Mas Receptor Agonists for Neurodegeneration

Mas Receptor Agonists for Neurodegeneration

Overview

<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">Mas Receptor Agonists for Neurodegeneration</th>
</tr>
<tr>
<td class="label">Axis</td>
<td>Components</td>
</tr>
<tr>
<td class="label"><strong>Classical (pro-inflammatory)</strong></td>
<td>ACE → Angiotensin II → AT1R</td>
</tr>
<tr>
<td class="label"><strong>Counter-regulatory (neuroprotective)</strong></td>
<td>ACE2 → Ang-(1-7) → MasR</td>
</tr>
<tr>
<td class="label">Agent</td>
<td>Type</td>
</tr>
<tr>
<td class="label">Ang-(1-7)</td>
<td>Peptide</td>
</tr>
<tr>
<td class="label">AVE 0991</td>
<td>Non-peptide</td>
</tr>
<tr>
<td class="label">CGEN-856S</td>
<td>Non-peptide</td>
</tr>
<tr>
<td class="label">DIZE</td>
<td>ACE2 activator</td>
</tr>
<tr>
<td class="label">Compound 21</td>
<td>AT2R agonist</td>
</tr>
</table>

The Mas receptor (MasR) is the canonical receptor for angiotensin-(1-7) [Ang-(1-7)] and represents the central effector of the protective arm of the brain renin-angiotensin system [RAS](/mechanisms/renin-angiotensin-system). The ACE2-Ang-(1-7)-MasR axis opposes the pro-inflammatory classical axis (ACE/Ang II/AT1R) and represents a promising therapeutic target for neurodegenerative diseases.

Mas Receptor Agonists for Neurodegeneration

Overview

<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">Mas Receptor Agonists for Neurodegeneration</th>
</tr>
<tr>
<td class="label">Axis</td>
<td>Components</td>
</tr>
<tr>
<td class="label"><strong>Classical (pro-inflammatory)</strong></td>
<td>ACE → Angiotensin II → AT1R</td>
</tr>
<tr>
<td class="label"><strong>Counter-regulatory (neuroprotective)</strong></td>
<td>ACE2 → Ang-(1-7) → MasR</td>
</tr>
<tr>
<td class="label">Agent</td>
<td>Type</td>
</tr>
<tr>
<td class="label">Ang-(1-7)</td>
<td>Peptide</td>
</tr>
<tr>
<td class="label">AVE 0991</td>
<td>Non-peptide</td>
</tr>
<tr>
<td class="label">CGEN-856S</td>
<td>Non-peptide</td>
</tr>
<tr>
<td class="label">DIZE</td>
<td>ACE2 activator</td>
</tr>
<tr>
<td class="label">Compound 21</td>
<td>AT2R agonist</td>
</tr>
</table>

The Mas receptor (MasR) is the canonical receptor for angiotensin-(1-7) [Ang-(1-7)] and represents the central effector of the protective arm of the brain renin-angiotensin system [RAS](/mechanisms/renin-angiotensin-system). The ACE2-Ang-(1-7)-MasR axis opposes the pro-inflammatory classical axis (ACE/Ang II/AT1R) and represents a promising therapeutic target for neurodegenerative diseases.

This page covers Mas receptor agonists — both peptide and non-peptide compounds — that activate this neuroprotective axis for the treatment of Alzheimer's disease [AD](/diseases/alzheimers-disease), Parkinson's disease [PD](/diseases/parkinsons-disease), ALS, and other neurodegenerative conditions.

The ACE2-Ang-(1-7)-Mas Axis

The brain RAS operates as a dual-axis system:

In healthy brains, these axes are balanced. In aging and neurodegeneration, ACE2 expression declines while ACE activity increases, shifting the balance toward AT1R overactivation and creating a self-amplifying cycle of [neuroinflammation](/mechanisms/neuroinflammation), oxidative stress, and neuronal death.

MasR is a Gαs-coupled GPCR expressed primarily on neurons in the [hippocampus](/brain-regions/hippocampus), [cortex](/brain-regions/cortex), cardiovascular centers in the brainstem, as well as on [microglia](/cell-types/microglia) and cerebrovascular endothelium.

Mas Receptor Signaling Mechanisms

When Ang-(1-7) binds to MasR, it activates several neuroprotective signaling cascades:

Evidence in Neurodegenerative Diseases

Alzheimer's Disease

Multiple lines of evidence support MasR agonism as a therapeutic strategy for AD:

• ACE2 reduction: Brain ACE2 expression is significantly reduced in AD patients, correlating with increasing [amyloid-beta](/proteins/amyloid-beta-protein) and [tau pathology](/mechanisms/tau-pathology). This reduces Ang-(1-7) production and shifts the RAS balance toward the pro-inflammatory axis.
• Cognitive preservation: Ang-(1-7) administration improves cognitive function in AD animal models through anti-inflammatory and anti-amyloid effects.
• Amyloid reduction: ACE2 activation (via diminazene aceturate) reduces amyloid pathology in Tg2576 mice and improves cognitive outcomes.
• Neuroinflammation: MasR signaling suppresses NF-κB-dependent inflammatory responses in microglia and astrocytes.

