Adenosine A2A Receptor Gene Knockout Prevents l-3,4-Dihydroxyphenylalanine-Induced Dyskinesia by Downregulation of Striatal GAD67 in 6-OHDA-Lesioned Parkinson's Mice.

Su-Bing Yin,Shuang Chen,Xia-Wei Zheng,Guo-Qing Zheng,Wen-Ting Yang,Xiao-Guang Zhang

doi:10.3389/fneur.2017.00088

Abstract

l-3,4-Dihydroxyphenylalanine (l-DOPA) remains the primary pharmacological agent for the symptomatic treatment of Parkinson’s disease (PD). However, the development of l-DOPA-induced dyskinesia (LID) limits the long-term use of l-DOPA for PD patients. Some data have reported that adenosine A2A receptor (A2AR) antagonists prevented LID in animal model of PD. However, the mechanism in which adenosine A2AR blockade alleviates the symptoms of LID has not been fully clarified. Here, we determined to knock out (KO) the gene of A2AR and explored the possible underlying mechanisms implicated in development of LID in a mouse model of PD. A2AR gene KO mice were unilaterally injected into the striatum with 6-hydroxydopamine (6-OHDA) in order to damage dopamine neurons on one side of the brain. 6-OHDA-lesioned mice were then injected once daily for 21 days with l-DOPA. Abnormal involuntary movements (AIMs) were evaluated on days 3, 8, 13, and 18 after l-DOPA administration, and real-time polymerase chain reaction and immunohistochemistry for glutamic acid decarboxylase (GAD) 65 and GAD67 were performed. We found that A2AR gene KO was effective in reducing AIM scores and accompanied with decrease of striatal GAD67, rather than GAD65. These results demonstrated that the possible mechanism involved in alleviation of AIM symptoms by A2AR gene KO might be through reducing the expression of striatal GAD67.

Highlights

Parkinson’s disease (PD) is a common progressive neurodegenerative disorder characterized by bradykinesia, rigidity, resting tremor, and postural instability [1]
We determined to knock out (KO) the gene of A2A receptor (A2AR) and explored the possible underlying mechanisms implicated in development of l-DOPA-induced dyskinesia (LID) in a mouse model of PD
These results demonstrated that the possible mechanism involved in alleviation of Abnormal involuntary movements (AIMs) symptoms by A2AR gene KO might be through reducing the expression of striatal GAD67

Summary

Introduction

Parkinson’s disease (PD) is a common progressive neurodegenerative disorder characterized by bradykinesia, rigidity, resting tremor, and postural instability [1]. Long-term therapy with l-3,4-dihydroxyphenylalanine (l-DOPA), A2AR KO Prevents LID the most common and effective symptomatic treatment for PD, often leads to the severe side effects such as dystonic, choreic, and ballistic movements, collectively referred to as l-DOPA-induced dyskinesia (LID) [3]. 10% of patients have experienced LID in the first year of dopamine replacement therapy, and the incidence of LID is up to nearly 95% in patients who survive 15 years from diagnosis [4, 5]. LID severely affects quality of life and leads to enormous social and economic burden to patients and their caregivers. Current effective treatment strategy for LID is mainly by a reduction in drug dose, which has a rebound of parkinsonian symptoms [6]. An effective and satisfying management of LID is still urgently needed of PD therapy

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