Background/Purpose: Cognitive dysfunction affects the majority of patients with systemic lupus erythematosus (SLE), however it is grossly under-recognized, the pathogenesis is poorly understood, and no treatments are available. The anti-NMDA receptor (NMDA) antibody, a subset of anti-DNA antibodies cross-reactive with the NMDAR, and termed DNRAbs, has been strongly associated with cognitive dysfunction in both mouse models and humans. In a mouse model, DNRAb-mediated brain pathology proceeds through two stages: excitotoxic neuron loss, followed by persistent neuroinflammation resulting in alteration in neuronal integrity and spatial memory impairment. The renin-angiotensin system is emerging as a promising target in neurodegenerative diseases with angiotensin II as the most neuroactive peptide. We have previously shown that ACE inhibition can preserve and treat the dendritic damage and cognitive impairment that occurs in DNRAb-positive mice. We now tested whether direct inhibition of angiotensin signaling with angiotensin receptor blockers (ARBs) has a similar neuroprotective effect.

Methods: Mice immunized with DNRAbs and then treated with lipopolysaccharide (LPS) to breach the blood brain barrier and allow transient access of antibody to the hippocampus, were studied for loss of neuronal dendritic complexity using Golgi and analyzed using Sholl analysis. Mice received the ARB telmisartan in drinking water or control (regular drinking water) for two weeks, starting one week post LPS.

Results: Dendritic complexity was preserved in DNRAb-positive mice treated with telmisartan compared to those not treated (p< 0.001, KS). Moreover, dendritic complexity was considered normal in telmisartan-treated mice when compared to DNRAb-negative mice (not significant, KS).

Conclusion: These findings suggest that angiotensin receptor blockers can preserve neuronal dendritic complexity in the DNRAb mouse model. Future studies looking at microglial activation and spatial memory behavioral deficits are warranted. Angiotensin receptor blockers could be a potential therapeutic target for cognitive impairment in SLE and may serve as an alternative to ACE inhibitors in those that cannot tolerate them.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/angiotensin-receptor-blockers-prevent-loss-of-dendritic-complexity-in-a-lupus-mouse-model-of-cognitive-impairment/