Uncontrolled blood pressure and therapeutic inertia in treated hypertensive patients: A retrospective cohort study using a UK general practice database.

Uncontrolled blood pressure (BP) and therapeutic inertia pose significant challenges in effectively managing hypertension. This study objective was to quantify levels of uncontrolled BP and therapeutic inertia among patients treated for hypertension in primary care. This retrospective cohort study used data recorded by general practitioners from the UK Clinical Practice Research Datalink database. Adults with primary hypertension who received a recorded prescription for any antihypertensive drug between January 2015 and June 2017 (index date) were included, with a follow-up of 18 months. Primary outcomes included the percentage of patients with uncontrolled BP (defined as systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg) and of apparent therapeutic inertia (defined as two consecutive uncontrolled BP records without treatment change) during follow-up. Finally, of 581 260 patients receiving antihypertensive drug(s), 37.2% (n = 216 014) had uncontrolled BP at the index date and 30.3% (n = 175 955) had no record of BP at this date. During follow-up, 59.2% had ≥1 record of uncontrolled BP, in 22% all records showed uncontrolled BP, and 12.8% had no record of BP. Among those with uncontrolled BP at the index date, 72.9% had ≥1 record of uncontrolled BP during follow-up, and in 28.3% all records showed uncontrolled BP. Therapeutic inertia was observed in 33.1% of patients overall, and in 55.7% of those with uncontrolled BP at the index date. In conclusion, BP recording was infrequent, possibly reflecting both a low frequency of measurement and potential under-recording. Uncontrolled BP and therapeutic inertia appear to be widespread in UK general practice.

New procognitive enhancers acting at the histamine H3 and AMPA receptors reverse natural forgetting in mice: comparisons with donepezil and memantine in the object recognition task.

This study evaluated the procognitive effects of S 38093 (a new inverse agonist of the histaminergic H3 receptor) and S 47445 (a new α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) in 2-3-month-old Swiss mice as compared with donepezil and memantine, two main reference compounds in the treatment of Alzheimer's disease. The object recognition task allows the study of natural forgetting and is classically used in assessing drug effects on memory. Here, we show that mice exhibit significant object recognition at short (15 min) but not long (24 h) retention intervals separating the familiarization and recognition phases. S 47445 (1.0, 3.0, and 10.0 mg/kg) and S 38093 (0.3, 1.0, and 3.0 mg/kg), both administered postoperatively, 1 h before familiarization and recognition sessions, rescued memory at the long retention interval; their memory-enhancing effects were as powerful as those obtained with donepezil or memantine (1.0 and 3.0 mg/kg for both compounds). Thus, S 38093 and S 47445, detected as positive controls in the object recognition task, are promising compounds for the treatment of amnesic syndromes.

Preclinical Evaluation of White Led-Activated Non-porphyrinic Photosensitizer OR141 in 3D Tumor Spheroids and Mouse Skin Lesions.

Photodynamic therapy (PDT) is used to treat malignancies and precancerous lesions. Near-infrared light delivered by lasers was thought for a while to be the most appropriate option to activate photosensitizers, mostly porphyrins, in the depth of the diseased tissues. More recently, however, several advantages including low cost and reduced adverse effects led to consider light emitting diodes (LED) and even daylight as an alternative to use PDT to treat accessible lesions. In this study we examined the capacity of OR141, a recently identified non-porphyrin photosensitizer (PS), to exert significant cytotoxic effects in various models of skin lesions and tumors upon white light activation. Using different cancer cell lines, we first identified LED lamp as a particularly suited source of light to maximize anti-proliferative effects of OR141. We then documented that OR141 diffusion and light penetration into tumor spheroids both reached thresholds compatible with the induction of cell death deep inside these 3D culture models. We further identified Arlasove as a clinically suitable solvent for OR141 that we documented by using Franz cells to support significant absorption of the PS through human skin. Finally, using topical but also systemic administration, we validated growth inhibitory effects of LED-activated OR141 in mouse skin tumor xenograft and precancerous lesions models. Altogether these results open clinical perspectives for the use of OR141 as an attractive PS to treat superficial skin malignant and non-malignant lesions using affordable LED lamp for photoactivation.

Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing.

