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Experiencing traumatic childhood is a risk factor for developing substance use disorder, but the mechanisms that underlie this relationship have not been determined. Adverse childhood experiences affect the immune system, and the immune system mediates the effects of psychostimulants. However, whether this system is involved in the etiology of substance use disorder in individuals who have experienced early life stress is unknown. METHODS: In this study, we performed a series of ex vivo and in vivo experiments in mice and humans to define the function of the immune system in the early life stress-induced susceptibility to the neurobehavioral effects of cocaine. RESULTS: We provide evidence that exposure to social stress at an early age permanently sensitizes the peripheral (splenocytes) and brain (microglia) immune responses to cocaine in mice. In the brain, microglial activation in the ventral tegmental area of social-stress mice was associated with functional alterations in dopaminergic neurotransmission, as measured by whole-cell voltage clamp recordings in dopamine neurons. Notably, preventing immune activation during the social-stress exposure reverted the effects of dopamine in the ventral tegmental area and the cocaine-induced behavioral phenotype to control levels. In humans, cocaine modulated toll-like receptor 4-mediated innate immunity, an effect that was enhanced in those addicted to cocaine who had experienced a difficult childhood. CONCLUSIONS: Collectively, our findings demonstrate that sensitization to cocaine in early life-stressed individuals involves brain and peripheral immune responses and that this mechanism is shared between mice and humans

Background: Neurofibrillary tangles and senile plaques are hallmarks of Alzheimer's disease (AD) although the molecular basis of their coexistence remains elusive. The peptidyl-prolyl cis/trans isomerase Pin1 acts on both tau and amyloid precursor protein to regulate their functions by influencing tau phosphorylation and amyloid precursor protein processing. Objective: In order to identify potential biomarkers for AD in easily accessible cells and to gain insight into the relationship between the brain and peripheral compartments in AD pathology, we investigated Pin1 expression and activity in the peripheral blood mononuclear cells of subjects with late-onset AD (LOAD) and age-matched controls (CT). Methods: Gene and protein expression, promoter methylation, Ser 16 phosphorylation and activity of Pin1 were evaluated in 32 samples from subjects with LOAD and in 28 samples from CT. Results: In LOAD subjects, there was a statistically significant reduction in Ser 16 phosphorylation (-30%; p = 0.041) and promoter methylation (-8%; p = 0.001), whereas Pin1 expression was significantly increased (+74%; p = 0.018). Conclusion: The modifications of Pin1 found in LOAD subjects support its involvement in the pathogenesis of the disease with an important role being played by epigenetic mechanisms. Copyright © 2012 S. Karger AG, Basel.

Functional impairment after development of focal CNS lesions depends highly on damage that occurs in regions that are remote but functionally connected to the primary lesion site. These remote effects include cell death and structural changes, and they are important predictors of outcome in several pathologies, such as stroke, multiple sclerosis, and brain trauma. A greater understanding of the neuropathological mechanisms that exist in regions that are remote from focal primary lesions is therefore essential for the development of neuroprotective strategies. Endocannabinoids constitute a novel class of lipids that regulate mammalian cell apoptosis and the pathogenesis of neuroinflammatory and neurodegenerative diseases. In addition to well-described pharmacological actions in the brain, such as analgesia, hypokinesia, and hypothermia, endocannabinoids have been recently reported to control neuronal cell fate in various neuropathological conditions. Following brain injury, endocannabinoids are released, causing both protective and degenerative effects. Several hypotheses have been proposed to explain their role, but the mechanisms by which they act are largely unknown. New evidence indicates that the endocannabinoid system is a key participant in the determination of cell fate in remote cell death and its associated mechanisms. This review addresses recent findings on endocannabinoid function, focusing particularly on the relationships between the nitrergic, purinergic, and endocannabinoid systems.

A recent phase 1 trial of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474 led to the death of one volunteer and produced mild-to-severe neurological symptoms in four others. Although the cause of the clinical neurotoxicity is unknown, it has been postulated, given the clinical safety profile of other tested FAAH inhibitors, that off-target activities of BIA 10-2474 may have played a role. Here we use activity-based proteomicmethods to determine the protein interaction landscape of BIA 10-2474 in human cells and tissues. This analysis revealed that the drug inhibits several lipases that are not targeted by PF04457845, a highly selective and clinically tested FAAH inhibitor. BIA 10-2474, but not PF04457845, produced substantial alterations in lipid networks in human cortical neurons, suggesting that promiscuous lipase inhibitors have the potential to cause metabolic dysregulation in the nervous system.

