Brain RAS in CNS Diseases: Beneficial Effects of Small Molecule Agonists and Inhibitors

Neurodegenerative diseases are unrelenting, unforgiving and cruel given the long duration of patient suffering due to the impact of progressive damage within specific brain locations. In the case of dementias, there is a direct impact on memory and cognitive processing, and the loss of personal dignity and worth. Ultimately, the patient loses the ability to maintain basic hygiene placing attentional responsibilities on family members and support staff. With respect to neurodegenerative diseases of the eye, the patient must deal with progressive deleterious changes in vision resulting from retinal damage. This review discusses the role of the Renin-Angiotensin System (RAS) in cardiovascular disease, Alzheimer’s and Parkinson’s diseases, Type 2-induced dementia, depression, glaucoma, macular degeneration and diabetic retinopathy. We conclude with a consideration of the challenges posed regarding the development of new drugs designed to treat dementias, depression, and neurodegenerative diseases of the eye. The use of small molecule agonist and antagonist analogs of RAS components is discussed. These analogs can be configured to pass the blood-brain barrier and target relevant receptor proteins in specific brain structures or they can be applied topically to the eye to discourage increases in intraocular pressure, decreased retinal microvascular blood flow, tissue inflammation and oxidative stress as well as the accumulation of extracellular material (drusen) that can disrupt normal vision. Along with suggested drug development strategies, several important drug targets are identified in an effort to focus attention, and facilitate research efforts, to improve drug efficacy and thus provide better clinical outcomes for these patients.