Genetic inactivation of the adenosine A2A receptor exacerbates brain damage in mice with experimental autoimmune encephalomyelitis

• Published in: Journal of neurochemistry 2012-10, Vol.123 (1), p.100-112
• Main Authors: Yao, Shu-Qin, Li, Zheng-Zheng, Huang, Qing-Yuan, Li, Fang, Wang, Zhao-Wei, Augusto, Elisabete, He, Jin-Cai, Wang, Xiao-Tong, Chen, Jiang-Fan, Zheng, Rong-Yuan
• Format: Article
• Language: English
• Subjects: Adenosine; adenosine A1 receptors; Adenosine A2A receptors; Autoimmune diseases; Biological and medical sciences; Brain damage; CD4+ T cells; Cerebrospinal fluid. Meninges. Spinal cord; experimental autoimmune encephalomyelitis (EAE); Genetics; Medical sciences; microglial cells; multiple sclerosis; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Nervous system (semeiology, syndromes); Neurology; Neurons; Rodents
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2012.07807.x

Studies with multiple sclerosis patients and animal models of experimental autoimmune encephalomyelitis (EAE) implicate adenosine and adenosine receptors in modulation of neuroinflammation and brain injury. Although the involvement of the A1 receptor has been recently demonstrated, the role of the adenosine A2A receptor (A2AR) in development of EAE pathology is largely unknown. Using mice with genetic inactivation of the A2A receptor, we provide direct evidence that loss of the A2AR exacerbates EAE pathology in mice. Compared with wild‐type mice, A2AR knockout mice injected with myelin oligodendroglia glycoprotein peptide had a higher incidence of EAE and exhibited higher neurological deficit scores and greater decrease in body weight. A2AR knockout mice displayed increased inflammatory cell infiltration and enhanced microglial cell activation in cortex, brainstem, and spinal cord. In addition, demyelination and axonal damage in brainstem were exacerbated, levels of Th1 cytokines increased, and Th2 cytokines decreased. Collectively, these findings suggest that extracellular adenosine acting at A2ARs triggers an important neuroprotective mechanism. Thus, the A2A receptor is a potential target for therapeutic approaches to multiple sclerosis. The role of the adenosine A2A receptor (A2AR) in development of multiple sclerosis pathology was critically evaluated in EAE model using the A2AR knockout mice. A2AR knockout exacerbates EAE‐induced demyelination, axonal injury, neurobehavioral deficits, and inflammatory responses. The A2AR represents an important neuroprotective mechanism and therapeutic target to modify multiple sclerosis pathology.