Diminazene aceturate (Berenil), a new use for an old compound?

Kuriakose, Shiby; Uzonna, Jude E.

doi:10.1016/j.intimp.2014.05.027

Cited by 52 publications

(35 citation statements)

References 34 publications

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“…Nonetheless, Ang-(1-7) may still act to increase perfusion at the level of the microcirculation in such a way that it is not detected by our measures of CBF. Other potential non-ACE2 mediated effects of diminazene, specifically those that may independently reduce inflammation 17 , cannot be ruled out as contributing to the neuroprotective effects we have observed. As the current study is limited to exploring the neuroprotective benefits of targeting this axis in the acute and subacute phase of ischemic stroke, there remains the important question of the impact of such treatments on longer-term outcomes and late mortality.…”

Section: Discussionmentioning

confidence: 84%

“…4A-C) as well as central 5 administration of diminazene demonstrated neuroprotective efficacy, as intravenous drug administration is a preferred route in humans in emergent settings. There is evidence to indicate that peripheral diminazene can cross the intact blood brain barrier 17 , but in the setting of stroke, well-characterized barrier leakiness allows many compounds to cross 16 .…”

Section: Discussionmentioning

confidence: 99%

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Activation of the Neuroprotective Angiotensin-Converting Enzyme 2 in Rat Ischemic Stroke

et al. 2015

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The angiotensin converting enzyme 2/angiotensin-(1-7)/Mas axis represents a promising target for inducing stroke neuroprotection. Here, explored stroke-induced changes in expression and activity of endogenous angiotensin converting enzyme 2 and other system components in Sprague Dawley rats. To evaluate the clinical feasibility of treatments that target this axis and that may act in synergy with stroke-induced changes, we also tested the neuroprotective effects of diminazene aceturate, an angiotensin converting enzyme 2 activator, administered systemically post-stroke. Amongst rats that underwent experimental endothelin-1-induced ischemic stroke, angiotensin converting enzyme 2 activity in the cerebral cortex and striatum increased in the 24 hours after stroke. Serum angiotensin converting enzyme 2 activity was decreased within 4h post stroke, but rebounded to reach higher than baseline levels 3d post-stroke. Treatment following stroke with systemically-applied diminazene resulted in decreased infarct volume and improved neurological function without apparent increases in cerebral blood flow. Central infusion of A-779, a Mas receptor antagonist, resulted in larger infarct volumes in diminazene-treated rats, and central infusion of the angiotensin converting enzyme 2 inhibitor MLN-4760 alone worsened neurological function. The dynamic alterations of the protective angiotensin converting enzyme 2 pathway following stroke suggest that it may be a favorable therapeutic target. Indeed, significant neuroprotection resulted from post-stroke angiotensin converting enzyme 2 activation, likely via Mas signaling in a blood flow-independent manner. Our findings suggest that stroke therapeutics that target the angiotensin converting enzyme 2/angiotensin-(1-7)/Mas axis may interact cooperatively with endogenous stroke-induced changes, lending promise to their further study as neuroprotective agents.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Activation of the Neuroprotective Angiotensin-Converting Enzyme 2 in Rat Ischemic Stroke

et al. 2015

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“…Considering the importance of kinase signaling in the signal transduction that results from AT1R activation [66], mechanisms of anti-AngII action that involve kinase inhibition seem particularly plausible. Along these lines, it has recently been reported that the administration of an ACE2 activator [69], diminazene aceturate (Berenil ® ), resulted in significantly downregulated phosphorylation of MAPKs, including ERK, p38, and c-Jun N-terminal kinases, as well as the NF-κB p65 subunit in mice [70]. We have shown that administration of diminazene aceturate significantly reduces infarct size in rat ischemic stroke [24••], which may be the result of such reductions in inflammation, oxidative stress, and apoptosis secondary to the decreased phosphorylation of these pro-inflammatory mediators.…”

