Individual Response to Radiation of Individuals with Neurofibromatosis Type I: Role of the ATM Protein and Influence of Statins and Bisphosphonates.

Neurofibromatosis type 1 (NF1) is a disease characterized by high occurrence of benign and malignant brain tumours and caused by mutations of the neurofibromin protein. While there is an increasing evidence that NF1 is associated with radiosensitivity and radiosusceptibility, few studies have dealt with the molecular and cellular radiation response of cells from individuals with NF1. Here, we examined the ATM-dependent signalling and repair pathways of the DNA double-strand breaks (DSB), the key-damage induced by ionizing radiation, in skin fibroblast cell lines from 43 individuals with NF1.

AZP2006, a new promising treatment for Alzheimer's and related diseases.

Progranulin (PGRN) is a protein with multiple functions including the regulation of neuroinflammation, neuronal survival, neurite and synapsis growth. Although the mechanisms of action of PGRN are currently unknown, its potential therapeutic application in treating neurodegenerative diseases is huge. Thus, strategies to increase PGRN levels in patients could provide an effective treatment.

Chloroquine and chloroquinoline derivatives as models for the design of modulators of amyloid Peptide precursor metabolism.

The amyloid precursor protein (APP) plays a central role in Alzheimer's disease (AD). Preventing deregulated APP processing by inhibiting amyloidogenic processing of carboxy-terminal fragments (APP-CTFs), and reducing the toxic effect of amyloid beta (Aβ) peptides remain an effective therapeutic strategy. We report the design of piperazine-containing compounds derived from chloroquine structure and evaluation of their effects on APP metabolism and ability to modulate the processing of APP-CTF and the production of Aβ peptide.

Dual orexin actions on dorsal raphe and laterodorsal tegmentum neurons: noisy cation current activation and selective enhancement of Ca2+ transients mediated by L-type calcium channels.

The hypocretin/orexins (Hcrt/Orxs) are hypothalamic neuropeptides that regulate stress, addiction, feeding, and arousal behaviors. They depolarize many types of central neurons and can increase [Ca2+]i in some, including those of the dorsal raphe (DR) and laterodorsal tegmental (LDT) nuclei-two structures likely to contribute to the behavioral actions of Hcrt/Orx. In this study, we used simultaneous whole cell and Ca2+-imaging methods in mouse brain slices to compare the Hcrt/Orx-activated current in DR and LDT neurons and to determine whether it contributes to the Ca2+ influx evoked by Hcrt/Orx.

Prospects for the resistance to HIV protease inhibitors: current drug design approaches and perspectives.

One of the major challenges raised by HIV chemotherapy is the insurgence of viral resistance to drugs. Resistance to antiviral therapy has been observed for each of the different classes of anti-viral drugs: nucleoside reverse-transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors. The crucial question for AIDS drug research community is: Should we continue the search of new anti-HIV drugs which can overcome HIV resistance insurgence or should we consider resistance to anti-HIV drugs as a futile challenge? This review, focussed specifically on HIV antiprotease drugs, highlights the different strategies which have been developed to design new anti-protease drugs which could overcome HIV resistance, and also reviews the different classes of compounds (peptidomimetic or non-peptidomimetic) actually under investigation in order to face the problem of HIV resistance to drug.

Novel cyclized Pifithrin-alpha p53 inactivators: synthesis and biological studies.

Starting from various cyclic or bicyclic ketones, we have synthesized novel Pifithrin-alpha analogues bearing different methyl substituted phenyl ketone groups at the N3-position of the 2-iminothiazole heterocycle. From stability studies in a biological medium as well as under specific chemical conditions, we have shown by NMR techniques that through a dehydration process, some derivatives can generate their corresponding cyclized analogues. All of the new analogues, Pifithrin-like and polycyclic dehydrated derivatives were assessed for their p53 inactivation potency by measuring survival of cortical neurons, whose death was induced by the DNA-damaging agent etoposide.

Cortical and pontine variations occurring in the voltammetric no signal throughout the sleep-wake cycle in the rat.

Voltammetric measurements of nitric oxide (NO) were performed either in the frontal cortex (Cx) or in the nucleus raphe dorsalis (nRD) of rats equipped for polygraphic recordings. In the frontal cortex, the 650 mV signal related to NO exhibited its highest height during the waking state (W) and decreased slightly during slow-wave sleep (SWS) and even more during paradoxical sleep (PS). In the nRD, opposite variations were observed, i.

New antiviral nucleoside prodrugs await application.

In this review, we intend to highlight outstanding concepts of antiviral nucleoside prodrugs which have been developed in recent years, so as to improve the efficacy of a given antiviral drug or to overcome some drug deficiencies. Examples of antiviral carrier-linked nucleoside prodrugs or nucleoside bioprecursors are described, and their active mechanisms discussed. The described nucleoside prodrugs are classified in two structural classes: prodrugs bearing molecular modifications on the sugar moiety and prodrugs bearing molecular modifications on the nucleic base.

Discovery of highly potent Src SH2 binders: structure-activity studies and X-ray structures.

