Effects of Adenosine Receptor Antagonists on the In Vivo LPS-Induced Inflammation Model of Parkinson’s Disease

Abstract

The study shows effects of the nonselective adenosine A1/A2A receptor antagonist caffeine and the selective A2A receptor antagonist KW6002 on LPS-induced changes in the extracellular levels of dopamine (DA), glutamate, adenosine, hydroxyl radical, and A2A receptor density in the rat striatum. Intrastriatal LPS (10 μg) injection decreased extracellular level of DA and increased the level of adenosine, glutamate, and hydroxyl radical on the ipsilateral side 24 h after LPS administration. Caffeine (10 and 20 mg/kg i.p.) and KW6002 (1.5 and 3 mg/kg i.p.) given once daily for 6 days and on the 7th day 2 h before and 4 h after LPS injection reversed the LPS-induced changes in extracellular levels of DA, adenosine, glutamate, and hydroxyl radical production. Moreover, LPS-induced decrease in the striatal A2A receptor density was increased by caffeine and KW6002. In order to show the late LPS effect on oxidative damage of DA neurons, the contents of DA, DOPAC, HVA, and hydroxyl radical were determined 72 h after LPS (10 μg) administration into both striata. LPS decreased striatal and substantia nigra content of DA, DOPAC, and HVA while increased striatal but not nigral content of hydroxyl radical. Caffeine (20 mg/kg) and KW60002 (3 mg/kg) given once daily for 6 days and on the 7th day 2 h before and 4 h after intrastriatal injection of LPS normalized the content of DA and its metabolites in both brain regions as well as decreased LPS-induced increase in the striatal level of hydroxyl radical. In conclusion, our data demonstrated antioxidant effects of caffeine and KW6002 in the inflammatory model of PD.

A2AR‐induced transcriptional deregulation in astrocytes: An in vitro study

“…Here, we provide new insights into the potential impact of A 2A R upregulation on transcriptional deregulation in astrocytes. A 2A R is a modulator of several physiological responses essential to brain homeostasis such as blood brain barrier maintenance, neurotransmitter release, and inflammation (Gołembiowska et al, 2013;Ouyang et al, 2013;Bhamidipati et al, 2013;Kim & Bynoe, 2015), processes that are highly associated with neurodegenerative diseases, such as AD and PD (Cunha, 2016). The relationship between A 2A R and AD in the control of cognitive impairment has been extensively observed in several experimental models (Canas et al, 2009;Laurent et al, 2014;Laurent et al, 2014;Lee et al, 2018;Silva et al, 2018).…”

Health benefits of methylxanthines in neurodegenerative diseases

“…Blockade of P1 receptors by MTXs in the brain seems to be the main mode of action of these drugs in the CNS. Antagonizing adenosine receptors is related to their psychostimulant and anti‐inflammatory potential (Fig. ).…”

The perspective of caffeine and caffeine derived compounds in therapy

“…Why caffeine is effective in the prevention of Parkinson disease is not known. Maybe anti-neuroinfl ammation combined with a reduction of neuron´s oxidative damage is behind the protective effect (126). Molecular mechanism of such effect is again hardly to be tracked and some pathways can be only hypothesized (32).…”