antagonists.³ Blockade did not interfere with alpha-synuclein oligomerization but did reduce the percentage of cells displaying alpha-synuclein inclusions.³ In patients, higher caffeine consumption was associated with a lower rate of starting L-Dopa treatment.⁴ Each additional 50 mg of caffeine was associated with lower UPDRS and NMSQuest scores.⁴ Conclusions. A2AR clearly represent an important target for PD drug development. The effects of A2AR antagonists may involve controlling the latter stages of alpha-synuclein aggregation.³ Caffeine consumption was associated with a reduction in the accrual of motor and non-motor symptoms throughout 4-year follow-up in newly diagnosed PD, which highlights the rationale for using A2A antagonists.⁴ Istradefylline, an A2A antagonist, gained FDA approval in 2019 as an adjunctive therapy for certain PD patients.² Going forward, phase IV clinical studies will allow long-term monitoring to evaluate the numerous possible benefits of Istradefylline on Parkinson’s Disease progression.⁶

1. Schepici G, Silvestro S, Bramanti P, Mazzon E. Caffeine: An Overview of Its Beneficial Effects in Experimental Models and Clinical Trials of Parkinson’s Disease. Int J Mol Sci. 2020;21(13):4766. Published 2020 Jul 4. doi:10.3390/ijms21134766
2. Jankovic J, Tan EK. Parkinson’s disease: etiopathogenesis and treatment. J Neurol Neurosurg Psychiatry. 2020;91(8):795-808. doi:10.1136/jnnp-2019-322338
3. Ferreira DG, Batalha VL, Vicente Miranda H, et al. Adenosine A2A Receptors Modulate α-Synuclein Aggregation and Toxicity. Cereb Cortex. 2017;27(1):718-730. doi:10.1093/cercor/bhv268
4. Moccia M, Erro R, Picillo M, et al. Caffeine consumption and the 4-year progression of de novo Parkinson’s disease. Parkinsonism Relat Disord. 2016;32:116-119. doi:10.1016/j.parkreldis.2016.08.005
5. Garcez ML, Damiani AP, Pacheco R, et al. Caffeine Neuroprotection Decreases A2A Adenosine Receptor Content in Aged Mice. Neurochem Res. 2019;44(4):787-795. doi:10.1007/s11064-018-02710-3
6. Chen JF, Cunha RA. The belated US FDA approval of the adenosine A2A receptor antagonist istradefylline for treatment of Parkinson’s disease. Purinergic Signal. 2020;16(2):167-174. doi:10.1007/s11302-020-09694-2
7. Schepici G, Silvestro S, Bramanti P, Mazzon E. Caffeine: An Overview of Its Beneficial Effects in Experimental Models and Clinical Trials of Parkinson’s Disease. Int J Mol Sci. 2020;21(13):4766. Published 2020 Jul 4. doi:10.3390/ijms21134766