Cannabinoids in the treatment of epilepsy: current status and future prospects

Cannabidiol (CBD) is one of the prominent phytocannabinoids found in Cannabis sativa, differentiating from Δ9-tetrahydrocannabinol (THC) for its non-intoxicating profile and its antianxiety/antipsychotic effects. CBD is a multi-target drug whose anti-convulsant properties are supposed to be independent of endocannabinoid receptor CB1 and might be related to several underlying mechanisms, such as antagonism on the orphan GPR55 receptor, regulation of adenosine tone, activation of 5HT1A receptors and modulation of calcium intracellular levels. CBD is a lipophilic compound with low oral bioavailability (6%) due to poor intestinal absorption and high first-pass metabolism. Its exposure parameters are greatly influenced by feeding status (ie, high fatcontaining meals). It is mainly metabolized by cytochrome P 450 (CYP) 3A4 and 2C19, which it strongly inhibits. A proprietary formulation of highly purified, plant-derived CBD has been recently licensed as an adjunctive treatment for Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS), while it is being currently investigated in tuberous sclerosis complex. The regulatory agencies’ approval was granted based on four pivotal double-blind, placebocontrolled, randomized clinical trials (RCTs) on overall 154 DS patients and 396 LGS ones, receiving CBD 10 or 20 mg/kg/day BID as active treatment. The primary endpoint (reduction in monthly seizure frequency) was met by both CBD doses. Most patients reported adverse events (AEs), generally from mild to moderate and transient, which mainly consisted of somnolence, sedation, decreased appetite, diarrhea and elevation in aminotransferase levels, the last being documented only in subjects on concomitant valproate therapy. The interaction between CBD and clobazam, likely due to CYP2C19 inhibition, might contribute to some AEs, especially somnolence, but also to CBD clinical effectiveness. Cannabidivarin (CBDV), the propyl analogue of CBD, showed anti-convulsant properties in pre-clinical studies, but a plant-derived, purified proprietary formulation of CBDV recently failed the Phase II RCT in patients with uncontrolled focal seizures

Keck Imaging of Binary L Dwarfs

We present Keck near-infrared imaging of three binary L dwarf systems, all of which are likely to be sub-stellar. Two are lithium dwarfs, and a third exhibits an L7 spectral type, making it the coolest binary known to date. All have component flux ratios near 1 and projected physical separations between 5 and 10 AU, assuming distances of 18 to 26 pc from recent measurements of trigonometric parallax. These surprisingly similar binaries represent the sole detections of companions in ten L dwarf systems which were analyzed in the preliminary phase of a much larger dual-epoch imaging survey. The detection rate prompts us to speculate that binary companions to L dwarfs are common, that similar-mass systems predominate, and that their distribution peaks at radial distances in accord both with M dwarf binaries and with the radial location of Jovian planets in our own solar system. To fully establish these conjectures against doubts raised by biases inherent in this small preliminary survey, however, will require quantitative analysis of a larger volume-limited sample which has been observed with high resolution and dynamic range.Comment: LaTex manuscript in 13 pages, 3 postscript figures, Accepted for publication in the Letters of the Astrophysical Journal; Postscript pre-print version available at: http://www.hep.upenn.edu/PORG/papers/koerner99a.p

Effects of the satiety signal oleoylethanolamide on binge-like food consumption in female rats

Several lines of evidence document the association between eating disorders and modern lifestyle, encompassing calorie-rich diets and psychological stress. Binge-eating disorder (BED) is a eating disorder characterized by excessive consumption of food in a short period of time, along with loss of control and psychological distress. Among the networks that partake in the neurobiological bases of BED a large body of evidence supports the activation of the hypothalamic-pituitary-adrenal stress (HPA) axis. Pharmacological treatments for BED are limited thus highlighting the need to identify novel targets that could lead to the development of more effective therapies. A large body of evidence has accumulated on the role played by the lipid signal oleoylethanolamide (OEA) as a pharmacological target for controlling aberrant eating disorders. As a drug, OEA reduces food intake and body weight gain in laboratory rodents by inducing a state of satiety. Additionaly, OEA dampens the hyperactivity of the HPA axis and ameliorates the effects of stress. On the bases of these premises, in the present study we investigated the effects of OEA on high palatable food (HPF) intake in a rat model of BED. Moreover, we assessed the impact of OEA on the corticotropin-releasing factor (CRF) system which plays a critical role in stress and on the oxytocinergic system which is crucial in mediating the pro-satiety effect of OEA. We used female rats with a history of intermittent food restriction which show binge-like palatable food consumption after the exposure to a “frustration stress”. On the test day, we either exposed or did not expose the rats to the sight of the palatable food (frustration stress) before assessing food consumption. OEA was administered at three different doses (2.5, 5, 10 mg/kg i.p.) and HPF intake was monitored over 2h. After the behavioural experiment brains were collected and in-situ hybridization experiment was performed to analyse CRF and oxytocin mRNA expression in selected brain areas. Our results demonstrate that OEA (10 mg/kg) was able to selectively prevent binge eating; the antibinge effect was accompained by a reduction of CRF mRNA within the central-amygdala. Finally, in keeping with our previous observations we found that the antibinge effect of OEA was accompanied by a significant increase of oxytocin mRNA at hypothalamic level. In the current study, we provide for the first time evidence to support that the endogenous fatty-gut lipid OEA exerts a selective inhibitory effects on binge-like eating behavior in female rats, supporting the hypothesis that OEA might represent a novel potential pharmacological target for the treatment of aberrant eating patterns