Section: Mechanisms Of Ang-(1-7)-induced Neuroprotectionmentioning

confidence: 99%

Neuroprotective Mechanisms of the ACE2–Angiotensin-(1-7)–Mas Axis in Stroke

et al. 2015

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The discovery of beneficial neuroprotective effects of the angiotensin converting enzyme 2–angiotensin-(1-7)–Mas axis [ACE2–Ang-(1-7)–Mas] in ischemic and hemorrhagic stroke has spurred interest in a more complete characterization of its mechanisms of action. Here, we summarize findings that describe the protective role of the ACE2–Ang-(1-7)–Mas axis in stroke, along with a focused discussion on the potential mechanisms of neuroprotective effects of Ang-(1-7) in stroke. The latter incorporates evidence describing the actions of Ang-(1-7) to counter the deleterious effects of angiotensin II (AngII) via its type 1 receptor, including anti-inflammatory, anti-oxidant, vasodilatory, and angiogenic effects, and the role of altered kinase–phosphatase signaling. Interactions of Mas with other receptors, including bradykinin receptors and AngII type 2 receptors are also considered. A more complete understanding of the mechanisms of action of Ang-(1-7) to elicit neuroprotection will serve as an essential step toward research into potential targeted therapeutics in the clinical setting.

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“…toxicity decreased significantly by exchanging the trifluoromethyl substituent with the halogens bromine, fluorine and chlorine (5)(6)(7)(8). The concentration of the compounds at which respectively a growth inhibition of 50% and 90% of the M. tuberculosis H37Ra-lux laboratory strain was observed as compared to the negative control.…”

Section: Biologymentioning

confidence: 99%

“…Because the recommended TB treatment is very demanding on the patient, non-compliance has contributed to the emergence of strains of drug-resistant M. tuberculosis. [6][7][8] However, by replacing the amidine moieties of diminazene with alternative electron-withdrawing groups, such as nitro substituents, the DNA binding properties are abrogated. However, when classified as extensively drug-resistant tuberculosis (XDR) TB, the MDR M. tuberculosis strain has acquired additional resistance to one or more of the second-line drugs.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and in vitro investigation of halogenated 1,3‐bis(4‐nitrophenyl)triazenide salts as antitubercular compounds

et al. 2017

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The diverse pharmacological properties of the diaryltriazenes have sparked the interest to investigate their potential to be repurposed as antitubercular drug candidates. In an attempt to improve the antitubercular activity of a previously constructed diaryltriazene library, eight new halogenated nitroaromatic triazenides were synthesized and underwent biological evaluation. The potency of the series was confirmed against the Mycobacterium tuberculosis lab strain H37Ra, and for the most potent derivative, we observed a minimal inhibitory concentration of 0.85 μm. The potency of the triazenide derivatives against M. tuberculosis H37Ra was found to be highly dependent on the nature of the halogenated phenyl substituent and less dependent on cationic species used for the preparation of the salts. Although the inhibitory concentration against J774A.1 macrophages was observed at 3.08 μm, the cellular toxicity was not mediated by the generation of nitroxide intermediate as confirmed by electron paramagnetic resonance spectroscopy, whereas no in vitro mutagenicity could be observed for the new halogenated nitroaromatic triazenides when a trifluoromethyl substituent was present on both the aryl moieties.

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Diminazene aceturate (Berenil), a new use for an old compound?

Cited by 52 publications

References 34 publications

Activation of the Neuroprotective Angiotensin-Converting Enzyme 2 in Rat Ischemic Stroke

Activation of the Neuroprotective Angiotensin-Converting Enzyme 2 in Rat Ischemic Stroke

Neuroprotective Mechanisms of the ACE2–Angiotensin-(1-7)–Mas Axis in Stroke

Synthesis and in vitro investigation of halogenated 1,3‐bis(4‐nitrophenyl)triazenide salts as antitubercular compounds

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