Targeting Adenosine Signaling in Parkinson's Disease: From Pharmacological to Non-pharmacological Approaches

Abstract

Parkinson's disease (PD) is one of the most prevalent neurodegenerative disease displaying negative impacts on both the health and social ability of patients and considerable economical costs. The classical anti-parkinsonian drugs based in dopaminergic replacement are the standard treatment, but several motor side effects emerge during long-term use. This mini-review presents the rationale to several efforts from pre-clinical and clinical studies using adenosine receptor antagonists as a non-dopaminergic therapy. As several studies have indicated that the monotherapy with adenosine receptor antagonists reaches limited efficacy, the usage as a co-adjuvant appeared to be a promising strategy. The formulation of multi-targeted drugs, using adenosine receptor antagonists and other neurotransmitter systems than the dopaminergic one as targets, have been receiving attention since Parkinson's disease presents a complex biological impact. While pharmacological approaches to cure or ameliorate the conditions of PD are the leading strategy in this area, emerging positive aspects have arisen from non-pharmacological approaches and adenosine function inhibition appears to improve both strategies.

PET Imaging of the Adenosine A2A Receptor in the Rotenone-Based Mouse Model of Parkinson’s Disease with [18F]FESCH Synthesized by a Simplified Two-Step One-Pot Radiolabeling Strategy

“…Activation of the A 2A R by adenosine or appropriate agonists results in the inhibition of the D 2 R and, thus, in reduced dopamine binding [2,4,5]. Pharmacological inhibition of the A 2A R amplifies the D 2 R-dependent signaling cascade and improves motor symptoms [2,3,5,6]. Since the A 2A R modulates the dopamine binding affinity of the D 2 R, selective A 2A R antagonists have great potential as appropriate non-dopaminergic PD therapeutics [2,3,6].…”

“…Pharmacological inhibition of the A 2A R amplifies the D 2 R-dependent signaling cascade and improves motor symptoms [2,3,5,6]. Since the A 2A R modulates the dopamine binding affinity of the D 2 R, selective A 2A R antagonists have great potential as appropriate non-dopaminergic PD therapeutics [2,3,6]. In clinical phase II and III trials, the A 2A R antagonists istradefylline, preladenant, and tozadenant improved motor symptoms in PD patients [7][8][9].…”

Focusing on Adenosine Receptors as a Potential Targeted Therapy in Human Diseases

“…Stroke NNC-21-0136 [123] Sleep CPA [155] Anxiety and depression MRS5474 [151] TRR469 [150] Cognition and memory ASP5854 [159] Alzheimer's disease Sleep CGS21680 [133] Anxiety and depression Istradefylline [208] Cognition and memory ASP5854 [159] Alzheimer's disease MSX-3 [212] Huntington's diseases ZM241385 [220] Parkinson's diseases Tozadenant/SYN115, DT1133, ZM241385, ST1535, and istradefylline [61] Preladenant, ASP5854, vipadenant (DC) [61] SCH900800, and BIIB014 [221] KW-6002 [134] Schizophrenia APEC, CGS21680, NECA, CV-1808, and DPMA [210] MSX-3, DMPX, SCH58261, and ZM241385 [210] Pain CGS21680 [155] Spongosine (DC) [204] Epilepsy ZM241385 [202] Drug addiction CGS21680 and NECA [215] A 3 AR Stroke IB-MECA [222] CI-IB-MECA [223] LJ-1251 [72] Epilepsy ANR235 [224] A 2B AR mediates anti-inflammatory effects in neutrophils by inhibiting adhesion to endothelial cells [23], preventing the production of TNF-α and IL-1β, as well as macrophage proliferation, and stimulating IL-10 secretion from macrophages [216]. Interestingly, A 2B AR has proinflammatory and anti-inflammatory actions in mouse bone marrow-derived mast cells (BMMCs) [225].…”

Antioxidant and Neuroprotective Effects of Caffeine against Alzheimer’s and Parkinson’s Disease: Insight into the Role of Nrf-2 and A2AR Signaling

“…Apart from the elevated oxidative stress, activated microglial cells and the subsequent release of the inflammatory mediators have also been shown to play a prominent role in the execution of neuronal cell loss in PD [141]. The pharmacological inhibition of A2AR activates dopamine receptor-2, suppresses neuroinflammation by regulating the level of dopamine, and relieves the symptoms of PD [142]. The elevated oxidative stress and reduced level of dopamine due to the activation of A2AR in the substantia nigra and striatum of PD patients induce overall neuroinflammation and PD symptoms [143].…”