The ontogeny of haematopoiesis in the marine teleost Leiostomus xanthurus and a comparison of the site of initial haematopoiesis with Opsanus tau

The ontogeny of haematopoiesis in the perciform fish, spot Leiostomus xanthurus, differed from that reported as the norm for fishes, as exemplified by the cypriniform zebrafish Danio rerio, and observed in the batrachoidiform oyster toadfish Opsanus tau. Erythropoiesis in spot was first evident in the head kidney of yolk-sac larvae 3 days after hatching (DAH). No embryonic intermediate cell mass (ICM) of primitive stem cells or blood islands on the yolk were apparent within embryos. Erythrocytes were first evident in circulation near the completion of yolk absorption, c. 5 DAH, when larvae were c. 20 mm notochord length (LN). Erythrocyte abundance increased rapidly with larval development for c. 14 to 16 DAH, then became highly variable following changes in cardiac chamber morphology and volume. Erythrocytic haemoglobin (Hb) was not detected within whole larvae until they were 12 DAH or c. 31 mm LN, well after yolk and oil-globule absorption. The Hb was not quantified until larvae were >47 DAH or >7 mm standard length. The delayed appearance of erythrocytes and Hb in spot was similar to that reported for other marine fishes with small embryos and larvae. In oyster toadfish, a marine teleost that exhibits large embryos and larvae, the ICM and Hb were first evident in two bilateral slips of erythropoietic tissue in the embryos, c. 5 days after fertilization. Soon thereafter, erythrocytes were evident in the heart, and peripheral and vitelline circulation. Initial haematopoiesis in oyster toadfish conformed with that described for zebrafish. While the genes that code for the development of haematopoiesis are conserved among vertebrates, gene expression lacks phylogenetic pattern among fishes and appears to conform more closely with phenotypic expression related to physiological and ecological influences of overall body size and environmental oxygen availability

Preclinical and clinical evidence for a distinct regulation of mu opioid and type 1 cannabinoid receptor genes expression in obesity

Among endogenous signaling networks involved in both rewarding and homeostatic mechanisms of obesity, a relevant role is played by the endocannabinoid (ECS) and the opioid (EOS) systems. We here studied the transcriptional regulation of ECS and EOS genes in the hypothalamus of Diet-induced obesity rats, a preclinical model of obesity, as well as in humans with obesity and healthy controls. A significant and selective increase in type 1 cannabinoid receptor gene (Cnr1) expression was observed at the beginning of obesity development (5 weeks on high fat diet) as well as after 21 weeks of high diet exposure. After 5 weeks on high fat diet, selective up-regulation of mu opioid receptor gene (Oprm1) expression was also observed. Consistently, epigenetic studies showed a selective and significant decrease in DNA methylation at specific CpG sites at both gene promoters in overweight rats, but only after 5 weeks on high fat diet. Moreover, significantly lower levels of DNA methylation were observed at selected CpG sites of both receptor gene promoters, analyzed in peripheral blood mononuclear cells from younger (<30 years old) humans with obesity, as well as in those with shorter time length from disease onset. Taken together, we here provide evidence of selective, synergistic and time-dependent transcriptional regulation of CNR1 and OPRM1 genes in overweight rats, as well as in human subjects. These alterations in genes regulation could contribute to the development of the obese phenotype, and we thus suggest CNR1 and OPRM1 epigenetic modulation as possible biomarkers of obesity development. Due to the reversible nature of the epigenetic hallmark, our data might also open new avenue to early environmental strategies of intervention

Modulation of pain sensitivity by chronic consumption of highly palatable food followed by abstinence: emerging role of fatty acid amide hydrolase

There is a strong relationship between palatable diet and pain sensitivity, and the cannabinoid and opioid systems might play an important role in this correlation. The palatable diet used in many animal models of obesity is the cafeteria (CAF) diet, based on human food with high sugar, salt, and fat content. In this study, we investigated whether long-term exposure to a CAF diet could modify pain sensitivity and explored the role of the cannabinergic system in this modification. Male Sprague–Dawley rats were divided into two groups: one fed with standard chow only (CO) and the other with extended access (EA) to a CAF diet. Hot plate and tail flick tests were used to evaluate pain sensitivity. At the end of a 40-day CAF exposure, EA rats showed a significant increase in the pain threshold compared to CO rats, finding probably due to up-regulation of CB1 and mu-opioid receptors. Instead, during abstinence from palatable foods, EA animals showed a significant increase in pain sensibility, which was ameliorated by repeated treatment with a fatty acid amide hydrolase inhibitor, PF-3845 (10 mg/kg, intraperitoneally), every other day for 28 days. Ex vivo analysis of the brains of these rats clearly showed that this effect was mediated by mu-opioid receptors, which were up-regulated following repeated treatment of PF-3845. Our data add to the knowledge about changes in pain perception in obese subjects, revealing a key role of CB1 and mu-opioid receptors and their possible pharmacological crosstalk and reinforcing the need to consider this modulation in planning effective pain management for obese patients