ACE2-Ang-(1-7)-Mas and AT2R pathways offer neurotherapeutic potential against inflammation and cognitive decline.

The renin-angiotensin system (RAS) is widely known for regulating blood pressure and fluid homeostasis. However, a local brain RAS significantly influences neurovascular regulation, inflammation, oxidative stress, synaptic plasticity, and cognitive function. Traditional RAS activation via angiotensin II type 1 receptor (AT1R) signaling can promote detrimental effects in the CNS. This review addresses the critical gap in understanding how the protective RAS arm, specifically the ACE2-angiotensin-(1-7)-Mas receptor axis, angiotensin II type 2 receptor (AT2R), and alamandine/Mas-related G protein-coupled receptor D (MrgD) pathway, can counteract these harmful effects and offer neuroprotection. Current treatments for neurological diseases often lack comprehensive anti-inflammatory and neuroprotective mechanisms, highlighting the need for novel therapeutic frameworks.

This comprehensive review critically summarized experimental evidence regarding the neurotherapeutic relevance of the protective RAS arm. The authors focused on three key pathways: the ACE2-angiotensin-(1-7)-Mas receptor axis, the angiotensin II type 2 receptor (AT2R), and the alamandine/Mas-related G protein-coupled receptor D (MrgD) pathway. The review synthesized findings predominantly from cell culture and animal models, including those for ischemic stroke, Alzheimer's disease, Parkinson's disease, and multiple sclerosis. The primary objective was to evaluate how these protective pathways might counterbalance the detrimental angiotensin II type 1 receptor signaling, which contributes to neuroinflammation and neuronal damage. The authors systematically analyzed preclinical data to assess the potential of these mechanisms in reducing neuroinflammation, oxidative injury, vascular dysfunction, and neuronal loss.

Experimental evidence strongly suggests that the protective RAS arm, encompassing the ACE2-angiotensin-(1-7)-Mas receptor axis, AT2R, and alamandine/MrgD pathway, actively counterbalances the pro-inflammatory and damaging angiotensin II type 1 receptor signaling within the central nervous system. These pathways demonstrate significant potential in mitigating key pathological processes associated with various neurological conditions. > Specifically, activation of these protective RAS components has been shown to reduce neuroinflammation, oxidative injury, vascular dysfunction, and neuronal loss across preclinical models of ischemic stroke, Alzheimer's disease, Parkinson's disease, and multiple sclerosis. For instance, angiotensin-(1-7) acting via the Mas receptor and alamandine through MrgD are implicated in anti-inflammatory and antioxidant effects, while AT2R activation contributes to neuroprotection and improved vascular function. The review highlights a consistent pattern of beneficial modulation, suggesting a broad neurotherapeutic applicability for these pathways. However, the current evidence remains largely preclinical, derived from in vitro cell cultures and in vivo animal models, with human data still indirect or from early translational studies.