Remimazolam alleviates neuropathic pain via regulating bradykinin receptor B1 and autophagy

Xie, Haiyu; Lu, Feng; Liu, Weilian; Wang, Enfu; Wang, Lifeng; Zhong, Maolin

doi:10.1093/jpp/rgab080

Cited by 27 publications

(19 citation statements)

References 34 publications

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“…It is also not clear whether remimazolam itself has these effects; no data appear to be presented relating to remimazolam itself, although it is implied by the title of this publication. Recently, it has also been reported that remimazolam alleviates neuropathic pain via regulating the bradykinin B 1 receptor and autophagy ( Xie et al, 2021 ). Studies to examine inhibition by flumazenil and the effects of other benzodiazepines, such as midazolam, would be useful in order to determine whether this effect is mediated via the benzodiazepine site on the GABA A receptor or some other effect of remimazolam or its metabolite.…”

Section: Remimazolammentioning

confidence: 99%

Remimazolam: Non-Clinical and Clinical Profile of a New Sedative/Anesthetic Agent

Kilpatrick¹

2021

Front. Pharmacol.

129

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A program to identify novel intravenous sedatives with a short and predictable duration of action was initiated in the late 1990’s by Glaxo Wellcome. The program focussed on the identification of ester-based benzodiazepine derivatives that are rapidly broken down by esterases. Remimazolam was identified as one of the lead compounds. The project at Glaxo was shelved for strategic reasons at the late lead optimization stage. Via the GSK ventures initiative, the program was acquired by the small biotechnology company, TheraSci, and, through successive acquisitions, developed as the besylate salt at CeNeS and PAION. The development of remimazolam besylate has been slow by industry standards, primarily because of the resource limitations of these small companies. It has, however, recently been approved for anesthesia in Japan and South Korea, procedural sedation in the United States, China, and Europe, and for compassionate use in intensive care unit sedation in Belgium. A second development program of remimazolam was later initiated in China, using a slightly different salt form, remimazolam tosylate. This salt form of the compound has also recently been approved for procedural sedation in China. Remimazolam has the pharmacological profile of a classical benzodiazepine, such as midazolam, but is differentiated from other intravenous benzodiazepines by its rapid conversion to an inactive metabolite resulting in a short onset/offset profile. It is differentiated from other intravenous hypnotic agents, such as propofol, by its low liability for cardiovascular depression, respiratory depression, and injection pain. The benzodiazepine antagonist flumazenil can reverse the effects of remimazolam in case of adverse events and further shorten recovery times. The aim of this review is to provide an analysis of, and perspective on, published non-clinical and clinical information on 1) the pharmacology, metabolism, pharmacokinetics, and pharmacodynamic profile of remimazolam, 2) the profile of remimazolam compared with established agents, 3) gaps in the current understanding of remimazolam, 4) the compound’s discovery and development process and 5) likely future developments in the clinical use of remimazolam.

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Section: Remimazolammentioning

confidence: 99%

Remimazolam: Non-Clinical and Clinical Profile of a New Sedative/Anesthetic Agent

Kilpatrick¹

2021

Front. Pharmacol.

129

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“…Through TLR4 receptor downregulation, remimazolam was shown to interfere with lipopolysaccharide (LPS)-induced endotoxemia via blockade of NF-kB signaling pathway and reversal of LPS-induced phosphorylation of Akt and Erk protein kinases essential for neuronal survival [32 ▪▪ ]. The interaction with NF-kB was also beneficial in promoting glioma cell apoptosis in vitro [33] and in alleviating neuropathic pain in adult rats [34].…”

Section: Remimazolam: a Novel Ultra-short-acting Benzodiazepinementioning

confidence: 99%

Novel anesthetics in pediatric practice: is it time?

Useinovic¹,

Jevtović-Todorović²

2022

Current Opinion in Anaesthesiology

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Purpose of reviewSteadily mounting evidence of anesthesia-induced developmental neurotoxicity has been a challenge in pediatric anesthesiology. Considering that presently used anesthetics have, in different animal models, been shown to cause lasting behavioral impairments when administered at the peak of brain development, the nagging question, 'Is it time for the development of a new anesthetic' must be pondered. Recent findingsThe emerging 'soft analogs' of intravenous anesthetics aim to overcome the shortcomings of currently available clinical drugs. Remimazolam, a novel ester-analog of midazolam, is a well tolerated intravenous drug with beneficial pharmacological properties. Two novel etomidate analogs currently in development are causing less adrenocortical suppression while maintaining equally favorable hemodynamic stability and rapid metabolism. Quaternary lidocaine derivatives are explored as more potent and longer lasting alternatives to currently available local anesthetics. Xenon, a noble gas with anesthetic properties, is being considered as an anesthetic-sparing adjuvant in pediatric population. Finally, alphaxalone is being reevaluated in a new drug formulation because of its favorable pharmacological properties.

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“…Autophagy is widely believed to be associated with multiple neurodegenerative diseases, and microglial activation is closely related to neuroinflammation (Plaza-Zabala et al 2017;Su et al 2016). Previous studies have reported that LPS stimulates autophagy in microglia (Qin et al 2018;Xie et al 2021). To further determine the role of autophagy in LPS-induced microglial activation, BV2 cells were treated with 3-MA (autophagy inhibitor) and LPS alone or together.…”

Section: Autophagy Can Be Involved In the Role Of Cd147 In Lps-induce...mentioning

confidence: 99%

Lipopolysaccharide induces inflammatory microglial activation through CD147-mediated matrix metalloproteinase expression

Yao

Liu

Tang

et al. 2022

Environ Sci Pollut Res

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Microglia-mediated neuroinflammation plays a vital role in the pathophysiological processes of multiple neurodegenerative diseases. Lipopolysaccharide (LPS) is an environmental poison that can induce inflammatory microglial activation. Matrix metalloproteinases (MMPs) are vital factors regulating microglial activation, and CD147 is a key MMP inducer, which can induce inflammation by inducing MMPs. However, whether it is involved in the regulation of microglial activation has not been reported. In this study, the role of CD147 in LPS-induced microglial inflammatory activation was investigated by establishing in vivo and in vitro models. The results suggested that LPS-induced microglial activation was accompanied by the induction of CD147 expression while the inhibition of CD147 expression could inhibit LPS-induced microglial inflammatory activation. In addition, the results also indicated that the role of CD147 in LPS-induced pro-inflammatory activation of microglia was related to its downstream MMP-3, MMP-8, and autophagy. Furthermore, the inhibition of MMP-3, MMP-8, and autophagy attenuated LPS-induced inflammatory activation of microglia. At the same time, there was a certain interaction between MMPs and autophagy, which is shown that inhibiting the expression of MMPs could inhibit autophagy, whereas inhibiting autophagy could inhibit the expression of MMPs. Taken together, we provided the first evidence that CD147/MMPs can be involved in LPS-induced inflammatory activation of microglia through an autophagy-dependent manner. Supplementary Information The online version contains supplementary material available at 10.1007/s11356-022-24292-y.

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Remimazolam alleviates neuropathic pain via regulating bradykinin receptor B1 and autophagy

Cited by 27 publications

References 34 publications

Remimazolam: Non-Clinical and Clinical Profile of a New Sedative/Anesthetic Agent

Remimazolam: Non-Clinical and Clinical Profile of a New Sedative/Anesthetic Agent

Novel anesthetics in pediatric practice: is it time?

Lipopolysaccharide induces inflammatory microglial activation through CD147-mediated matrix metalloproteinase expression

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