Optimization of the hydrophobic moiety of caprolactam/thiazepinone based compounds led to the identification of potent Src SH2 binders in two different series incorporating a phosphotyrosine group (RU 81843) or a phosphobenzoic group (RU 79181). The X-ray co-structures with the Src SH2 domain revealed different binding modes for RU 81843 and RU 79181, and an excellent fit between RU81843 and the Src SH2 protein thus explaining its high potency (9 nM, 15-fold more potent than pYEEI reference peptide).

[Influence of cerebral and peripheral nitric oxide on sleep/wake cycle in the rat].

Through a polygraphic and pharmacological approach conducted in the rat, it is established that L-NAME (N-nitro-L-arginine methyl ester; an inhibitor of the endothelial and neuronal NO-synthases), administered intraperitoneally (i.p., 100 mg/kg) increases significantly slow wave sleep (SWS) and paradoxical sleep (PS).

Direct and indirect excitation of laterodorsal tegmental neurons by Hypocretin/Orexin peptides: implications for wakefulness and narcolepsy.

Compelling evidence links the recently discovered hypothalamic peptides Hypocretin/Orexin (Hcrt/Orx) to rapid eye movement sleep (REM) control and the sleep disorder narcolepsy, yet how they influence sleep-related systems is not well understood. We investigated the action of Hcrt/Orx on mesopontine cholinergic (MPCh) neurons of the laterodorsal tegmental nucleus (LDT), a target group whose function is altered in canine narcolepsy and appears pivotal for normal REM and wakefulness. Extracellular recordings from mouse brainstem slices revealed that Hcrt/Orx evoked prolonged firing of LDT neurons.

Nitric oxide and sleep in the rat: a puzzling relationship.

To date, only a few studies indicate that nitric oxide may play a role in the regulation of the sleep-wake cycle. However, data reported are controversial and the part played by nitric oxide in sleep-wake cycle regulation still remains uncertain. In the present report, we studied the effects on sleep amounts of two different nitric oxide synthase inhibitors: N-nitro-L-arginine methyl ester, a non-selective nitric oxide synthase inhibitor, and 7-nitro-indazole, a specific inhibitor of neuronal nitric oxide synthase.

Localization of nitric oxide-synthesizing neurons sending projections to the dorsal raphe nucleus of the rat.

The origin of the nerve fibers immunoreactive for neuronal nitric oxide synthase (nNOS) in the rat dorsal raphe nucleus (DRN) was determined by combining the use of cholera toxin subunit b (CTb) as a retrograde tracer and nNOS immunohistochemistry with a monoclonal anti-nNOS antibody. Double labeled CTb-nNOS cell bodies were distributed from the rostral diencephalon to the caudal medulla oblongata, in about 20 areas of the brain. Several of the areas displaying double labeled cells are known for their involvement in the control of the sleep-wake cycle and/or transmission of nociception.

Comparative distribution of nitric oxide synthase- and serotonin-containing neurons in the raphe nuclei of four mammalian species.

Monoclonal antibodies were generated against serotonin (5-HT) and the C-terminal portion of the neuronal form of nitric oxide synthase (nNOS), the enzyme producing nitric oxide in neurons. These antibodies were used to compare the distribution of 5-HT- and nNOS-containing neurons in the raphe nuclei of four animal species (rat, mouse, guinea pig, and cat). It was found that the rat was the only species in which the raphe nuclei contain a substantial number of nNOS-immunoreactive (IR) cell bodies.

5-Hydroxyindoles compounds and nitric oxide voltammetric detection in the rat brain: changes occurring throughout the sleep-wake cycle.

The release of serotonin may occur throughout the sleep-wake cycle according to 2 different modalities: - by the axonal nerve endings during waking; - by the dendrites and/or the soma of the nucleus raphe dorsalis (nRD) during sleep. Neuronal nitric oxide (NO), synthesised by constitutive NO synthase (NOS), is colocalized with neurotransmitters such as GABA, acetylcholine, somatostatin, serotonin, etc. In order to evaluate its modalities of release throughout the rat sleep-wake cycle, a sensor allowing its specific detection in freely moving animals was prepared.

Voltammetric detection of nitric oxide (NO) in the rat brain: its variations throughout the sleep-wake cycle.

A sensor allowing the specific detection of nitric oxide (NO) is reported. Together with differential pulsed voltammetry, it allows the detection of a 650 mV signal either in NO solutions or in the rat frontal cortex. The intraperitoneal (i.

[Action duality of nitrogen oxide (NO) in experimental African trypanosomiasis].

Patients with human African trypanosomiasis present a major dysruption of the circadian rhythmicity of the sleep-wake cycle, which was also found in rats infected with Trypanosoma brucei brucei (T.b.b.

[Voltametric detection of cerebral NO in rats. Variations of the signal throughout the sleep-wakefulness cycle].

Nitric oxide (NO) is synthesized in the neurons by constitutive NO synthase (NOS). Within given neuronal sets, this enzyme is colocalized with different other neurotransmitters such as, for example, GABA, acethylcholine or serotonin. Our attention has been focused on the fact that serotoninergic neurons, well known for their involvement in sleep triggering and maintenance, synthesize also NO.