The Cannabinoid-Like Compound, VSN16R, Acts on Large Conductance, Ca2+-Activated K+ Channels to Modulate Hippocampal CA1 Pyramidal Neuron Firing

Large conductance, Ca2+-activated K+ (BKCa) channels are widely expressed in the central nervous system, where they regulate action potential duration, firing frequency and consequential neurotransmitter release. Moreover, drug action on, mutations to, or changes in expression levels of BKCa can modulate neuronal hyperexcitability. Amongst other potential mechanisms of action, cannabinoid compounds have recently been reported to activate BKCa channels. Here, we examined the effects of the cannabinoid-like compound (R,Z)-3-(6-(dimethylamino)-6-oxohex-1-en-1-yl)-N-(1-hydroxypropan-2-yl) benzamide (VSN16R) at CA1 pyramidal neurons in hippocampal ex vivo brain slices using current clamp electrophysiology. We also investigated effects of the BKCa channel blockers iberiotoxin (IBTX) and the novel 7-pra-martentoxin (7-Pra-MarTx) on VSN16R action. VSN16R (100 μM) increased first and second fast after-hyperpolarization (fAHP) amplitude, decreased first and second inter spike interval (ISI) and shortened first action potential (AP) width under high frequency stimulation protocols in mouse hippocampal pyramidal neurons. IBTX (100 nM) decreased first fAHP amplitude, increased second ISI and broadened first and second AP width under high frequency stimulation protocols; IBTX also broadened first and second AP width under low frequency stimulation protocols. IBTX blocked effects of VSN16R on fAHP amplitude and ISI. 7-Pra-MarTx (100 nM) had no significant effects on fAHP amplitude and ISI but, unlike IBTX, shortened first and second AP width under high frequency stimulation protocols; 7-Pra-MarTx also shortened second AP width under low frequency stimulation protocols. However, in the presence of 7-Pra-MarTx, VSN16R retained some effects on AP waveform under high frequency stimulation protocols; moreover, VSN16R effects were revealed under low frequency stimulation protocols. These findings demonstrate that VSN16R has effects in native hippocampal neurons consistent with its causing an increase in initial firing frequency via activation of IBTX-sensitive BKCa channels. The differential pharmacological effects described suggest that VSN16R may differentially target BKCa channel subtypes

Intake and time dependence of blueberry flavonoid–induced improvements in vascular function: a randomized, controlled, double-blind, crossover intervention study with mechanistic insights into biological activity

Background: There are very limited data regarding the effects of blueberry flavonoid intake on vascular function in healthy humans. Objectives: We investigated the impact of blueberry flavonoid intake on endothelial function in healthy men and assessed potential mechanisms of action by the assessment of circulating metabolites and neutrophil NADPH oxidase activity. Design: Two randomized, controlled, double-blind, crossover human-intervention trials were conducted with 21 healthy men. Initially, the impact of blueberry flavonoid intake on flow-mediated dilation (FMD) and polyphenol absorption and metabolism was assessed at baseline and 1, 2, 4, and 6 h after consumption of blueberry containing 766, 1278, and 1791 mg total blueberry polyphenols or a macronutrient- and micronutrient-matched control drink (0 mg total blueberry polyphenols). Second, an intake-dependence study was conducted (from baseline to 1 h) with 319, 637, 766, 1278, and 1791 mg total blueberry polyphenols and a control. Results: We observed a biphasic time-dependent increase in FMD, with significant increases at 1–2 and 6 h after consumption of blueberry polyphenols. No significant intake-dependence was observed between 766 and 1791 mg. However, at 1 h after consumption, FMD increased dose dependently to ≤766 mg total blueberry polyphenol intake, after which FMD plateaued. Increases in FMD were closely linked to increases in circulating metabolites and by decreases in neutrophil NADPH oxidase activity at 1–2 and 6 h. Conclusions: Blueberry intake acutely improves vascular function in healthy men in a time- and intake-dependent manner. These benefits may be mechanistically linked to the actions of circulating phenolic metabolites on neutrophil NADPH oxidase activity. This trial was registered at clinicaltrials.gov as NCT01292954 and NCT01829542.</p

Unpublished description by M.R. James of Cambridge, University Library, MS Gg.1.21 (Acts of the Apostles, with gloss)

Between 1926 and 1930, M.R. James was employed by Cambridge University Library to prepare descriptions of its medieval manuscripts, with a view to superseding the information provided by the five-volume catalogue published between 1856 and 1867. In all, James prepared descriptions of over 1,200 of the Library's manuscripts. However, the unfinished (and often hurried) state of his work, together with the difficulty of deciphering his handwriting, meant that plans to publish his work in the years immediately after his death in 1936 had to be abandoned. Between 2002 and 2011, transcriptions of James's notes were compiled piecemeal by University Library staff, with a view to making them more widely available, but also to aid the preservation of the originals (now accessioned into the University Archives as UA ULIB 7/3/74). This transcription was prepared by Dr Martin Blake. For further information, see: James Freeman, 'Unpublished descriptions of western medieval manuscripts at Cambridge University Library', Transactions of the Cambridge Bibliographical Society (2020); James Freeman, 'M.R. James's descriptions', Cambridge University Library Special Collections Subject Guide (https://www.lib.cam.ac.uk/collections/departments/manuscripts-university-archives/subject-guides/medieval-manuscripts-2/mr); Jayne Ringrose, 'The legacy of M.R. James in Cambridge University Library', in The legacy of M.R. James: Papers from the 1995 Cambidge Symposium, ed. by Lynda Dennison (Donington: Shaun Tyas, 2001), pp. 23-36