Neurodegenerative disorders of ageing (NDAs) such as Alzheimer disease, Parkinson disease, frontotemporal dementia, Huntington disease and amyotrophic lateral sclerosis represent a major socio-economic challenge in view of their high prevalence yet poor treatment. They are often called 'proteinopathies' owing to the presence of misfolded and aggregated proteins that lose their physiological roles and acquire neurotoxic properties. One reason underlying the accumulation and spread of oligomeric forms of neurotoxic proteins is insufficient clearance by the autophagic-lysosomal network. Several other clearance pathways are also compromised in NDAs: chaperone-mediated autophagy, the ubiquitin-proteasome system, extracellular clearance by proteases and extrusion into the circulation via the blood-brain barrier and glymphatic system. This article focuses on emerging mechanisms for promoting the clearance of neurotoxic proteins, a strategy that may curtail the onset and slow the progression of NDAs.

Pharmacological characterisation of S 47445, a novel positive allosteric modulator of AMPA receptors.

S 47445 is a novel positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors (AMPA-PAM). S 47445 enhanced glutamate's action at AMPA receptors on human and rat receptors and was inactive at NMDA and kainate receptors. Potentiation did not differ among the different AMPA receptors subtypes (GluA1/2/4 flip and flop variants) (EC50 between 2.5-5.4 µM), except a higher EC50 value for GluA4 flop (0.7 µM) and a greater amount of potentiation on GluA1 flop. A low concentration of S 47445 (0.1 µM) decreased receptor response decay time of GluA1flop/GluA2flip AMPA receptors and increased the sensitivity to glutamate. Furthermore, S 47445 (0.1 and 0.3 µM) in presence of repetitive glutamate pulses induced a progressive potentiation of the glutamate-evoked currents from the second pulse of glutamate confirming a rapid-enhancing effect of S 47445 at low concentrations. The potentiating effect of S 47445 (1 µM) was concentration-dependently reversed by the selective AMPA receptor antagonist GYKI52466 demonstrating the selective modulatory effect of S 47445 on AMPA receptors. Using an AMPA-kainate chimera approach, it was confirmed that S 47445 binds to the common binding pocket of AMPA-PAMs. S 47445 did not demonstrate neurotoxic effect against glutamate-mediated excitotoxicity in vitro, in contrast significantly protected rat cortical neurons at 10 µM. S 47445 was shown to improve both episodic and spatial working memory in adult rodents at 0.3 mg/kg, as measured in the natural forgetting condition of object recognition and T-maze tasks. Finally, no deleterious effect on spontaneous locomotion and general behavior was observed up to 1000 mg/kg of S 47445 given acutely in rodents, neither occurrence of convulsion or tremors. Collectively, these results indicate that S 47445 is a potent and selective AMPA-PAM presenting procognitive and potential neuroprotective properties. This drug is currently evaluated in clinical phase 2 studies in Alzheimer's disease and in Major Depressive Disorder.

Tau accumulation in the retina promotes early neuronal dysfunction and precedes brain pathology in a mouse model of Alzheimer's disease.

BACKGROUND: Tau is an axon-enriched protein that binds to and stabilizes microtubules, and hence plays a crucial role in neuronal function. In Alzheimer's disease (AD), pathological tau accumulation correlates with cognitive decline. Substantial visual deficits are found in individuals affected by AD including a preferential loss of retinal ganglion cells (RGCs), the neurons that convey visual information from the retina to the brain. At present, however, the mechanisms that underlie vision changes in these patients are poorly understood. Here, we asked whether tau plays a role in early retinal pathology and neuronal dysfunction in AD. METHODS: Alterations in tau protein and gene expression, phosphorylation, and localization were investigated by western blots, qPCR, and immunohistochemistry in the retina and visual pathways of triple transgenic mice (3xTg) harboring mutations in the genes encoding presenilin 1 (PS1M146 V), amyloid precursor protein (APPSwe), and tau (MAPTP301L). Anterograde axonal transport was assessed by intraocular injection of the cholera toxin beta subunit followed by quantification of tracer accumulation in the contralateral superior colliculus. RGC survival was analyzed on whole-mounted retinas using cell-specific markers. Reduction of tau expression was achieved following intravitreal injection of targeted siRNA. RESULTS: Our data demonstrate an age-related increase in endogenous retinal tau characterized by epitope-specific hypo- and hyper-phosphorylation in 3xTg mice. Retinal tau accumulation was observed as early as three months of age, prior to the reported onset of behavioral deficits, and preceded tau aggregation in the brain. Intriguingly, tau build up occurred in RGC soma and dendrites, while tau in RGC axons in the optic nerve was depleted. Tau phosphorylation changes and missorting correlated with substantial defects in anterograde axonal transport that preceded RGC death. Importantly, targeted siRNA-mediated knockdown of endogenous tau improved anterograde transport along RGC axons. CONCLUSIONS: Our study reveals profound tau pathology in the visual system leading to early retinal neuron damage in a mouse model of AD. Importantly, we show that tau accumulation promotes anterograde axonal transport impairment in vivo, and identify this response as an early feature of neuronal dysfunction that precedes cell death in the AD retina. These findings provide the first proof-of-concept that a global strategy to reduce tau accumulation is beneficial to improve axonal transport and mitigate functional deficits in AD and tauopathies.

