|Vickram Ramkumar , Ph.D.
Adenosine, a byproduct of ATP, produces its physiological effects by interacting with specific cell surface proteins termed adenosine receptors (ARs). Three subtypes of ARs have been described to date - A1, A2 and A3AR subtypes, which are encoded by different genes and show distinct tissue distribution and pharmacological profiles. A major goal of this laboratory is to understand the mechanism(s) by which adenosine protects against cell injury, especially under condition of increased reactive oxygen species (ROS), i.e. following ischemia and exposure to drugs which generate ROS. We show that adenosine stimulates ROS scavenging by activating antioxidant enzymes and also reduces the generation of ROS via the NADPH oxidase pathway. These actions of adenosine are produced via activation of the A1 and A3 subtypes and are manifested in the ability of adenosine to protect against drug-induced ototoxicity and nephrotoxicity, and against HIV-1 dependent neuronal apoptosis. Furthermore, we show that adenosine reduces the inflammatory response through inhibition of nuclear factor (NF)-kB, a transcription factor essential for mediating the inflammatory response and which is activated by ROS. Interestingly, NF-kB induces expression of these ARs. As such, we believe that the adenosine plays a crucial role in limiting ROS-mediated cellular damage and activation of NF-kB –dependent inflammatory response. Selective activators of these ARs could prove beneficial in treating conditions characterized by high ROS generation and/or inflammation.
Mukherjea D, Jajoo S, Sheehan KE, Kaur T, Sheth S, Bunch J, Perro C, Rybak LP, Ramkumar V (2011) NOX3 NADPH oxidase couples transient receptor potential vanilloid to STAT1-mediated inflammation and hearing loss. Antioxid Redox Signal 14:999-1010.
Kaur T, Mukherjea D, Sheehan K, Jajoo S, Rybak LP, and Ramkumar V. (2011) Short interfering RNA against STAT1 attenuates cisplatin induced ototoxicity in the rat by suppressing inflammation. Cell Death Diseases 2:e180. doi: 10.1038/cddis.2011.63.
Ramkumar V, Jhaveri K, Xie X, Jajoo S, and Toth L. (2011) Nuclear Factor kB and Adenosine Receptors Biochemical and Behavioral Profiling. Current Neuropharmacology 9:342-349.
Mukherjea D, Rybak LP, Sheehan K, Kaur T, Ramkumar V, Sheth S, and Jajoo S. (2011). The Design and Screening of Drugs to Prevent Acquired Sensorineural Hearing Loss. Expert Opinions in Drug Discovery, in press.
Jajoo S, Sheth S, Mukherjea D, Kaur T, Rybak LP, and Ramkumar V. (2011) Targeting adenosine receptors for the treatment of cancers. Current Topics in Biochemical Research, in press.
Ramkumar V, Jajoo S, Mukherjea D, Sheth S, and Rybak LP. (2011) Adenosine receptors and melanoma. Melanoma, Yohei Tanaka, editor, InTech Open Access Publisher (ISBN 978-953-307-291-3).