Deletion of adenosine A1 or A2A receptors reduces l-3,4-dihydroxyphenylalanine-induced dyskinesia in a model of Parkinson's disease

Abstract

Adenosine A2A receptor antagonism provides a promising approach to developing nondopaminergic therapy for Parkinson’s disease (PD). Clinical trials of A2A antagonists have targeted PD patients with L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in an effort to improve parkinsonian symptoms. The role of adenosine in the development of LID is little known, especially regarding its actions via A1 receptors. We aimed to examine the effects of genetic deletion and pharmacological blockade of A1 and/or A2A receptors on the development of LID, on the induction of molecular markers of LID including striatal preprodynorphin and preproenkephalin (PPE), and on the integrity of dopaminergic nigrostriatal neurons in hemiparkinsonian mice. Following a unilateral 6-hydroxydopamine lesion A1, A2A and double A1-A2A knockout (KO) and wild-type littermate mice, and mice pretreated with caffeine (an antagonist of both A1 and A2A receptors) or saline were treated daily for 18–21 days with a low dose of L-DOPA. Total abnormal involuntary movements (AIMs, a measure of LID) were significantly attenuated (p<0.05) in A1 and A2A KOs, but not in A1-A2A KOs and caffeine-pretreated mice. An elevation of PPE mRNA ipsilateral to the lesion in WT mice was reduced in all KO mice. In addition, neuronal integrity assessed by striatal dopamine content was similar in all KOs and caffeine-pretreated mice following 6-hydroxydopamine lesioning. Our findings raise the possibility that A1 or A2A receptors blockade might also confer a disease-modifying benefit of reduced risk of disabling LID, whereas the effect of their combined inactivation is less clear.

Using caffeine and other adenosine receptor antagonists and agonists as therapeutic tools against neurodegenerative diseases: A review

“…1; Federico and Spalluto, 2012; Glade, 2010; Marjo and Miia, 2010; Müller and Jacobson, 2011; Ojeda-López et al, 2012; Paul et al, 2011; Ramlackhansingh et al, 2011; Rosim et al, 2011; Schenone et al, 2010). Experimental evidence supports the use of caffeine and other adenosine receptor antagonists as well as adenosine receptor agonists in the reduction of hyperalgesia, antinociception, excitotoxicity, inflammatory response, dyskinesia, akinesia, sensory and motor deficits and neuronal cell death related to the pathophysiology of the neurodegenerative diseases discussed (Camilo and Goldstein, 2004; Ding et al, 2007; Horiuchi et al, 2010; Kowaluk, 1998; Kitta et al, 2012; Tomić et al, 2006; Xiao et al, 2011). The seemingly paradoxical use of adenosine receptor agonists and antagonists to treat similar diseases suggests that factors such as dosage, drug delivery method, state of disease progression, extracellular concentrations of potential excitotoxic transmitters and known anatomical and pharmacological relationship between adenosine and dopamine receptors as they influence glutamate release must be taken into consideration when designing treatment strategies.…”

Extracellular nucleotide and nucleoside signaling in vascular and blood disease

“…The implications of purinergic signaling extend far beyond the present review. For example, important findings on the role of purinergic signaling in disease mechanisms of the central nervous system-such as Parkinson disease 108,109 or cancer 110 -have not been addressed here. There are many instances in which signaling events through adenosine P1 vs nucleotide P2 receptors mediate effects that go in opposing directions and are often associated with completely opposite outcomes in biological systems.…”

Paeoniflorin Promotes Non-rapid Eye Movement Sleep via Adenosine A1 Receptors

“…Male R,A 1 R KO mice and their wild-type (WT) littermate controls of the inbred C57BL/6 strains from heterozygotes were generated as previously described elsewhere (Johansson et al, 2001). Polymerase chain reaction with the animal tail DNA was used to determine their genotypes (Goldman et al, 2010;Xiao et al, 2011). We also used glutamate decarboxylase 67 (GAD67)-green fluorescent protein (GFP) knock-in mice, in which GFP is expressed in GABAergic neurons under control of the endogenous GAD67 promoter (Tamamaki et al, 2003).…”