Lipophilicity of PCBs and fatty acids determines their mobilisation from blubber of weaned northern elephant seal pups.

Polychlorinated biphenyls (PCBs) exhibit lipophilic properties that lead to their bioaccumulation in adipose tissue. Following PCB exposition, northern elephant seals (Mirounga angustirostris) concentrate high amounts of these pollutants in their large adipose tissue stores. During lipolytic periods such as the post-weaning fast, fatty acids (FAs), which form triglycerides, and PCBs are both mobilised from adipose tissue. Our results showed that the degree of lipophilicity of FAs and PCBs impacted their release: the more lipophilic FAs and PCBs tended to be more conserved in blubber over the fast than the less lipophilic ones. This led to an enrichment of more lipophilic compounds within adipocytes with the progression of the fast. Life history patterns that include fasting may thus influence the profile of blubber lipids and contaminants.

Mobilisation of blubber fatty acids of northern elephant seal pups (Mirounga angustirostris) during the post-weaning fast.

Northern elephant seal pups were longitudinally sampled at Año Nuevo State Reserve during the post-weaning fast, in order to evaluate the changes of fatty acid (FA) profiles in serum as well as in the inner and outer layers of blubber. The major FAs of inner and outer blubber layers were broadly similar to those found in NES maternal milk previously measured, suggesting a direct deposit of dietary FAs in the blubber during the suckling period. The outer blubber layer contained more medium-chain monounsaturated FAs that contribute in keeping the fluidity of this tissue at cold temperatures. It was compensated by higher proportions of saturated FAs in the inner blubber layer. The FA signature of inner blubber, the layer that is mainly mobilised during energy deprivation, slightly differed from the signature of serum. There were greater proportions of medium-chain saturated FAs and ω-6 polyunsaturated FAs, and lower proportions of long-chain saturated FAs, medium-chain monounsaturated FAs and long-chain monounsaturated FAs in serum as compared to inner blubber. We also demonstrated that lipophilicity is the main factor governing the mobilisation of FAs from blubber. The least lipophilic FAs were preferentially hydrolysed from blubber, leading to an enrichment of the more lipophilic FAs in this tissue with the progression of the fast. The expression levels of HSL and ATGL, which are two enzymes involved in the lipolytic process, remained stable during the post-weaning fast. This suggests that the pups have developed the enzymatic mechanisms for an efficient lipolysis as soon as the first week of fast.

Bioaccumulation of hydroxylated polychlorinated biphenyls and pentachlorophenol in the serum of northern elephant seal pups (Mirounga angustirostris).

Northern elephant seals (NES) (Mirounga angustirostris) from the Año Nuevo State Reserve (CA, USA) were sampled at 1-, 4-, 7- and 10-week post-weaning. Concentrations of hydroxylated polychlorinated biphenyls (HO-PCBs) and their parent PCBs were measured in the serum of each individual. The ΣHO-PCB concentrations in the serum increased significantly between early and late fast (from 282 ± 20 to 529 ± 31 pg/mL). This increase might result from a mobilisation of HO-PCBs transferred from the mother during gestation and/or lactation and stored in the pup's liver. Food deprivation has been shown to exacerbate biotransformation capacities in mammals, birds and fish. The HO-penta-CBs was the predominant homologue group, followed by HO-hexa-CBs and HO-hepta-CBs. No preferential pathway for the metabolism of HO-PCBs (HO-direct insertion or NIH-shift of a chlorine atom) could be evidenced. The concentrations of pentachlorophenol (PCP) in the serum of weaned NES increased from 103 ± 7 pg/mL at early fast to 246 ± 41 pg/mL at late fast, which is within the range of PCP concentrations usually encountered in marine mammals.

