Diminazene aceturate or losartan ameliorates the functional, radiological and histopathological alterations in knee osteoarthritis rodent model: repurposing of the ACE2/Ang1‐7/MasR cascade

Abstract

PURPOSE: Current therapies for osteoarthritis (OA) are limited to analgesics and anti-inflammatory drugs. Considering the importance of oxidative stress and inflammatory mediators in OA etiology, we tested the hypothesis that targeting the renin-angiotensin-aldosterone system (RAAS) can improve OA anomalies. Diminazene (DIZE), an activator of angiotensin-converting enzyme 2 and the angiotensin 2 type-1 receptor blocker losartan (LOS) were used for this purpose. METHODS: OA was induced by a single intra-articular injection of monosodium iodoacetate. The effects of exposure to DIZE or LOS for 21 days on OA anomalies in rats' knees were investigated. Evaluation of motor function, nociception, and inflammatory response was done using rotarod, knee bend and knee swelling tests. Markers of knee joint inflammation, and cellular oxidation in addition to the RAAS biomarkers, were assessed in knee tissues, along with radiological and histopathological investigations. RESULTS: Elevations in inflammatory and oxidative markers in knee tissues of OA rats were mostly improved by the two therapeutic drugs. Such effect was also reflected in the rotarod, knee bend and knee swelling tests. Treatment with DIZE has shown a more prominent effect than LOS in controlling OA-associated inflammation and cellular oxidation. Markers of RAAS have also shown better responsiveness to DIZE over LOS. CONCLUSIONS: DIZE has shown a prominent increase in the angiotensin 1-7 amount, highlighting the involvement of the signaling pathway in the immunomodulatory effect. The radiological and histopathology examination came to confirm the outcome of biochemical markers, nominating diminazene aceturate as a possible therapeutic option for OA.