The novel cannabinoid antagonist SM-11 reduces hedonic aspect of food intake through a dopamine-dependent mechanism.

Cannabinoids, endogenous and exogenously administered, are known to positively regulate food intake and energy balance. Since CB1 receptor antagonists reduce food intake and antagonize overweight, we developed a new CB1 receptor antagonist in an attempt to identify a compound with potential application in overeating disorders. The newly developed SM-11 compound dose-dependently decreases food intake in rats by 15-20%. Moreover, SM-11 reduces self-administration of palatable food in both food restricted and ad libitum fed rats, suggesting an action on the hedonic component of food intake. Thus, we next tested the effect of SM-11 on the stimulating properties of the CB1 receptor agonist WIN55,212-2 (WIN) on the electrophysiological activity of Nucleus Accumbens-projecting dopaminergic neurons of the ventral tegmental area (VTA). SM-11 fully and readily antagonized the WIN-induced increments in single spiking and burst firing of antidromically-identified dopamine neurons. When administered to naïve (no WIN-pretreated) rats, SM-11 did not alter basal neuronal activity, thereby suggesting a pure antagonistic profile. SM-11 thus appears as a promising candidate in the search of potential anti-obesity medications.

Proton-minibeam radiation therapy: a proof of concept.

PURPOSE: This Monte Carlo simulation work aims at studying a new radiotherapy approach called proton-minibeam radiation therapy (pMBRT). The main objective of this proof of concept was the evaluation of the possible gain in tissue sparing, thanks to the spatial fractionation of the dose, which could be used to deposit higher and potentially curative doses in clinical cases where tissue tolerances are a limit for conventional methods. METHODS: Monte Carlo simulations (GATE v.6) have been used as a method to calculate the ratio of the peak-to-valley doses (PVDR) for arrays of proton minibeams of 0.7 mm width and several center-to-center distances, at different depths in a water phantom. The beam penumbras were also evaluated as an important parameter for tissue sparing, for example, in the treatment of non-cancer diseases like epilepsy. Two proton energies were considered in this study: a clinically relevant energy (105 MeV) and a very high energy (1 GeV), to benefit from a reduced lateral scattering. For the latter case, an interlaced geometry was also evaluated. RESULTS: Higher or similar PVDR than the ones obtained in x-rays minibeam radiation therapy were achieved in several pMBRT configurations. In addition, for the two energies studied, the beam penumbras are smaller than in the case of Gamma Knife radiosurgery. CONCLUSIONS: The high PVDR obtained for some configurations and the small penumbras in comparison with existing radiosurgery techniques, suggest a potential gain in healthy tissue sparing in this new technique. Biological studies are warranted to assess the effects of pMBRT on both normal and tumoral tissues.