Hippocampal Injections of Oligomeric Amyloid ß-peptide (1-42) Induce Selective Working Memory Deficits and Long-lasting Alterations of ERK Signaling Pathway.

Increasing evidence suggests that abnormal brain accumulation of soluble rather than aggregated amyloid-ß1-42 oligomers (Aßo(1-42)) plays a causal role in Alzheimer's disease (AD). However, as yet, animal's models of AD based on oligomeric amyloid-ß1-42 injections in the brain have not investigated their long-lasting impacts on molecular and cognitive functions. In addition, the injections have been most often performed in ventricles, but not in the hippocampus, in spite of the fact that the hippocampus is importantly involved in memory processes and is strongly and precociously affected during the early stages of AD. Thus, in the present study, we investigated the long-lasting impacts of intra-hippocampal injections of oligomeric forms of Aßo(1-42) on working and spatial memory and on the related activation of ERK1/2. Indeed, the extracellular signal-regulated kinase (ERK) which is involved in memory function had been found to be activated by amyloid peptides. We found that repeated bilateral injections (1injection/day over 4 successive days) of oligomeric forms of Aßo(1-42) into the dorsal hippocampus lead to long-lasting impairments in two working memory tasks, these deficits being observed 7 days after the last injection, while spatial memory remained unaffected. Moreover, the working memory deficits were correlated with sustained impairments of ERK1/2 activation in the medial prefrontal cortex (mPFC) and the septum, two brain areas tightly connected with the hippocampus and involved in working memory. Thus, our study is first to evidence that sub-chronic injections of oligomeric forms of Aßo(1-42) into the dorsal hippocampus produces the main sign of cognitive impairments corresponding to the early stages of AD, via long-lasting alterations of an ERK/MAPK pathway in an interconnected brain networks.

Positive allosteric modulators of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid receptors belonging to 4-cyclopropyl-3,4-dihydro-2h-1,2,4-pyridothiadiazine dioxides and diversely chloro-substituted 4-cyclopropyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides.

Two 4-ethyl-substituted pyridothiadiazine dioxides belonging to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor positive allosteric modulators were cocrystallized with the GluA2 ligand binding domain in order to decipher the impact of the position of the nitrogen atom on their binding mode at the AMPA receptors. The latter was found to be very similar to that of previously described benzothiadiazine-type AMPA receptor modulators. The affinity of the two compounds for the receptor was determined by isothermal titration calorimetry. Accordingly, the synthesis and biological evaluation of novel 4-cyclopropyl-substituted pyridothiadiazine dioxides was performed and completed with the synthesis of the corresponding chloro-substituted 4-cyclopropyl-3,4-dihydro-2H-benzothiadiazine 1,1-dioxides. The "8-aza" compound 32 was found to be the most potent pyridothiadiazine-type AMPA receptor potentiator in vitro, whereas the 7-chloro-substituted compound 36c emerged as the most promising benzothiadiazine dioxide. Due to proper drug-likeness and low in vivo acute toxicity in mice, 36c was chosen for a more complete preclinical evaluation. The compound was able to easily cross the blood-brain barrier. In an in vivo object recognition test with CD1 mice, oral administration of 36c was found to significantly improve cognition performance at doses as low as 1 mg/kg.

PCB-153 shows different dynamics of mobilisation from differentiated rat adipocytes during lipolysis in comparison with PCB-28 and PCB-118.

BACKGROUND: Polychlorinated biphenyls (PCBs) are persistent organic pollutants. Due to their lipophilic character, they are preferentially stored within the adipose tissue. During the mobilisation of lipids, PCBs might be released from adipocytes into the bloodstream. However, the mechanisms associated with the release of PCBs have been poorly studied. Several in vivo studies followed their dynamics of release but the complexity of the in vivo situation, which is characterised by a large range of pollutants, does not allow understanding precisely the behaviour of individual congeners. The present in vitro experiment studied the impact of (i) the number and position of chlorine atoms of PCBs on their release from adipocytes and (ii) the presence of other PCB congeners on the mobilisation rate of such molecules. METHODOLOGY/PRINCIPAL FINDINGS: Differentiated rat adipocytes were used to compare the behaviour of PCB-28, -118 and -153. Cells were contaminated with the three congeners, alone or in cocktail, and a lipolysis was then induced with isoproterenol during 12 hours. Our data indicate that the three congeners were efficiently released from adipocytes and accumulated in the medium during the lipolysis. Interestingly, for a same level of cell lipids, PCB-153, a hexa-CB with two chlorine atoms in ortho-position, was mobilised slower than PCB-28, a tri-CB, and PCB-118, a penta-CB, which are both characterised by one chlorine atom in ortho-position. It suggests an impact of the chemical properties of pollutants on their mobilisation during periods of negative energy balance. Moreover, the mobilisation of PCB congeners, taken individually, did not seem to be influenced by the presence of other congeners within adipocytes. CONCLUSION/SIGNIFICANCE: These results not only highlight the obvious mobilisation of PCBs from adipocytes during lipolysis, in parallel to lipids, but also demonstrate that the structure of congeners defines their rate of release from adipocytes.

