Chapter 4 - Targeting renin–angiotensin system: a strategy for drug development against neurological disorders

There are increasing reports of involvement of local renin–angiotensin system (RAS) in the central nervous system (CNS). The angiotensin-converting enzyme (ACE)/angiotensin II (Ang II)/angiotensin receptor 1 (AT1R) axis of the RAS is primarily proinflammatory. Since inflammation is the key to the progression of neurodegenerative disorders, this axis has been associated with neurological disorders. Thus, targeting this axis through repurposing of drugs approved for hypertension is a viable therapeutic strategy. However, ensuring brain availability while avoiding peripheral effects is a challenge. Novel formulations or prodrugs have been developed to address this. Another therapeutic strategy is to target the antiinflammatory components of the RAS. The ACE2/Ang (1–7)/MasR axis, Ang II/AT2R axis, and/or Ang IV/AT4R (insulin-regulated aminopeptidase, IRAP) axis have potential to balance the inflammatory effects of AT1R axis. Thus, there have been efforts to activate these axes to confer protection against neuronal inflammation. However, expression of these axes in higher age group is considered to be less. Nonetheless, under certain neurological disease condition, these axes are relatively more expressed, and it is possible to develop a therapeutic strategy to target them.