Differential Expression of Adenosine P1 Receptor ADORA1 and ADORA2A Associated with Glioma Development and Tumor-Associated Epilepsy
Level of adenosine, an endogenous astrocyte-based neuromodulator, is primarily regulated by adenosine P1 receptors. This study assessed expression of adenosine P1 receptors, ADORA1 (adenosine A1 receptor) and ADORA2A (adenosine A2a receptor) and their association with glioma development and epilepsy in glioma patients. Expression of ADORA1/ADORA2A was assessed immunohistochemically in 65 surgically removed glioma tissue and 21 peri-tumor tissues and 8 cases of normal brain tissues obtained from hematoma patients with cerebral trauma. Immunofluorescence, Western blot, and qRT-PCR were also used to verify immunohistochemical data. Adenosine P1 receptor ADORA1 and ADORA2A proteins were localized in the cell membrane and cytoplasm and ADORA1/ADORA2A immunoreactivity was significantly stronger in glioma and peri-tumor tissues that contained infiltrating tumor cells than in normal brain tissues (p < 0.05). The World Health Organization (WHO) grade III gliomas expressed even higher level of ADORA1 and ADORA2A. Western blot and qRT-PCR confirmed immunohistochemical data. Moreover, higher levels of ADORA1 and ADORA2A expression occurred in high-grade gliomas, in which incidence of epilepsy were lower (p < 0.05). In contrast, a lower level of ADORA1/ADORA2A expression was found in peri-tumor tissues with tumor cell presence from patients with epilepsy compared to patients without epilepsy (p < 0.05). The data from the current study indicates that dysregulation in ADORA1/ADORA2A expression was associated with glioma development, whereas low level of ADORA1/ADORA2A expression could increase susceptibility of tumor-associated epilepsy.
KeywordsADORA1 ADORA2A Glioma Epilepsy Immunohistochemistry
This study was supported in part by grants from the Scientific Research Foundation of State Education Ministry for the Returned Overseas Chinese Scholars (#2013.1792) and the Department of Science and Technology of Hunan Province, China (#2013FJ4367).
Compliance with Ethical Standards
Conflict of interest
The authors declared that there is no conflict of interest in this work.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee of Xiangya Hospital of Central South University (Changsha, Hunan, China) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- 2.Stewart L, Burdett S, Glioma Meta-analysis Trialists Group (GMT) (2002) Chemotherapy for high-grade glioma. Cochrane Database Syst Rev (4):CD003913. doi: 10.1002/14651858.CD003913
- 11.Silva IR, Nehlig A, Rosim FE, Vignoli T, Persike DS, Ferrandon A, Sinigaglia-Coimbra R, Fernandes MJ (2011) The A1 receptor agonist R-Pia reduces the imbalance between cerebral glucose metabolism and blood flow during status epilepticus: could this mechanism be involved with neuroprotection? Neurobiol Dis 41(1):169–176CrossRefPubMedGoogle Scholar
- 12.Mohammad-Zadeh M, Mirnajafi-Zadeh J, Fathollahi Y, Javan M, Jahanshahi A, Noorbakhsh SM, Motamedi F (2009) The role of adenosine A(1) receptors in mediating the inhibitory effects of low frequency stimulation of perforant path on kindling acquisition in rats. Neuroscience 158(4):1632–1643CrossRefPubMedGoogle Scholar
- 16.Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LJ, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321(5897):1807–1812CrossRefPubMedPubMedCentralGoogle Scholar