Mobilisation of lipophilic pollutants from blubber in northern elephant seal pups (Mirounga angustirostris) during the post-weaning fast.

Northern elephant seals (NES) (Mirounga angustirostris) from the Año Nuevo State Reserve (CA, USA) were longitudinally sampled during the post-weaning fast in order to study the mobilisation and redistribution of various classes of persistent organic pollutants (POPs), such as polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), dichlorodiphenyldichloroethylene (p,p'-DDE) and hexachlorobenzene (HCB) between blubber and blood. Inner and outer blubber layers were analysed separately. Organohalogenated compounds were detected in all blubber samples in the decreasing order of their concentrations: p,p'-DDE > PCBs ⪢ HCB > PBDEs. The concentrations of all studied compounds were homogeneously distributed in the blubber layer at early fast, since the concentrations of POPs were statistically not different in the inner and outer layers. With the progression of the fast, the concentrations of PBDEs, PCBs and p,p'-DDE increased more sharply in inner blubber than in outer blubber. As a result, their levels became significantly higher in inner blubber as compared to outer blubber at late fast. The rise of pollutant concentrations in blubber might result from a less efficient mobilisation than triglycerides and/or a reuptake by adipocytes of some of the pollutants released into the circulation. The mobilisation of pollutants from blubber was higher at late fast. An increase of pollutant concentrations was observed in serum between early and late fast. Lower halogenated congeners (i.e. tetra-CBs) were present in higher proportions in serum, whereas the higher halogenated congeners (i.e. hepta-CBs) were mainly found in the inner and outer blubber layers. The transfer ratios of both PBDEs and PCBs from inner blubber to serum decreased with the number of chlorine and bromine atoms. In addition, the distribution of both types of compounds between serum and blubber was strongly influenced by their lipophilic character (logKow values), with more lipophilic compounds being less efficiently released from blubber to serum.

Efficient in vitro adipocyte model of long-term lipolysis: a tool to study the behavior of lipophilic compounds.

The triglycerides (TGs) stored in the white adipose tissue are mobilized during periods of negative energy balance. To date, there is no in vitro model of adipocytes imitating a long period of negative energy balance in which triglycerides are highly mobilized. Such model would allow studying the mobilization of TGs and lipophilic compounds trapped within the adipose tissue (e.g., pollutants and vitamins). The present study aims at developing a performing long-term in vitro lipolysis in adipocytes, resulting in a significant decrease of TG stores. Lipolysis was induced on differentiated rat adipocytes by a lipolytic medium with or without isoproterenol for 12 h. The condition with isoproterenol was duplicated, once with medium renewal every 3 h and once without medium renewal. Adding isoproterenol efficiently triggered lipolysis in a short time (3 h). However, a single stimulation by isoproterenol, without medium renewal, was not sufficient to reduce the TG content during a longer term (12 h). A reesterification of fatty acids occurred after a few hours of lipolysis, resulting in a novel increase of cellular lipids. Regular medium renewal combined with repeated isoproterenol stimulations led to almost emptied cells after 12 h. However, medium renewal without isoproterenol stimulation for 12 h was as efficient in terms of lipid mobilization. Our study demonstrates that, over a short-term period, isoproterenol is required to exert a significant lipolytic effect on adipocytes. During a long-term period, the presence of isoproterenol is no longer essential. Instead, medium renewal becomes the main factor involved in cell emptying. The efficiency of this protocol was demonstrated by visual tracking of the cells and by monitoring the dynamics of release of a lipophilic compound, PCB-153, from adipocytes during lipolysis.

Deficits of psychomotor and mnesic functions across aging in mouse lemur primates.

