In This Issue Cite This: ACS Chem. Neurosci. 2017, 8, 2099-2099
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UNCAGING cGMP
beads extracted substantially more MBLAC1 than beads without Cef; target engagement was further validated by competition assay of MBLAC1-containing cell lysates with free Cef prior to incubation. The interaction was further characterized using a technique called backscattering interferometry (BSI), which probes the kinetic and equilibrium properties of ligand-target interactions. It was found that Cef binds MBLAC1 with high specificity and affinity, affirming this protein as a target of interest for further drug discovery.
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Caged compounds are bioactive molecules that, in their “caged” form, are rendered inactive by photochemical protecting groups. Exposure to light removes the protecting group, “uncaging” the molecule, and thus allowing its activity to be controlled in cells using light. In this issue, Agarwal and co-workers (DOI: 10.1021/ acschemneuro.7b00237) develop a caged version of an important signaling molecule in the brain, cyclic guanosine monophosphate (cGMP). Building on their previous work developing a derivative of 7-diethylaminocourmarin (DEAC) called DEAC450, the authors synthesize a DEAC450-cGMP conjugate, generating the first caged cGMP that is photolyzed by blue LED light (473 nm). Intracellular uncaging of DEAC450-cGMP successfully modulated the activation of cyclic gated cation channels in cholinergic interneurons.
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pubs.acs.org/chemneuro
Traumatic brain injury is a serious issue that has recently gained widespread attention for its prevalence (DOI: 10.1021/ acschemneuro.7b00291). Understanding the biochemical changes that occur after injury enables the identification of biomarkers for early diagnosis and treatment. In this issue, Barbacci et al. (DOI: 10.1021/acschemneuro.7b00189) investigate the effects of traumatic brain injury on lipids, which comprise over 50% of brain mass. Using mass spectrometry imaging (MSI), the authors focused on monitoring ceramides, a class of lipids known to be biomarkers of cell death, in the brains of rats postinjury. Brain MS images showed elevated ceramide levels in injured versus noninjured populations and that ceramides primarily localized around the point of injury. Ceramide levels were attenuated upon treatment with dynorphin binding decoy peptide, identifying a therapeutic response.
UNCOVERING NEW CNS DRUG TARGETS
It has recently been reported that the β-lactam antibiotic ceftriaxone (Cef) demonstrates CNS activity independent of its antimicrobial properties. Significantly, Cef has been shown to normalize irregular levels of the signaling molecule glutamate in the CNS by elevating expression of glutamate transporters, which are important drug targets for treatment of neurodegenerative diseases such as ALS and Parkinson’s. Despite its potency, the precise CNS target for Cef remains largely unknown. Here, Retzlaff et al. (DOI: 10.1021/acschemneuro.7b00232) investigate a possible target for Cef engagement in the CNS. In C. elegans, it was previously found that the protein SWIP-10 played a role in modulating glutamine homeostasis. In this work, the mammalian orthologue Metallo-β-lactamase DomainContaining Protein 1 (MBLAC1) was investigated as a possible target for Cef. Drug−protein interactions were assayed using cyanogen bromide conjugated Cef for affinity capture of MBLAC1 from cell lysates. It was found that Cef-immobilized © 2017 American Chemical Society
VISUALIZING TRAUMATIC BRAIN INJURY
Published: October 18, 2017 2099
DOI: 10.1021/acschemneuro.7b00381 ACS Chem. Neurosci. 2017, 8, 2099−2099
