Nonpsychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability

Epilepsy is the most common neurological disorder, with over 50 million people worldwide affected. Recent evidence suggests that the transient receptor potential cation channel subfamily V member 1 (TRPV1) may contribute to the onset and progression of some forms of epilepsy. Since the two nonpsychotropic cannabinoids cannabidivarin (CBDV) and cannabidiol (CBD) exert anticonvulsant activity in vivo and produce TRPV1-mediated intracellular calcium elevation in vitro, we evaluated the effects of these two compounds on TRPV1 channel activation and desensitization and in an in vitro model of epileptiform activity. Patch clamp analysis in transfected HEK293 cells demonstrated that CBD and CBDV dose-dependently activate and rapidly desensitize TRPV1, as well as TRP channels of subfamily V type 2 (TRPV2) and subfamily A type 1 (TRPA1). TRPV1 and TRPV2 transcripts were shown to be expressed in rat hippocampal tissue. When tested on epileptiform neuronal spike activity in hippocampal brain slices exposed to a Mg2+-free solution using multielectrode arrays (MEAs), CBDV reduced both epileptiform burst amplitude and duration. The prototypical TRPV1 agonist, capsaicin, produced similar, although not identical effects. Capsaicin, but not CBDV, effects on burst amplitude were reversed by IRTX, a selective TRPV1 antagonist. These data suggest that CBDV antiepileptiform effects in the Mg2+-free model are not uniquely mediated via activation of TRPV1. However, TRPV1 was strongly phosphorylated (and hence likely sensitized) in Mg2+-free solution-treated hippocampal tissue, and both capsaicin and CBDV caused TRPV1 dephosphorylation, consistent with TRPV1 desensitization. We propose that CBDV effects on TRP channels should be studied further in different in vitro and in vivo models of epilepsy.

First Results with the RISING active stopper

This paper outlines some of the physics opportunities available with the GSI RISING active stopper and presents preliminary results from an experiment aimed at performing beta-delayed gamma-ray spectroscopic studies in heavy-neutron-rich nuclei produced following the projectile fragmentation of a 1 GeV per nucleon 208Pb primary beam. The energy response of the silicon active stopping detector for both heavy secondary fragments and beta-particles is demonstrated and preliminary results on the decays of neutron-rich Tantalum (Ta) to Tungsten (W) isotopes are presented as examples of the potential of this technique to allow new structural studies in hitherto experimentally unreachable heavy, neutron-rich nuclei. The resulting spectral information inferred from excited states in the tungsten daughter nuclei are compared with results from axially symmetric Hartree–Fock calculations of the nuclear shape and suggest a change in ground state structure for the N = 116 isotone 190W compared to the lighter isotopes of this element.

New insights into the structure of exotic nuclei using the RISING active stopper

This conference paper outlines the operation and some of the preliminary physics results using the GSI RISING active stopper. Data are presented from an experiment using combined isomer and beta‐delayed gamma‐ray spectroscopy to study low‐lying spectral and decay properties of heavy‐neutron‐rich nuclei around A∼190 produced following the relativistic projectile fragmentation of 208Pb primary beam. The response of the RISING active stopper detector is demonstrated for both the implantation of heavy secondary fragments and in‐situ decay of beta‐particles. Beta‐delayed gamma‐ray spectroscopy following decays of the neutron‐rich nucleus 194Re is presented to demonstrate the experimental performance of the set‐up. The resulting information inferred from excited states in the W and Os daughter nuclei is compared with results from Skyrme Hartree‐Fock predictions of the evolution of nuclear shape.

Blockade of ActRIIB signaling triggers muscle fatigability and metabolic myopathy

Myostatin regulates skeletal muscle size via the activin receptor IIB (ActRIIB). However, its effect on muscle energy metabolism and energy dependent muscle function remains largely unexplored. This question needs to be solved urgently since various therapies for neuromuscular diseases based on blockade of ActRIIB signaling are being developed. Here we show in mice that four months of pharmacological abrogation of ActRIIB signaling by treatment with soluble ActRIIB-Fc triggers extreme muscle fatigability. This is associated with elevated serum lactate levels and a severe metabolic myopathy in the mdx mouse, an animal model of Duchenne muscular dystrophy. Blockade of ActRIIB signaling down-regulates Porin, a crucial ADP/ATP shuttle between cytosol and mitochondrial matrix leading to a consecutive deficiency of oxidative phosphorylation as measured by in vivo Phophorus Magnetic Resonance Spectroscopy (31P-MRS). Further, ActRIIB blockade reduces muscle capillarization, which further compounds the metabolic stress. We show that ActRIIB regulates key determinants of muscle metabolism, such as Pparβ, Pgc1α, and Pdk4 thereby optimizing different components of muscle energy metabolism. In conclusion, ActRIIB signaling endows skeletal muscle with high oxidative capacity and low fatigability. The severe metabolic side effects following ActRIIB blockade caution against deploying this strategy, at least in isolation, for treatment of neuromuscular disorders.