Owing to a similar cerebral neuro-anatomy, non-human primates are viewed as the most valid models for understanding cognitive deficits. This study evaluated psychomotor and mnesic functions of 41 young to old mouse lemurs (Microcebus murinus). Psychomotor capacities and anxiety-related behaviors decreased abruptly from middle to late adulthood. However, mnesic functions were not affected in the same way with increasing age. While results of the spontaneous alternation task point to a progressive and widespread age-related decline of spatial working memory, both spatial reference and novel object recognition (NOR) memory tasks did not reveal any tendency due to large inter-individual variability in the middle-aged and old animals. Indeed, some of the aged animals performed as well as younger ones, whereas some others had bad performances in the Barnes maze and in the object recognition test. Hierarchical cluster analysis revealed that declarative-like memory was strongly impaired only in 7 out of 25 middle-aged/old animals. These results suggest that this analysis allows to distinguish elder populations of good and bad performers in this non-human primate model and to closely compare this to human aging.

Working memory deficits and related disinhibition of the cAMP/PKA/CREB are alleviated by prefrontal α4ß2*-nAChRs stimulation in aged mice.

The present study investigates in aged mice the working memory (WM) enhancing potential of the selective α4ß2* nicotinic receptor agonist S 38232 as compared with the cholinesterase inhibitor donepezil, and their effect on cAMP response element binding protein (CREB) phosphorylation (pCREB) as a marker of neuronal activity. We first showed that aged mice exhibit a WM deficit and an increase of pCREB in the prelimbic cortex (PL) as compared with young mice, whereas no modification appears in the CA1. Further, we showed that systemic administration of S 38232 restored WM in aged mice and alleviated PL CREB overphosphorylation. Donepezil alleviated age-related memory deficits, however, by increasing pCREB in the CA1, while pCREB in PL remained unaffected. Finally, whereas neuronal inhibition by lidocaine infusion in the PL appeared deleterious in young mice, the infusion of Rp-cAMPS (a compound known to inhibit CREB phosphorylation) or S 38232 rescued WM in aged animals. Thus, by targeting the α4ß2*-nicotinic receptor of the PL, S 38232 alleviates PL CREB overphosphorylation and restores WM in aged mice, which opens new pharmacologic perspectives of therapeutic strategy.

Accumulation of polychlorinated biphenyls in adipocytes: selective targeting to lipid droplets and role of caveolin-1.

BACKGROUND: Polychlorinated biphenyls (PCBs) are persistent environmental pollutants that preferentially accumulate in lipid-rich tissues of contaminated organisms. Although the adipose tissue constitutes a major intern reservoir of PCBs and recent epidemiological studies associate PCBs to the development of obesity and its related disorders, little is known about the mechanisms involved in their uptake by the adipose tissue and their intracellular localization in fat cells. METHODOLOGY/PRINCIPAL FINDINGS: We have examined the intracellular distribution of PCBs in mouse cultured adipocytes and tested the potential involvement of caveolin-1, an abundant adipocyte membrane protein, in the uptake of these compounds by fat cells. We show that 2,4,4'-trichlorobiphenyl (PCB-28), 2,3',4,4',5-pentachlorobiphenyl (PCB-118) and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153) congeners rapidly and extensively accumulate in 3T3-L1 or mouse embryonic fibroblast (MEF) derived cultured adipocytes. The dynamics of accumulation differed between the 3 congeners tested. By subcellular fractionation of primary adipocytes, we demonstrate that these pollutants were almost exclusively recovered within the lipid droplet fraction and practically not associated to cell membranes. The absence of caveolin-1 expression in primary adipocytes from cav-1 deficient mice did not modify lipid droplet selective targeting of PCBs. In cav-1 KO MEF differentiated adipocytes, PCB accumulation was decreased, which correlated with reduced cell triglyceride content. Conversely, adenoviral mediated cav-1 overexpressing in 3T3-L1 cells, which had no impact on total cell lipid content, did not change PCB accumulation. CONCLUSION/SIGNIFICANCE: Our data indicate that caveolin-1 per se is not required for selective PCB accumulation, but rather point out a primary dependence on adipocyte triglyceride content. If the crucial role of lipid droplets in energy homeostasis is considered, the almost exclusive accumulation of PCBs in these organelles warrants future attention as the impairment of their function could be linked to the worldwide obesity epidemic.

S 18986 reverses spatial working memory impairments in aged mice: comparison with memantine.

