Molecular targets of cannabidiol in neurological disorders

Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD’s beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular phar- macology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD’s relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeu- tics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent with modulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug’s action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excluding unlikely and implausible targets, the remaining molecular targets of CBD with plausible evidence for involvement in therapeutic effects in neurological disorders (e.g., voltage-dependent anion channel 1, G protein-coupled receptor 55, CaV3.x, etc.) are associated with either the regulation of, or responses to changes in, intracellular calcium levels. While no causal proof yet exists for CBD’s effects at these targets, they represent the most probable for such investigations and should be prioritized in further studies of CBD’s therapeutic mechanism of action.

Trafficking and signaling of G protein-coupled receptors in the nervous system: implications for disease and therapy

G protein-coupled receptors (GPCRs) are expressed throughout the nervous system where they regulate multiple physiological processes, participate in neurological diseases, and are major targets for therapy. Given that many GPCRs respond to neurotransmitters and hormones that are present in the extracellular fluid and which do not readily cross the plasma membrane, receptor trafficking to and from the plasma membrane is a critically important determinant of cellular responsiveness. Moreover, trafficking of GPCRs throughout the endosomal system can initiate signaling events that are mechanistically and functionally distinct from those operating at the plasma membrane. This review discusses recent advances in the relationship between signaling and trafficking of GPCRs in the nervous system. It summarizes how receptor modifications influence trafficking, discusses mechanisms that regulate GPCR trafficking to and from the plasma membrane, reviews the relationship between trafficking and signaling, and considers the implications of GPCR trafficking to drug development.

The 'direct costs' of livestock disease: The development of a system of models for the analysis of 30 endemic livestock diseases in Great Britain

The 'direct costs' attributable to 30 different endemic diseases of farm animals in Great Britain are estimated using a standardised method to construct a simple model for each disease that includes consideration of disease prevention and treatment costs. The models so far developed provide a basis for further analyses including cost-benefit analyses for the economic assessment of disease control options. The approach used reflects the inherent livestock disease information constraints, which limit the application of other economic analytical methods. It is a practical and transparent approach that is relatively easily communicated to veterinary scientists and policy makers. The next step is to develop the approach by incorporating wider economic considerations into the analyses in a way that will demonstrate to policy makers and others the importance of an economic perspective to livestock disease issues.

Updated estimates of the costs associated with thirty four endemic livestock diseases in Great Britain: A note

This Note outlines the further development of a system of models for the estimation of the costs of livestock diseases first presented by Bennett (2003). The models have been developed to provide updated and improved estimates of the costs associated with 34 endemic diseases of livestock in Great Britain, using border prices and including assessments of the impact of diseases on human health and animal welfare. Results show that, of the diseases studied, mastitis has the highest costs for cattle diseases, enzootic abortion for sheep diseases, swine influenza for pig diseases and salmonellosis for poultry diseases.

The survival advantage of milk and dairy consumption: An overview of evidence from cohort studies of vascular diseases, diabetes and cancer

Objectives: To conduct it detailed evaluation, with meta-analyses, of the published evidence on milk and dairy consumption and the incidence of vascular diseases and diabetes. Also to summarise the evidence on milk and dairy consumption and cancer reported by the World Cancer Research Fund and then to consider the relevance of milk and dairy consumption to survival in the UK, a typical Western community. Finally, published evidence on relationships with whole milk and fat-reduced milks was examined. Methods: Prospective cohort studies of vascular disease and diabetes with baseline data on milk or dairy consumption and a relevant disease outcome were identified by searching MEDLINE, and reference lists in the relevant published reports. Meta-analyses of relationships in these reports were conducted. The likely effect of milk and dairy consumption on survival was then considered, taking into account the results of published overviews of relationships of these foods with cancer. Results: From meta-analysis of 15 studies the relative risk of stroke and/or heart disease in subjects with high milk or dairy consumption was 0.84 (95% CI 0.76, 0,93) and 0.79 (0.75, 0.82) respectively, relative to the risk in those with low consumption. Four studies reported incident diabetes as an outcome, and the relative risk in the Subjects with the highest intake of milk or diary foods was 0.92 (0.86, 0.97). Conclusions: Set against the proportion of total deaths attributable to the life-threatening diseases in the UK, vascular disease, diabetes and cancer, the results of meta-analyses provide evidence of an overall survival advantage from the consumption of milk and dairy foods.

