The endocannabinoid system:no longer anonymous in the control of nitrergic signalling?

The endocannabinoid system (ECS) is a key cellular signalling system which has been implicated in the regulation of diverse cellular functions. Importantly, growing evidence suggests that the biological actions of the ECS may, in part, be mediated through its ability to regulate the production and/or release of nitric oxide, a ubiquitous bioactive molecule which functions as a versatile signalling intermediate. Herein, we review and discuss evidence pertaining to ECS mediated regulation of nitric oxide production, the involvement of reactive nitrogen species in regulating ECS induced signal transduction, as well as highlighting emerging work supporting nitrergic modulation of ECS function. Importantly, the studies outlined reveal that interactions between the ECS and nitrergic signalling systems can be both stimulatory and inhibitory in nature, depending on cellular context. Moreover, such crosstalk may act to maintain proper cell function, whereas abnormalities in either system can undermine cellular homeostasis and contribute to various pathologies associated with their dysregulation. Consequently, future studies targeting these signalling systems may provide new insights into the potential role of the ECS - nitric oxide signalling axis in disease development, and/or lead to the identification of novel therapeutic targets for the treatment of nitrosative stress-related neurological, cardiovascular and metabolic disorders

Ginkgo Biloba Extract Ameliorates Oxidative Phosphorylation Performance and Rescues Aβ-Induced Failure

Energy deficiency and mitochondrial failure have been recognized as a prominent, early event in Alzheimer's disease (AD). Recently, we demonstrated that chronic exposure to amyloid-beta (Abeta) in human neuroblastoma cells over-expressing human wild-type amyloid precursor protein (APP) resulted in (i) activity changes of complexes III and IV of the oxidative phosphorylation system (OXPHOS) and in (ii) a drop of ATP levels which may finally instigate loss of synapses and neuronal cell death in AD. Therefore, the aim of the present study was to investigate whether standardized Ginkgo biloba extract LI 1370 (GBE) is able to rescue Abeta-induced defects in energy metabolism

Small molecule inhibitors of Aβ-aggregation and neurotoxicity

Alzheimer disease (AD) is characterized pathologically by extracellular amyloid deposits composed of Aβ peptide, neurofibrillary tangles (NFTs) made up of hyperphosphorylated tau, and a deficit of cholinergic neurons in the basal forebrain. Presently, only symptomatic therapies are available for the treatment of AD and these therapies have a limited time frame of utility. Amyloid disorders represent the effects of chronic Aβ production and are not a secondary pathological effect caused by a distant trigger; therefore targeting Aβ is a viable pursuit. In this review, we will discuss the various small molecule anti-aggregation inhibitors that have been reported in the literature, with emphasis on compounds that are presently being investigated in clinical trials

A Semantic Similarity Measure for Scholarly Document Based on the Study of n-gram

The performance of information retrieval systems is closely related to the ability of similarity measures to accurately determine the similarity value between documents or between a query and a document. In this paper, the issue of similarity measures in the context of scholarly documents is addressed. A semantic similarity measure is proposed. This similarity measure is able to exploit the metadata contained in the scientific articles, as well as the important n-grams identified in them. To evaluate the accuracy of our similarity measure, a dataset of articles is built as well as their similarity values manually estimated by human experts. Experiments performed on this dataset using Pearson correlation show that the similarity values obtained using the proposed measure are very close to those estimated by human experts.</jats:p

Selective Inhibition of Alpha/Beta-Hydrolase Domain 6 Attenuates Neurodegeneration, Alleviates Blood Brain Barrier Breakdown, and Improves Functional Recovery in a Mouse Model of Traumatic Brain Injury

2-arachidonylglycerol (2-AG) is the most abundant endocannabinoid in the central nervous system and is elevated after brain injury. Because of its rapid hydrolysis, however, the compensatory and neuroprotective effect of 2-AG is short-lived. Although inhibition of monoacylglycerol lipase, a principal enzyme for 2-AG degradation, causes a robust increase of brain levels of 2-AG, it also leads to cannabinoid receptor desensitization and behavioral tolerance. Alpha/beta hydrolase domain 6 (ABHD6) is a novel 2-AG hydrolytic enzyme that accounts for a small portion of 2-AG hydrolysis, but its inhibition is believed to elevate the levels of 2-AG within the therapeutic window without causing side effect. Using a mouse model of traumatic brain injury (TBI), we found that post-insult chronic treatment with a selective ABHD6 inhibitor WWL70 improved motor coordination and working memory performance. WWL70 treatment reduced lesion volume in the cortex and neurodegeneration in the dendate gyrus. It also suppressed the expression of inducible nitric oxide synthase and cyclooxygenase-2 and enhanced the expression of arginase-1 in the ipsilateral cortex at 3 and 7 days post-TBI, suggesting microglia/macrophages shifted from M1 to M2 phenotypes after treatment. The blood-brain barrier dysfunction at 3 and 7 days post-TBI was dramatically reduced. Furthermore, the beneficial effects of WWL70 involved up-regulation and activation of cannabinoid type 1 and type 2 receptors and were attributable to the phosphorylation of the extracellular signal regulated kinase and the serine/threonine protein kinase AKT. This study indicates that the fine-tuning of 2-AG signaling by modulating ABHD6 activity can exert anti-inflammatory and neuroprotective effects in TBI

Genetic variants of methionine metabolism and X-ALD phenotype generation: results of a new study sample

X-linked adrenoleukodystrophy (X-ALD) is the most common inherited leukodystrophy. Nevertheless, no genotype-phenotype correlation has been established so far. Unidentified modifier genes or other cofactors are suspected to modulate phenotype and prognosis. We recently described polymorphisms of methionine metabolism as possible disease modifiers in X-ALD. To retest these findings, we analyzed 172 new DNA samples of X-ALD patients from different populations (France, Germany, USA, China) by genotyping eight genetic variants of methionine metabolism, including DHFR c.594+59del19bp, CBS c.844_855ins68, MTR c.2756A>G, MTHFR c.677C>T and c.1298A>C, MTRR c.60A>G, RFC1 c.80G>A, and Tc2 c.776C>G. We compared three X-ALD phenotypes: childhood-onset cerebral demyelinating inflammatory type (CCALD; n = 82), adulthood onset with focal cerebral demyelination (ACALD; n = 38), and adulthood onset without cerebral demyelination (AMN; n = 52). The association of genotypes and phenotypes was analyzed with univariate two-sided Pearson's chi(2). In the comparison between AMN and CCALD, the G allele of Tc2 c.776C>G was associated with X-ALD phenotypes (chi(2) = 6.1; P = 0.048). The prevalence of the GG genotype of Tc2 c.776C>G was higher in patients with CNS demyelination compared to those without CNS demyelination (chi(2) = 4.42; P = 0.036). The GG genotype was also more frequent in CCALD compared to AMN (chi(2) = 4.7; P = 0.031). The other polymorphisms did not show any significant associations in this study sample. Whereas the influence of other polymorphisms of methionine metabolism was not confirmed, the present study supports the previously made observation that the Tc2 genotype contributes to X-ALD phenotype generation