RATIONALE: Normal or pathological ageing is characterized by working-memory dysfunction paired with a marked reduction in several neurotransmitters activity. The development of therapeutic strategy centered on the glutamatergic system known to bear a critical role in cognitive functions, is therefore of major importance in the treatment of mild forms of AD or age-related memory dysfunctions. OBJECTIVES: In Experiment 1, we investigated the effects of ageing on spatial working memory measured by sequential alternation (SA). Thus, the decay of alternation rates over a series of trials separated by varying intertrial temporal intervals (ITI, from 5 sec to 180 sec) was studied in mice of different age groups. In Experiment 2, we investigated the memory-enhancing potential of S 18986--a modulator of AMPA receptors--on age-related SA impairments, in comparison with memantine--an antagonist of NMDA receptors--. RESULTS: In Experiment 1, aged mice responded at chance with shorter ITI's and exhibited greater levels of interference in the SA task as compared to young adult mice. In Experiment 2, (1) S 18986 at 0.03 and 0.1 mg/kg reversed the memory deficit in aged mice but did not modify performance in young adult mice; (2) memantine at 10 mg/kg also increased SA rates in aged mice but did not improve performance in young adult mice. CONCLUSION: The SA task is a useful tool to reveal age-induced time-dependent working memory impairments. As compared to memantine, S 18986--a compound targeting AMPA receptors--contributes a valuable therapy in the treatment of age-related cognitive dysfunctions or mild forms of AD.

SSR181507, a dopamine D2 receptor and 5-HT(1A) receptor ligand: evidence for mixed anxiolytic- and antidepressant-like activities.

SSR181507, a dopamine D2 receptor antagonist/partial agonist and 5-HT(1A) receptor agonist, is active in animal models of schizophrenia. Furthermore, it shows activity in several anxiety and/or depression models (Depoortere et al. 2003). Presently, we sought to further characterize the latter two activities in rats, using a step-down passive avoidance procedure, a shock-induced ultrasonic vocalization (UV) test in adult subjects and a social interaction test. SSR181507 (0.3 & 1 mg/kg ip), but not the atypical antipsychotics clozapine and olanzapine, decreased the latency time to step-down from a "safety" platform. Effects of SSR181507 were reversed by the selective 5-HT(1A) receptor antagonist SL88.0338. SSR181507 also reduced UV (0.3 & 1 mg/kg ip), an effect not reversed by SL88.0338, and observed with olanzapine, haloperidol, fluoxetine and the 5-HT(1A) receptor agonists 8-OH-DPAT and buspirone, but not diazepam. Furthermore, SSR181507 remained active following 3 weeks of administration (1 mg/kg ip, once daily) in the UV test. Lastly, SSR181507 (3 mg/kg ip) potentiated social interaction, an effect shared by diazepam and buspirone, but not by olanzapine, clozapine, haloperidol and 8-OH-DPAT. These data further strengthen previous findings that the putative atypical antipsychotic SSR181507 has mixed antidepressant and anxiolytic activities.

Variability of origin for the neocentromeric sequences in analphoid supernumerary marker chromosomes of well-differentiated liposarcomas.

Well-differentiated liposarcomas (WDLPS) and dedifferentiated liposarcomas are cytogenetically characterized by the presence of supernumerary ring or giant chromosomes containing amplified material from the 12q14-15 region. These chromosomes contain neocentromeres, which are able to bind the kinetochore proteins and to ensure a stable mitotic transmission although they do not show detectable alpha-satellite sequences. WDLPS is the sole solid tumor for which the presence of a neocentromere is a consistent and specific feature. By immunostaining with anti-centromere antibodies in combination with FISH analysis (immunoFISH) in four cases of WDLPS, we have shown that sequences from the region 12q14-21 region were not located at the neocentromere site. In addition, we have microdissected the neocentromeric region from a giant supernumerary chromosome in the 94T778 WDLPS cell line. By using immunoFISH and positional cloning we have shown that the neocentromere of this cell line originated from a region at 4p16.1, rich in AT sequences and in long interspersed nucleotide element (LINE)1, that was co-amplified with 12q14-15. We have observed that this 4p sequence was not involved in the neocentromere of the supernumerary giant chromosome present in the 93T449 WDLPS cell line derived from a metachronous recurrence of the same primary WDLPS than 94T778. Altogether, these results indicate that the neocentromeres in WDLPS originate from amplified chromosomal regions other than 12q14-15 and do not involve a specific and recurrent DNA sequence. These sequences might be activated for centromeric function by epigenetic mechanisms.