Influence of foliar diseases and their control by fungicides on grain yield and quality in wheat

Twenty-eight field experiments on sandy-loam soils in the UK (1982-2003) are reviewed by relating the extension of the green area duration of the flag leaf (GLADF) by fungicides to effects on yield and quality of winter wheat. Over all experiments mean grain yield = 8.85t ha(-1) at 85% DM. With regards quality, mean values were: thousand grain weight (TGW) = 44.5 g; specific weight (SWT) = 76.9 kg hl(-1); crude protein concentration (CP (N x 5.7)) = 12.5 % DM; Hagberg falling number (HFN) = 285 s; and sodium dodecyl sulphate (SDS)-sedimentation volume = 69ml. For each day (d) that fungicides increased GLADF there were associated average increases in yield (0.144 1 ha(-1) d(-1), se 0.0049, df = 333), TGW (0.56 gd(-1), se = 0.017) and SWT (0.22 kg hl(-1) d(-1), se 0.011). Some curvature was evident in all these relationships. When GLADF was delayed beyond 700 degrees Cd after anthesis, as was possible in cool wet seasons, responses were curtailed, or less reliable. Despite this apparent terminal sink limitation, fungicide effects on sink size, eg endosperm cell numbers or maximum water mass per grain, were not prerequisites for large effects on grain yield, TGW or SWT. Fungicide effects on CP were variable. Although the average response of CP was negative (-0.029%DM/d; se = 0.00338), this depended on cultivar and disease controlled. Controlling biotrophs such as rusts, (Puccinia spp.) tended to increase CP, whereas controlling a more necrotrophic pathogen (Septoria tritici) usually reducedCP. Irrespective of pathogen controlled, delaying senescence of the flag leaf was associated with increased nitrogen yields in the grain (averaging 2.24 kg N ha-1 d(-1), se = 0.0848) due to both increased N uptake into the above ground crop, and also more efficient remobilisation of N from leaf laminas. When sulphur availability appeared to be adequate, fungicide x cultivar interactions were similar on S as for CP, although N:S ratios tended to decline (i.e. improve for bread making) when S. tritici was controlled. On average, SDS-sedimentation volume declined (-0. 18 ml/d, se = 0.027) with increased GLADF, broadly commensurate with the average effect on CP. Hagberg falling number decreased as fungicide increased GLADF (-2.73 s/d, se = 0.178), indicating an increase in alpha-amylase activity.

Effects of straw and silicon soil amendments on some foliar and stem-base diseases in pot-grown winter wheat

Four foliar and two stem-base pathogens were inoculated onto wheat plants grown in different substrates in pot experiments. Soils from four different UK locations were each treated in three ways: (i) straw incorporated in the field at 10 t ha−1 several months previously; (ii) silicon fertilization at 100 mg L−1 during the experiment; and (iii) no amendments. A sand and vermiculite mix was used with and without silicon amendment. The silicon treatment increased plant silica concentrations in all experiments, but incorporating straw was not associated with raised plant silica concentrations. Blumeria graminis and Puccinia recondita were inoculated by shaking infected plants over the test plants, followed by suitable humid periods. The silicon treatment reduced powdery mildew (B. graminis) substantially in sand and vermiculite and in two of the soils, but there were no effects on the slight infection by brown rust (P. recondita). Phaeosphaeria nodorum and Mycosphaerella graminicola were inoculated as conidial suspensions. Leaf spot caused by P. nodorum was reduced in silicon-amended sand and vermiculite; soil was not tested. Symptoms of septoria leaf blotch caused by M. graminicola were reduced by silicon amendment in a severely infected sand and vermiculite experiment but not in soil or a slightly infected sand and vermiculite experiment. Oculimacula yallundae (eyespot) and Fusarium culmorum (brown foot rot) were inoculated as agar plugs on the stem base. Severity of O. yallundae was reduced by silicon amendment of two of the soils but not sand and vermiculite; brown foot rot symptoms caused by F. culmorum were unaffected by silicon amendment. The straw treatment reduced severity of powdery mildew but did not detectably affect the other pathogens. Both straw and silicon treatments appeared to increase plant resistance to all diseases only under high disease pressure.

Who knows best? Awareness of divided attention difficulty in a neurological rehabilitation setting

Objective: To explore whether patients relearning to walk after acquired brain injury and showing cognitive-motor interference were aware of divided attention difficulty; whether their perceptions concurred with those of treating staff. Design: Patients and neurophysiotherapists (from rehabilitation and disabled wards) completed questionnaires. Factor analyses were applied to responses. Correlations between responses, clinical measures and experimental decrements were examined. Results: Patient/staff responses showed some agreement; staff reported higher levels of perceived difficulty; responses conformed to two factors. One factor (staff/patients alike) reflected expectations about functional/motor status and did not correlate with decrements. The other factor (patients) correlated significantly with dual-task motor decrement, suggesting some genuine awareness of difficulty (cognitive performance prioritized over motor control). The other factor (staff) correlated significantly with cognitive decrement (gait prioritized over sustained attention). Conclusions: Despite some inaccurate estimation of susceptibility; patients and staff do exhibit awareness of divided attention difficulty, but with a limited degree of concurrence. In fact, our results suggest that patients and staff may be sensitive to different aspects of the deficit. Rather than 'Who knows best?', it is a question of 'Who knows what?.