DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Reduced Disease Severity Following Novel Angiotensin 1-7 Treatment in MS Mouse Model

Posted June 15, 2021

Drs. Brett T. Lund, Ph.D., Eve E. Kelland, Ph.D, and Kathleen Rodgers, Ph.D. University of Southern California

Dr. Brett Lund Dr. Brett T. Lund

Multiple sclerosis (MS) is a chronic autoimmune and neurodegenerative disease of the central nervous system that is characterized by destruction of myelin, causing axonal loss and ultimately clinical symptoms and neurological disability. While there are several disease-modifying drugs available to treat MS, there are presently no treatments that offer neuroprotection in order to prevent disease progression. Components of the renin-angiotensin-system (RAS) have been implicated as novel mediators in the CNS and neurological disease. RAS exists as a balance between the vasoconstriction arm of angiotensin II and the angiotensin type 1 receptor and the vasodilation arm of angiotensin 1-7 (A(1-7) and the Mas receptor. A(1-7), which is formed from angiotensin-II, has direct effects on immune regulation, wound healing, stem cell mobilization, and decreases in inflammation, oxidative stress, and neuronal apoptosis. Preliminary data suggest that components of the RAS pathway in the CNS are an integral part of MS pathogenesis and significantly contribute to MS pathology.

With support from a fiscal year 2013 Multiple Sclerosis Research Program Idea Development Award, Dr. Lund and colleagues sought to test the therapeutic effect of A(1-7) treatment on MS disease course in an animal model. Initial observations revealed that A(1-7) treatment resulted in an improved clinical disease score over time. The most effective dose was 2 mg/kg/day A(1-7) in which the clinical disease score was reduced in all mice within 3–4 days of treatment and remained significantly reduced throughout the study. To understand the mechanism of the beneficial effects of A(1-7), the researchers assessed A(1-7) in a Mas knockout (KO) mouse model. After treating the KO mice with A(1-7), no beneficial effect was observed, confirming that the beneficial effects of A(1-7) were due to the interaction with the Mas receptor. Overall A(1-7) treatment in an MS animal model resulted in a reduction in clinical disease onset and severity, which was dependent on Mas receptor activation. Furthermore, reductions in clinical disease score correlated with reductions in immune infiltration, demyelination, and axonal loss in the spinal cords of experimental autoimmune encephalomyelitis mice treated with A(1-7). At the end of the study, the oxidative stress in tissues was reduced. The results of these studies suggest A(1-7) as a potential new therapy for the treatment of MS.

This study offered an innovative therapeutic potential for A(1-7) through immune regulation and protection from neurodegeneration. This work potentially identified a pivotal RAS component for therapeutic development in MS and other neurological diseases.

Link:

Public and Technical Abstracts: Reducing Disease Activity in Animal Models of MS by Activation of the Protective Arm of the Renin-Angiotensin System

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Last updated Tuesday, June 15, 2021