Abnormal accumulation of aggregated α-synuclein (aSyn) is a hallmark of sporadic and familial Parkinson's disease (PD) and related synucleinopathies. Recent studies suggest a neuroprotective role of adenosine A_2A receptor (A_2AR) antagonists in PD. Nevertheless, the precise molecular mechanisms underlying this neuroprotection remain unclear. We assessed the impact of A_2AR blockade or genetic deletion (A_2AR KO) on synaptic plasticity and neuronal cell death induced by aSyn oligomers. We found that impairment of LTP associated with aSyn exposure was rescued in A_2AR KO mice or upon A_2AR blockade, through an NMDA receptor-dependent mechanism. The mechanisms underlying these effects were evaluated in SH-SY5Y cells overexpressing aSyn and rat primary neuronal cultures exposed to aSyn. Cell death in both conditions was prevented by selective A_2AR antagonists. Interestingly, blockade of these receptors did not interfere with aSyn oligomerization but, instead, reduced the percentage of cells displaying aSyn inclusions. Altogether, our data raise the possibility that the well-documented effects of A_2AR antagonists involve the control of the latter stages of aSyn aggregation, thereby preventing the associated neurotoxicity. These findings suggest that A_2AR represent an important target for the development of effective drugs for the treatment of PD and related synucleinopathies.

1 The present paper reports changes in the urinary excretion of dopamine, 5‐hydroxytryptamine and amine metabolites in nitric oxide deprived hypertensive rats during long‐term administration of N^Gnitro‐L‐arginine methyl ester (l‐NAME). Aromatic L‐amino acid decarboxylase (AAAD) activity in renal tissues and the ability of newly‐formed dopamine to leave the cellular compartment where the synthesis of the amine has occurred were also determined.2 Twenty four hours after exposure to L‐NAME, both systolic (SBP) and diastolic (DBP) blood pressure were increased by 20mmHg; heart rate was slightly decreased. During the next 13 days both SBP and DBP increased progressively reaching 170± 3 and 116±3mmHg, respectively.3 Baseline urinary excretion of L‐DOPA, dopamine, 3,4‐dihydroxyphenylacetic acid (DOPAC), 3methoxytyramine (3‐MT) and homovanillic acid (HVA) during the 4 day period of stabilization averaged 4.4 ±0.5, 13.8 ± 0.3, 37.4 ±0.8, 180.0 ±2.7 and 206.1 ± 6.7 nmol day⁻¹, respectively. The urinary excretion of L‐DOPA, dopamine and DOPAC, but not that of 3‐MT and HVA, were increased from day 6–8 of L‐NAME administration onwards (L‐DOPA, up to 13.4 ±2.1; dopamine, up to 23.0 ±1.6; DOPAC, up to 62.8 ±3.7 nmol day⁻¹). Baseline daily urinary excretion of 5hydroxytryptamine and 5‐hydroxyindolacetic acid (5‐HIAA) averaged 73.5 ± 1.1 and 241.7 ± 5.4 nmol day⁻¹, respectively. During the first week of L‐NAME administration, the urinary excretion of both 5‐hydroxytryptamine and 5‐HIAA did not change significantly; however, as was found with dopamine and DOPAC, changes in the urinary excretion of 5‐hydroxytryptamine were evident during the second week of L‐NAME administration.4 In experiments performed on homogenates of isolated renal tubules, the decarboxylation of L‐DOPA to dopamine was dependent on the concentration of L‐DOPA used (10 to 5000 μm) and saturable at 1000 μm. AAAD activity as determined in homogenates (V_max, in nmol mg⁻¹protein h⁻¹; K_min μm) was significantly (P<0.01) higher in rats given L‐NAME for 14 days (V_max= 25 ± 2; K_m= 72 ± 10) than in control rats (V_max=14 ± 1; K_m= 63 ± 7), rats given L‐NAME for 7 days (V_max= 15 ± 1; K_m= 69 ± 5) and rats given L‐NAME plus L‐arginine (V_max=13 ± 1; K_m= 60 ± 3) for 14 days.5 A considerable amount of the total dopamine formed from added L‐DOPA in kidney slices escaped into the incubation medium. The application of the Michaelis‐Menten equation to the net transport of newly‐formed dopamine allowed the identification of a saturable (carrier‐mediated transfer) and a non‐saturable component (diffusion). No significant differences in the diffusional rate of transfer (0.14 ± 0.02 μmol⁻¹) were observed between the four experimental groups. However, the saturable outward transfer of dopamine (V_max, in μmol mg⁻¹protein h⁻¹; K_min μm) was higher in control animals (V_max= 2.3 ± 0.2; K_m= 568 ± 67) than that in rats treated with L‐NAME for 14 days (V_max= 0.8 ± 0.02; K_m= 241 ±21), but similar to that observed in rats receiving L‐NAME plus L‐arginine (V_max= 2.4 ± 0.2; K_m= 618 ± 61); the saturable dopamine outward rate of transfer in rats given L‐NAME for 7 days (V_max= 3.9 ± 0.2; K_m= 1006 ± 32) was higher than in controls.6 In conclusion, the present studies show that the hypertensive response resulting from the long‐term administration of L‐NAME is accompanied by an increased urinary excretion of dopamine and 5‐hydroxytryptamine, which appears to follow an enhanced activity of renal AAAD. The observation that the increased AAAD activity can be reversed by the administration of L‐arginine to L‐NAME‐treated rats favours the view that the adaptational response which results in an enhanced AAAD activity probably involves a decrease in the generation of nitric oxide.

Statins are the most commonly prescribed drugs for the treatment of dyslipidemia. They are also recommended in primary and secondary prevention of cardiovascular disease. In addition to decreasing cholesterol synthesis, statins interfere with the synthesis of isoprenoid intermediates, which may explain many of their pleiotropic properties, including their antioxidant effects. Oxidative stress is defined as an imbalance between the synthesis of reactive oxygen species and their elimination by antioxidant defense systems, with a prevailing pro-oxidant status that results in macromolecular damage and disruption of cellular redox signaling. Reactive oxygen species interfere with various processes that affect cardiac structure and function, contributing to the contractile dysfunction, myocardial hypertrophy and fibrosis observed in the pathophysiology of heart failure. By regulating several molecular pathways that control nicotinamide adenine dinucleotide phosphate oxidase and endothelial nitric oxide synthase activity, statins help restore redox homeostasis. These drugs also contribute to the control of inflammation and appear to have a protective role in various diseases. The results of observational studies and clinical trials with statins in heart failure have not been consensual. This review aims to analyze the role of oxidative stress in heart failure and the molecular mechanisms underlying statins' antioxidant properties. It also examines current scientific evidence on the use of these drugs as a specific treatment for heart failure.