A vertebrate model to reveal neural substrates underlying the transitions between conscious and unconscious states

Bedell, Victoria M.; Meng, Qing Cheng; Pack, Michael; Eckenhoff, Roderic G.

doi:10.1038/s41598-020-72669-1

Cited by 5 publications

(24 citation statements)

References 44 publications

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“…Instead of additivity, both AziFo and fropofol showed a dose-dependent antagonism of propofolinduced hypnosis as measured by a decrease in spontaneous movement (Figure 3). 19 AziFo Diazirine Half-Life. The UV−vis absorption spectrum of AziFo showed a local maximum from the diazirine at 317 nm with additional aromatic absorbance maxima at 273 and 267 nm (Figure S7).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…General Synthetic Procedures. Proton and 13 C NMR spectra were obtained on a Bruker DMX 500 MHz nuclear magnetic resonance spectrometer, and 19 F NMR spectra were obtained on a Bruker DMX 360 MHz nuclear magnetic resonance spectrometer. Spectra for compounds 1 and 3 are reported in the Supporting Information.…”

Section: ■ Methodsmentioning

confidence: 99%

“…1 H NMR (500 MHz, CDCl 3 ) δ 7.69 (t, J = 7.1, 1H), 7.60 (td, J = 7.1, 1.8 Hz, 1H), 7.25 (t, J = 7.8 Hz, 1H), 3.33 (p, J = 6.9 Hz, 1H), 1.29 (dd, J = 7.0, 2.4 Hz, 6H). 19 F-NMR (340 MHz, CDCl 3 ) −74.43 (d, J = 15.7 Hz, 3F), −114.97 (td, J = 15.7, 6.8 Hz, 1F) ppm. 13 Preparation of 3-(2-Fluoro-3-isopropylphenyl)-3-(trifluoromethyl)-3H-diazirine (Azi-fropofol) (1).…”

Section: ■ Methodsmentioning

confidence: 99%

“…1 H NMR (500 MHz, CDCl 3 ) 7.35 (t, J = 7.0 Hz, 1H), 7.30 (t, J = 7.0 Hz, 1H), 7.13 (t, J = 7.8 Hz), 3.27 (septet, J = 7 Hz, 1H), 1.25 ppm (d, J = 7 Hz, 6H). 19 Physicochemical Properties of AziFo. Octanol/water partition coefficients were calculated using XLOGP3.…”

Section: ■ Methodsmentioning

confidence: 99%

“…Shown here is the effect of coadministration of AziFo or fropofol (Frop) with propofol, and the resultant dose-dependent antagonism of propofol's effects (5 and 25 μM doses shown). Data for propofol alone has been previously published 19.…”

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confidence: 99%

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Synthesis and Characterization of a Diazirine-Based Photolabel of the Nonanesthetic Fropofol

White

Leace

Bedell

et al. 2020

ACS Chem. Neurosci.

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The mechanisms of general anesthetics have been debated in the literature for many years and continue to be of great interest. As anesthetic molecules are notoriously difficult to study due to their low binding affinities and multitude of binding partners, it is advantageous to have additional tools to study these interactions. Fropofol is a hydroxyl to fluorine-substituted propofol analogue that is able to antagonize the actions of propofol. Understanding fropofol’s ability to antagonize propofol would facilitate further characterization of the binding interactions of propofol that may contribute to its anesthetic actions. However, the study of fropofol’s molecular interactions has many of the same difficulties as its parent compound. Here, we present the synthesis and characterization of ortho-azi-fropofol (AziFo) as a suitable photoaffinity label (PAL) of fropofol that can be used to covalently label proteins of interest to characterize fropofol’s binding interactions and their contribution to general anesthetic antagonism.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Methodsmentioning

confidence: 99%

Section: ■ Methodsmentioning

confidence: 99%

Section: ■ Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Synthesis and Characterization of a Diazirine-Based Photolabel of the Nonanesthetic Fropofol

White

Leace

Bedell

et al. 2020

ACS Chem. Neurosci.

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Antagonism of propofol anesthesia by alkyl-fluorobenzene derivatives

Plasencia,

Rodgers,

Knighton

et al. 2024

Sci Rep

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Despite their frequent use across many clinical settings, general anesthetics are medications with lethal side effects and no reversal agents. A fluorinated analogue of propofol has previously been shown to antagonize propofol anesthesia in tadpoles and zebrafish, but little further investigation of this class of molecules as anesthetic antagonists has been conducted. A 13-member library of alkyl-fluorobenzene derivatives was tested in an established behavioral model of anesthesia in zebrafish at 5 days post fertilization. These compounds were examined for their ability to antagonize propofol and two volatile anesthetics, as well as their interaction with the anesthetic-binding model protein apoferritin. Two compounds provided significant antagonism of propofol, and when combined, were synergistic, suggesting more than one antagonist sensitive target site. These compounds did not antagonize the volatile anesthetics, indicating some selectivity amongst general anesthetics. For the compounds with the most antagonistic potency, similarities in structure and binding to apoferritin may be suggestive of competitive antagonism; however, this was not supported by a Schild analysis. This is consistent with multiple targets contributing to general anesthesia, but whether these are physiologic antagonists or are antagonists at only some subset of the many anesthetic potential targets remains unclear, and will require additional investigation.

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Brain-wide impacts of sedation on spontaneous activity and auditory processing in larval zebrafish

Favre-Bulle,

Muller,

Lee

et al. 2024

Preprint

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Despite their widespread use, we have limited knowledge of the mechanisms by which sedatives mediate their effects on brain-wide networks. This is, in part, due to the technical challenge of observing activity across large populations of neurons in normal and sedated brains. In this study, we examined the effects of the sedative dexmedetomidine, and its antagonist atipamezole, on spontaneous brain dynamics and auditory processing in zebrafish larvae. Our brain-wide, cellular-resolution calcium imaging reveals, for the first time, the brain regions involved in these network-scale dynamics and the individual neurons that are affected within those regions. Further analysis reveals a variety of dynamic changes in the brain at baseline, including marked reductions in spontaneous activity, correlation, and variance. The reductions in activity and variance represent a 'quieter' brain state during sedation, an effect that causes highly correlated evoked activity in the auditory system to stand out more than it does in un-sedated brains. We also observe a reduction in auditory response latencies across the brain during sedation, suggesting that the removal of spontaneous activity leaves the core auditory pathway free of impingement from other non-auditory information. Finally, we describe a less dynamic brain-wide network during sedation, with a higher energy barrier and a lower probability of brain state transitions during sedation. In total, our brain-wide, cellular-resolution analysis shows that sedation leads to quieter, more stable, and less dynamic brain, and that against this background, responses across the auditory processing pathway become sharper and more prominent.

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A vertebrate model to reveal neural substrates underlying the transitions between conscious and unconscious states

Cited by 5 publications

References 44 publications

Synthesis and Characterization of a Diazirine-Based Photolabel of the Nonanesthetic Fropofol

Synthesis and Characterization of a Diazirine-Based Photolabel of the Nonanesthetic Fropofol

Antagonism of propofol anesthesia by alkyl-fluorobenzene derivatives

Brain-wide impacts of sedation on spontaneous activity and auditory processing in larval zebrafish

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