Parkinson's Disease

The ACE2-Ang-(1-7)-Mas axis is particularly relevant to PD:

• Dopaminergic protection: Ang-(1-7) protects dopaminergic neurons in MPTP and 6-OHDA rodent models through NOX inhibition, anti-inflammatory cytokine production, and BDNF upregulation.
• Nigral RAS: The [substantia nigra](/brain-regions/substantia-nigra) has high expression of RAS components, making it particularly vulnerable to RAS dysregulation.
• Microglial polarization: MasR activation promotes microglial M2 (anti-inflammatory) polarization, reducing the chronic neuroinflammation characteristic of PD.
• Clinical correlation: PD patients taking AT1R blockers (ARBs) for hypertension show better preserved cognitive function compared to those taking other antihypertensives in prospective cohort studies.

ALS and FTD

Evidence for MasR agonism in ALS and FTD:

• Neuroprotection: AT2R and MasR agonists protect motor neurons in ALS models through anti-inflammatory and anti-oxidant mechanisms
• Motor neuron viability: The renin-angiotensin system is active in motor neurons, and RAS dysregulation contributes to motor neuron degeneration
• Combined approach: MasR agonism combined with AT2R agonism may provide synergistic neuroprotection

Mas Receptor Agonists

Peptide Agonists

Angiotensin-(1-7)

The endogenous ligand for MasR. While promising, Ang-(1-7) has limited clinical application due to:

• Short half-life in plasma
• Poor BBB penetration
• Requires continuous infusion or frequent dosing

Non-Peptide Agonists

AVE 0991

A synthetic non-peptide MasR agonist with better drug-like properties than Ang-(1-7):

• Mechanism: Selective MasR agonist
• Neuroprotective effects: Demonstrated neuroprotection in ischemia and PD models
• BBB penetration: Better CNS penetration than peptide agonists
• Advantages: Oral bioavailability potential

CGEN-856S

Another selective MasR agonist under preclinical investigation:

• Target: MasR (selective)
• Effects: Neuroprotection studies in various models
• Development stage: Preclinical

Diminazene Aceturate (DIZE)

Originally developed as an antiprotozoal agent, DIZE was found to be a potent ACE2 activator:

• Primary mechanism: ACE2 activator (increasing Ang-(1-7) production)
• Indirect MasR activation: Increases endogenous Ang-(1-7) levels
• Neuroprotective effects: Reduces neuroinflammation, improves cognition in AD models
• BBB penetration: Moderate

Therapeutic Strategies

Direct MasR Agonism

Direct activation of MasR using selective agonists:

• Advantage: Bypasses ACE2 activity limitation
• Challenge: Achieving adequate brain exposure
• Current compounds: AVE 0991, CGEN-856S

ACE2 Activation

Increasing endogenous Ang-(1-7) production:

• Compounds: Diminazene aceturate, recombinant ACE2
• Advantage: Addresses the root cause of reduced Ang-(1-7) in neurodegeneration
• Challenge: ACE2 activators are not selective for brain ACE2

Combination with AT2R Agonism

MasR and AT2R both mediate neuroprotective effects:

• Compound 21 (C21): AT2R agonist in clinical development
• Synergy: Combined MasR + AT2R agonism may provide additive neuroprotection
• Approach: Dual-acting compounds or combination therapy

Adjunctive with ARBs

Adding MasR agonism to ARB therapy:

• Rationale: ARBs block AT1R (pro-inflammatory) while allowing unopposed AT2R signaling
• Enhancement: Adding MasR agonist or ACE2 activator amplifies the protective axis
• Clinical precedent: ARBs are widely used for hypertension; combination may be feasible

Clinical Development Status

No MasR agonists are currently in late-stage clinical trials for neurodegenerative diseases. The field remains preclinical but active.

Mechanism Diagram

Cross-Linking Strategy

Targeting the ACE2-Ang-(1-7)-Mas axis addresses multiple neurodegenerative mechanisms simultaneously:

• [Neuroinflammation](/mechanisms/neuroinflammation): Direct anti-inflammatory signaling via MasR
• [Oxidative stress](/mechanisms/oxidative-stress): NADPH oxidase inhibition
• [Amyloid pathology](/mechanisms/amyloid-aggregation): Enhanced autophagic clearance
• [Tau pathology](/mechanisms/tau-pathway): Anti-inflammatory environment reduces tau kinases
• [Alpha-synuclein aggregation](/mechanisms/alpha-synuclein-aggregation): Reduced oxidative modifications
• [Mitochondrial dysfunction](/mechanisms/mitochondrial-dysfunction): Preserved mitochondrial membrane potential
• [Autophagy](/mechanisms/autophagy-lysosome-neurodegeneration): mTOR inhibition enhances clearance

See Also

• [Renin-Angiotensin System in Neurodegeneration](/mechanisms/renin-angiotensin-system)
• [Alzheimer's Disease Treatment](/therapeutics/alzheimers-disease-treatment)
• [Parkinson's Disease Treatment](/therapeutics/parkinson-treatment)
• [Neuroinflammation Therapeutics](/therapeutics/neuroinflammation-therapeutics)
• [AT2R Agonists](/therapeutics/at2r-agonist-therapy)
• [ACE Inhibitors](/therapeutics/ace-inhibitors)
• [Antioxidant Therapy](/therapeutics/antioxidant-therapy)

References