Compounds that Induce Arginase 1 to Enhance Neuroprotection

Dr. Rajiv Ratan has developed a HTS to identify compounds that activate arginase-1 and therefore neuroprotective. The patent application referenced below describes methods to use compounds that activate arginase 1 to treat traumas like spinal cord injury and stroke, as well as neurodegenerative diseases. Lansoprazole, tilorone, and resveratrol were among the most effective compounds in the screen.

Dr. Raj Ratan is a thought leader in the biochemical role played by the enzyme arginase in protecting neurons from apoptosis, or cell suicide. Arginase 1 and nitric oxide synthase (NOS) compete for the substrate, arginine. NOS uses arginine to create the neurotoxin, nitric oxide, while arginase catalyzes arginase to less harmful ornithine and urea. Hence inducing arginase 1 is neuroprotective.

This work is part of a larger project led by Dr. Ratan, which has screened drugs and drug-like compounds in high throughput screens relevant to the program of destruction, cell-suicide, and scarring that characterize damage to the CNS, including stroke, traumatic brain injury, and spinal cord injury. The project has sought compounds that have activity against multiple targets -- or against a single target that can set off wide-ranging protective programs.

The general approach is described in a recent piece in Stroke called "Novel multi-modal strategies to promote brain and spinal cord injury recovery".

The primary screens have sought:

• HIF activators / prolyl hydroxylase inhibitors (2009 J Neurosci; 2008 Ann N Y Acad Sci; 2008 Front. Bioscience ; 2007 Neurochem Res; 2004 Stroke);
• Arginase 1 activators (2010 J Neurosci; 2006 J Neurosci; 2004 J Nutrition)
• p21CIP1/WAF1 activators (2008 J Neurosci)
• ATF4 inhibitors (2008 J Exp Med)