Mechanisms of Ebselen as a Therapeutic and Its Pharmacology Applications

Wang, Jun; Wang, Peng; Dong, Chunfa; Zhao, Ying; Zhou, Jingxuan; Yuan, Chunling; Zou, Lili

doi:10.4155/fmc-2019-0218

Cited by 29 publications

(22 citation statements)

References 163 publications

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“…This was the case of retinoic acid and its isoform isotriteonin. Ebselen was another compound that inhibited TC formation, and it also has strong antioxidant properties in the cells (76, 77). Based on this result we suggested that ROS are required to induce this process.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological inhibition of titan-like cells formation suggests that accumulation of endogenous free radicals that correlate with mitochondrial changes are required to induce this transition inCryptococcus neoformans

García-Barbazán

García-Rodas

Sachse

et al. 2022

Preprint

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Cryptococcus neoformans is an encapsulated yeast able to cause disease (mainly meningoencephalitis) among immunosuppressed patients, mostly HIV+. This yeast can form the so-called titan cells in vivo, which are cells of an abnormal larger size due to an increase in both the capsule and the cell body size (total size reaching between 50-70 microns). This phenomenon can be partially reproduced in vitro to obtain cells of an intermediate size (25-30 um), which have been denominated titan-like cells. In this work, we have screened 1,520 compounds from the Prestwick Chemical Library and identified off-patent drugs that inhibited titan-like cell formation in vitro. We developed an automated fluorescence-based microscopy assay and identified 64 compounds as possible inhibitors of titan-like cells in vitro. We chose 10 of these compounds to confirm their inhibitory effect and confirmed them as inhibitors of titan-like cells with dose-response curves. Several of the compounds identified had antioxidant properties (i.e., retinoic acid), indicating a possible role of free radicals during titan cell formation. Using fluorescent probes, we found that there was an endogenous accumulation of ROS during cell growth, which was inhibited in the presence of retinoic acid. Furthermore, we found that during titanization, there were significant changes in the mitochondria, which is the main organelle where ROS are produced. We hypothesize that an intracellular increase of free radicals at the mitochondria might be a triggering signal to induce titanization.

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Section: Discussionmentioning

confidence: 99%

Pharmacological inhibition of titan-like cells formation suggests that accumulation of endogenous free radicals that correlate with mitochondrial changes are required to induce this transition inCryptococcus neoformans

García-Barbazán

García-Rodas

Sachse

et al. 2022

Preprint

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“…Recent work has shown that brain inflammation can lead to tinnitus-like behavior in animals ( Fuentes-Santamaría et al, 2017 ; Wang et al, 2019 ; Deng et al, 2020 ). If so, then ebselen would be a prime candidate for mitigating potential AG-induced inflammation ( Kalinec et al, 2017 ; Jiang et al, 2017b ; Wood and Zuo, 2017 ), as it has been implicated as a powerful anti-inflammatory and neuroprotective therapeutic ( Wang et al, 2020 ). AG-penetration of the blood brain barrier in humans is understudied, however it has been suggested that AGs might be particularly neurotoxic in patients with compromised blood brain barriers ( Segal et al, 1999 ), a condition which has been observed in CF patients ( Vaughn et al, 1996 ).…”

Section: Discussionmentioning

confidence: 99%

“…Encouragingly, recent work in mice has demonstrated that ebselen can reduce suprathreshold ABR wave fluctuations and hyperacusis caused by amikacin treatment ( Longenecker et al, 2020 ). Therefore, ebselen, with its variety of proposed anti-oxidant/anti-inflammatory mechanisms of action ( Wang et al, 2020 ), is a good candidate to investigate as a potential therapy for both peripheral and central sensory diseases.…”

Section: Introductionmentioning

confidence: 99%

Development of Tinnitus and Hyperacusis in a Mouse Model of Tobramycin Cochleotoxicity

Longenecker¹,

Gu²,

Homan³

et al. 2021

Front. Mol. Neurosci.