Several G protein-associated receptors and synaptic proteins function within lipid rafts, which are subdomains of the plasma membranes that contain high concentrations of cholesterol. In this study we addressed the possible role of lipid rafts in the control of endocannabinoid system in striatal slices. Disruption of lipid rafts following cholesterol depletion with methyl-beta-cyclodestrin (MCD) failed to affect synthesis and degradation of anandamide, while it caused a marked increase in the synthesis and concentration of 2-arachidonoylglycerol (2-AG), as well as in the binding activity of cannabinoid CB1 receptors. Surprisingly, endogenous 2-AG-mediated control of GABA transmission was not potentiated by MCD treatment and, in contrast, neither basal nor 3,5-Dihydroxyphenylglycine-stimulated 2-AG altered GABA synapses in cholesterol-depleted slices. Synaptic response to the cannabinoid CB1 receptor agonist HU210 was however intact in MCD-treated slices, indicating that reduced sensitivity of cannabinoid CB1 receptors does not explain why endogenous 2-AG is ineffective in inhibiting striatal GABA transmission after cholesterol depletion. Confocal microscopy analysis suggested that disruption of raft integrity by MCD might uncouple metabotropic glutamate 5-CB1 receptor interaction by altering the correct localization of both receptors in striatal neuron elements. In conclusion, our data indicate that disruption of raft integrity causes a complex alteration of the endocannabinoid signalling in the striatum.

Endocannabinoids are neuroprotective in vivo and in vitro, but the mechanisms by which they act are largely unknown. The present study addressed the role of cannabinoid receptors during remote cell death of central neurons in a model that is based on cerebellar lesions. A lesion in one cerebellar hemisphere induced remote cell death and type 2 cannabinoid receptor (CB2R) expression in contralateral precerebellar neurons. Of the selective agonists and antagonists that modulated cannabinoid receptor activity, we found that the CB2R agonist JWH-015 reduced neuronal loss and cytochrome-c release, leading to neurological recovery; these effects were reversed by the selective CB2R antagonist SR144528. Analysis of CB2R-triggered signal transduction demonstrated that in axotomized neurons, CB2R regulated Akt and JNK phosphorylation through a PI3K-dependent pathway, whereas other major signaling routes that are dependent on CB2R, such as ERK1/2 and p38, were not involved. This result was corroborated by the observation that the selective PI3K inhibitor LY294002 blocked the CB2R stimulation effects on neuronal survival as well as Akt and JNK phosphorylation levels. Together, these data demonstrate that axonal damage induces CB2R expression in central neurons and that stimulation of this receptor has a neuroprotective effect that is achieved through PI3K/Akt signaling.

Low-cost tungsten monometallic catalysts containing variable amounts of metal (4.5, 7.1 and 8.5%W) were prepared by impregnating alumina with ammonium metatungstate as an inexpensive precursor. The catalysts were characterized using ICP, XPS, XRD, TPR and hydrogen chemisorption. These techniques revealed mainly WO3-Al2O3 (W6+) species on the surface. The effects of the content of W nanoparticles and reaction temperature on activity and selectivity for the partial hydrogenation of 3-hexyne, a non-terminal alkyne, were assessed under moderate conditions of temperature and pressure. The monometallic catalysts prepared were found to be active and stereoselective for the production of (Z )-3-hexene, had the following order: 7.1WN/A > 8.5 WN/A ≥ 4.5 WN/A. Additionally, the performance of the synthesized xWN/A catalysts exhibited high sensitivity to temperature variation. In all cases, the maximum 3-hexyne total conversion and selectivity was achieved at 323 K. The performance of the catalysts was considered to be a consequence of two phenomena: a) the electronic effects, related to the high charge of W (+6), causing an intensive dipole moment in the hydrogen molecule (van der Waals forces) and leading to heterolytic bond rupture; the H+ and H- species generated approach a 3-hexyne adsorbate molecule and cause heterolytic rupture of the C≡C bond into C- = C+; and b) steric effects related to the high concentration of WO3 on 8.5WN/A that block the Al2O3 support. Catalyst deactivation was detected, starting at about 50 min of reaction time. Electrodeficient W6+ species are responsible for the formation of green oil at the surface level, blocking pores and active sites of the catalyst, particularly at low reaction temperatures (293 and 303 K). The resulting best catalyst, 7.1WN/A, has low fabrication cost and high selectivity for (Z )-3-hexene (94%) at 323 K. This selectivity is comparable to that of the classical and more expensive industrial Lindlar catalyst (5 wt% Pd). The