A _2A adenosine receptor overexpression and functionality, as well as TNF‐α levels, correlate with motor symptoms in Parkinson's disease

Abstract

The antagonistic interaction between adenosine and dopamine receptors could have important pathophysiological and therapeutic implications in Parkinson's disease (PD). The primary aim of this study was to investigate the expression, affinity, and density of A(1), A(2A), A(2B), and A(3) adenosine receptors (ARs) and D(2) dopamine receptors (D(2)Rs) in PD. An increase in A(2A)AR density in putamen was found. The presence and functionality of ARs in human lymphocyte and neutrophil membranes from patients with PD revealed a specific A(2A)AR alteration compared with healthy subjects. A statistically significant linear correlation among the A(2A)AR density, functionality, or tumor necrosis factor-alpha (TNF-alpha) levels and Unified Parkinson's Disease Rating Scale (UPDRS) motor score was reported. Adenosine concentration and TNF-alpha levels were increased in plasma of patients with PD. In rat adrenal pheochromocytoma (PC12) cells, a widely useful model, adenosine antagonists decreased dopamine uptake, and an opposite effect was mediated by A(2A) agonists. This is the first report showing the presence of an A(2A)AR alteration in putamen in PD that mirrors a similar up-regulation in human peripheral blood cells. Moreover, the correlation found between A(2A)AR density or A(2A) agonist potency and UPDRS motor score highlights the central role of A(2A)ARs in the pharmacological treatment of PD.

Striatal adenosine A2A receptor expression is controlled by S-adenosyl-L-methionine-mediated methylation

“…Hence, here, we aimed to shed light into the in vivo control of A 2A R expression, a GPCR with eventual increased prevalence in certain neurological conditions. Indeed, A 2A R levels have been shown to be increased in the putamen of some PD patients [5][6][7][8][9].…”

“…Indeed, several clinical trials have shown that the administration of istradefylline (or KW-6002), an A 2A R antagonist, ameliorates the dyskinesias induced by chronic levodopa treatment of PD patients [31][32][33][34][35][36][37][38]. Similarly, since A 2A R levels have been shown to be increased in the putamen of some PD patients [5][6][7][8][9], it seems likely that ADORA2A repression would be an alternative therapy to reduce A 2A R activity. Interestingly, several cerebral areas, such as cerebellum, show reduced A 2A R levels, a fact that has been correlated with a high percentage of DNA methylation in ADORA2A.…”

“…The A 2A R, mostly coupled to G s /G olf proteins [3], is expressed at high levels in only a few regions of the brain, namely primarily striatum, olfactory tubercle, and nucleus accumbens [4]. Interestingly, upregulation of A 2A R expression levels has been shown in the putamen and in peripheral blood cells from Parkinson's disease (PD) patients with levodopa-induced dyskinesias, wellcorrelating with the severity of the disease [5][6][7][8][9].…”

Minocycline exerts a neuroprotective action against 6-OHDA-induced neurotoxicity: in vivo and in vitro studies

“…Chronic neuroinflammation is a typical feature in neurodegenerative diseases, including PD, in which TNF-alpha expression appears to be upregulated representing a valuable target for intervention [51,52,53]. In addition, evidences indicate that TNFalpha may play a role in the selective vulnerability of the nigrostriatal pathway associated to dopaminergic neurotoxicity [54].…”

Vasoactive Neuropeptides in Autoimmune Diseases

“…They may also alter excitotoxicity, abort apoptosis and encourage the growth of neurite in the injured CNS (Barger et al, 1995;Berezovskaya et al, 1995;Imamura et al, 1990;Lazarov-Spiegler et al, 1996;Prewitt et al, 1997;Rabchevsky and Streit, 1997;Toku et al, 1998). Activated microglias are present in other areas of the CNS and therefore initiate and promote inflammation in different brain regions including the putamen, substantia nigra and cingulated cortex where they are responsible for the generation of lewy bodies (Li et al, 2010;McKeith and Mosimann, 2004;Varani et al, 2010). TNF-and IL-1 have similar signalling mechanisms and induce neurodegeneration in the CNS by activating NKFκB, thus facilitating oxidative damage and consequently neuronal damage (Wahner et al, 2007).…”