Principal Investigator:
Moses V. Chao, PhD
Skirball Institute of Biomolecular Medicine, Departments of Cell Biology and Physiology and Neuroscience
New York University School of Medicine, New York, New York 10016

Background
Neurotrophins, such as nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF), play a prominent role in the development of the vertebrate nervous system by promoting cell survival, differentiation, and cell death events. Two classes of cell surface receptors, the Trk receptor tyrosine kinase and the p75 neurotrophin receptor mediate the actions of neurotrophins. Binding of NGF to the Trk receptor activates signaling pathways that promote axonal and dendritic branching, and long-term potentiation and is essential for cell survival. The regulation of Trk tyrosine kinase activity would be an effective mechanism to combat diseases related to neuronal damage.

The neurotrophins have been investigated as potential therapeutic agents for the treatment of neurodegenerative diseases and nerve injury, such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, peripheral neuropathy, spinal cord injury and memory loss; however difficulties with drug delivery and several acute side affects have led to failures during clinical trials. Using a novel method for screening small molecules that exert a neurotrophic effect through transactivation of neurotrophin receptors, the present inventor has identified adenosine, a small molecule that transactivates the Trk receptor tyrosine kinase and mediates neuronal cell survival in the absence of neurotrophins. These findings suggest that small molecules may elicit neurotrophic effects for the treatment of neurodegenerative diseases without the use of neurotrophins.

Description of project
Adenosine is a neuromodulator, whose levels are increased during injury such as hypoxia or ischemia. Its effects are mediated through G protein-coupled receptors (GPCR) that mediate transmembrane signaling for a large number of ligands, including hormones, neurotransmitters, odorants and pheromones. Ligands for GPCR have been shown to transactivate receptors for epidermal growth factor, platelet-derived growth factor, and insulin-like growth factor.

The present invention identified adenosine and adenosine agonists as transactivators of Trk receptor phosphorylation, through a mechanism that requires the A2A GPCR-receptor. The activation does not require neurotrophin binding and is observed in both cultured and primary hippocampal neurons. To determine whether adenosine could replace nerve growth factor (NGF) in promoting neuronal survival, cells were grown without NGF both in the presence and absence of adenosine. Cells lacking both NGF and adenosine underwent rapid cell death whereas cells lacking NGF that were supplemented with adenosine survived. These findings provide a mechanism for the neuroprotective actions of adenosine, which are independent of neurotrophin presence or Trk tyrosine kinase receptor binding. That many cell types possess both adenosine and Trk receptors make adenosine an attractive alternative to neurotrophins that are currently being tested as potential therapeutic agents for neurodegenerative diseases.

Dr. Chao, an expert in the field of neurotrophin receptors and neurobiology, has recently published several papers related these findings. For more in-depth explanations of the invention and potential applications, please refer to "Activation of Trk neurotrophin receptors in the absence of neurotrophins" (Proceedings of the National Academy of Science 98(6):3555-60) or "Distinctive features of Trk neurotrophin receptor transactivation by G protein-coupled receptors" (Cytokine Growth Factor Reviews 198:1-7).

Application
The identification of adenosine as an transactivator or the Trk tyrosine kinase receptor suggests that it can replace neurotrophins as a potential treatment for a wide range of neurological disorders, including Alzheimer's disease, ALS, cerebral ischemia, sleep disorders, hyperalgesia, and Parkinson's disease. The use of a small molecule, such as adenosine, may circumvent many of the obstacles in drug delivery seen with neurotrophins. Further, through the use of well-defined assays, we propose high-throughput screening that will identify other small molecules that may serve as potential therapeutic agents for neurodegenerative diseases.