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Aminoglycosides (AG) antibiotics are a common treatment for recurrent infections in cystic fibrosis (CF) patients. AGs are highly ototoxic, resulting in a range of auditory dysfunctions. It was recently shown that the acoustic startle reflex (ASR) can assess behavioral evidence of hyperacusis and tinnitus in an amikacin cochleotoxicity mouse model. The goal of this study was to establish if tobramycin treatment led to similar changes in ASR behavior and to establish whether ebselen can prevent the development of these maladaptive neuroplastic symptoms. CBA/Ca mice were divided into three groups: Group 1 served as a control and did not receive tobramycin or ebselen, Group 2 received tobramycin (200 mg/kg/s.c.) and the vehicle (DMSO/saline/i.p.) daily for 14 continuous days, and Group 3 received the same dose/schedule of tobramycin as Group 2 and ebselen at (20 mg/kg/i.p.). Auditory brainstem response (ABR) and ASR hearing assessments were collected at baseline and 2, 6, 10, 14, and 18 weeks from the start of treatment. ASR tests included input/output (I/O) functions which assess general hearing and hyperacusis, and Gap-induced prepulse inhibition of the acoustic startle (GPIAS) to assess tinnitus. At 18 weeks, histologic analysis showed predominantly normal appearing hair cells and spiral ganglion neuron (SGN) synapses. Following 14 days of tobramycin injections, 16 kHz thresholds increased from baseline and fluctuated over the 18-week recovery period. I/O functions revealed exaggerated startle response magnitudes in 50% of mice over the same period. Gap detection deficits, representing behavioral evidence of tinnitus, were observed in a smaller subset (36%) of animals. Interestingly, increases in ABR wave III/wave I amplitude ratios were observed. These tobramycin data corroborate previous findings that AGs can result in hearing dysfunctions. We show that a 14-day course of tobramycin treatment can cause similar levels of hearing loss and tinnitus, when compared to a 14-day course of amikacin, but less hyperacusis. Evidence suggests that tinnitus and hyperacusis might be common side effects of AG antibiotics.

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“…This could be a potential adjuvant treatment in some anemias. Another promising preventive and therapeutic agent are the Gpx mimic Ebselen that has antioxidant properties and is being tested in different clinical trials [185]. There are also different types of inhibitors against ROS-inducing enzymes, including NOX and NOS (reviewed in [186]).…”

Section: Antioxidants and Redox Enzymesmentioning

confidence: 99%

Changing Perspectives from Oxidative Stress to Redox Signaling—Extracellular Redox Control in Translational Medicine

et al. 2022

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Extensive research has changed the understanding of oxidative stress that has been linked to every major disease. Today we distinguish oxidative eu- and distress, acknowledging that redox modifications are crucial for signal transduction in the form of specific thiol switches. Long underestimated, reactive species and redox proteins of the Thioredoxin (Trx) family are indeed essential for physiological processes. Moreover, extracellular redox proteins, low molecular weight thiols and thiol switches affect signal transduction and cell–cell communication. Here, we highlight the impact of extracellular redox regulation for health, intermediate pathophenotypes and disease. Of note, recent advances allow the analysis of redox changes in body fluids without using invasive and expensive techniques. With this new knowledge in redox biochemistry, translational strategies can lead to innovative new preventive and diagnostic tools and treatments in life sciences and medicine.

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Mechanisms of Ebselen as a Therapeutic and Its Pharmacology Applications

Cited by 29 publications

References 163 publications

Pharmacological inhibition of titan-like cells formation suggests that accumulation of endogenous free radicals that correlate with mitochondrial changes are required to induce this transition inCryptococcus neoformans

Pharmacological inhibition of titan-like cells formation suggests that accumulation of endogenous free radicals that correlate with mitochondrial changes are required to induce this transition inCryptococcus neoformans

Development of Tinnitus and Hyperacusis in a Mouse Model of Tobramycin Cochleotoxicity

Changing Perspectives from Oxidative Stress to Redox Signaling—Extracellular Redox Control in Translational Medicine

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