William Même

Bio: William Même is an academic researcher from Centre national de la recherche scientifique. The author has contributed to research in topics: Skeletal muscle & Hippocampal formation. The author has an hindex of 12, co-authored 24 publications receiving 455 citations. Previous affiliations of William Même include University of Orléans.

Characterization of human monocyte-derived microglia-like cells.

Abstract: Microglial cells are central to brain immunity and intervene in many human neurological diseases. The aim of this study was to develop a convenient cellular model for human microglial cells, suitable for HIV studies. Microglia derive from the hematogenous myelomonocytic lineage, possibly as a distinct subpopulation but in any case able to invade the CNS, proliferate, and differentiate into ameboid and then ramified microglia in the adult life. We thus attempted to derive microglia-like cells from human monocytes. When cultured with astrocyte-conditioned medium (ACM), monocytes acquired a ramified morphology, typical of microglia. They overexpressed substance P and the calcium binding protein Iba-1 and dimly expressed class II MHC, three characteristics of microglial cells. Moreover, they also expressed a potassium inward rectifier current, another microglia-specific feature. These monocyte-derived microglia-like cells (MDMi) were CD4(+)/CD14(+), evocative of an activated microglia phenotype. When treated with lipopolysaccharide (LPS), MDMi lost their overexpression of substance P, which returned to untreated monocyte-derived macrophage (MDM) level. Compared with MDM, MDMi expressed higher CD4 but lower CCR5 levels; they could be infected by HIV-1(BaL), but produced less virus progeny than MDM did. This model of human microglia may be an interesting alternative to primary microglia for large scale in vitro HIV studies and may help to better understand HIV-associated microgliosis and chronic inflammation in the brain.

Chronic exposure to glufosinate-ammonium induces spatial memory impairments, hippocampal MRI modifications and glutamine synthetase activation in mice.

Abstract: Glufosinate-ammonium (GLA), the active compound of a worldwide-used herbicide, acts by inhibiting the plant glutamine synthetase (GS) leading to a lethal accumulation of ammonia. GS plays a pivotal role in the mammalian brain where it allows neurotransmitter glutamate recycling within astroglia. Clinical studies report that an acute GLA ingestion induces convulsions and memory impairment in humans. Toxicological studies performed at doses used for herbicidal activity showed that GLA is probably harmless at short or medium range periods. However, effects of low doses of GLA on chronically exposed subjects are not known. In our study, C57BL/6J mice were treated during 10 weeks three times a week with 2.5, 5 and 10 mg/kg of GLA. Effects of this chronic treatment were assessed at behavioral, structural and metabolic levels by using tests of spatial memory, locomotor activity and anxiety, hippocampal magnetic resonance imaging (MRI) texture analysis, and hippocampal GS activity assay, respectively. Chronic GLA treatments have effects neither on anxiety nor on locomotor activity of mice but at 5 and 10 mg/kg induce (1) mild memory impairments, (2) a modification of hippocampal texture and (3) a significant increase in hippocampal GS activity. It is suggested that these modifications may be causally linked one to another. Since glutamate is the main neurotransmitter in hippocampus where it plays a crucial role in spatial memory, hippocampal MRI texture and spatial memory alterations might be the consequences of hippocampal glutamate homeostasis modification revealed by increased GS activity in hippocampus. The present study provides the first data that show cerebral alterations after chronic exposure to GLA.

IL-33 receptor ST2 regulates the cognitive impairments associated with experimental cerebral malaria.

Abstract: Cerebral malaria (CM) is associated with a high mortality rate and long-term neurocognitive impairment in survivors. The murine model of experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA (PbA)-infection reproduces several of these features. We reported recently increased levels of IL-33 protein in brain undergoing ECM and the involvement of IL-33/ST2 pathway in ECM development. Here we show that PbA-infection induced early short term and spatial memory defects, prior to blood brain barrier (BBB) disruption, in wild-type mice, while ST2-deficient mice did not develop cognitive defects. PbA-induced neuroinflammation was reduced in ST2-deficient mice with low Ifng, Tnfa, Il1b, Il6, CXCL9, CXCL10 and Cd8a expression, associated with an absence of neurogenesis defects in hippocampus. PbA-infection triggered a dramatic increase of IL-33 expression by oligodendrocytes, through ST2 pathway. In vitro, IL-33/ST2 pathway induced microglia expression of IL-1β which in turn stimulated IL-33 expression by oligodendrocytes. These results highlight the IL-33/ST2 pathway ability to orchestrate microglia and oligodendrocytes responses at an early stage of PbA-infection, with an amplification loop between IL-1β and IL-33, responsible for an exacerbated neuroinflammation context and associated neurological and cognitive defects.

Cyclopiazonic acid-induced changes in the contraction and Ca2+ transient of frog fast-twitch skeletal muscle

Abstract: The effects of cyclopiazonic acid (CPA) were investigated on isolated skeletal muscle fibers of frog semitendinosus muscle. CPA (0.5–10 μM) enhanced isometric twitch but produced little change in r...

Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment.

Abstract: Free radicals and other so-called 'reactive species' are constantly produced in the brain in vivo. Some arise by 'accidents of chemistry', an example of which may be the leakage of electrons from the mitochondrial electron transport chain to generate superoxide radical (O2*-). Others are generated for useful purposes, such as the role of nitric oxide in neurotransmission and the production of O2*- by activated microglia. Because of its high ATP demand, the brain consumes O2 rapidly, and is thus susceptible to interference with mitochondrial function, which can in turn lead to increased O2*- formation. The brain contains multiple antioxidant defences, of which the mitochondrial manganese-containing superoxide dismutase and reduced glutathione seem especially important. Iron is a powerful promoter of free radical damage, able to catalyse generation of highly reactive hydroxyl, alkoxyl and peroxyl radicals from hydrogen peroxide and lipid peroxides, respectively. Although most iron in the brain is stored in ferritin, 'catalytic' iron is readily mobilised from injured brain tissue. Increased levels of oxidative damage to DNA, lipids and proteins have been detected by a range of assays in post-mortem tissues from patients with Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis, and at least some of these changes may occur early in disease progression. The accumulation and precipitation of proteins that occur in these diseases may be aggravated by oxidative damage, and may in turn cause more oxidative damage by interfering with the function of the proteasome. Indeed, it has been shown that proteasomal inhibition increases levels of oxidative damage not only to proteins but also to other biomolecules. Hence, there are many attempts to develop antioxidants that can cross the blood-brain barrier and decrease oxidative damage. Natural antioxidants such as vitamin E (tocopherol), carotenoids and flavonoids do not readily enter the brain in the adult, and the lazaroid antioxidant tirilazad (U-74006F) appears to localise in the blood-brain barrier. Other antioxidants under development include modified spin traps and low molecular mass scavengers of O2*-. One possible source of lead compounds is the use of traditional remedies claimed to improve brain function. Little is known about the impact of dietary antioxidants upon the development and progression of neurodegenerative diseases, especially Alzheimer's disease. Several agents already in therapeutic use might exert some of their effects by antioxidant action, including selegiline (deprenyl), apomorphine and nitecapone.

Targeted Drug Delivery with Polymers and Magnetic Nanoparticles: Covalent and Noncovalent Approaches, Release Control, and Clinical Studies.

Abstract: Targeted delivery combined with controlled drug release has a pivotal role in the future of personalized medicine. This review covers the principles, advantages, and drawbacks of passive and active targeting based on various polymer and magnetic iron oxide nanoparticle carriers with drug attached by both covalent and noncovalent pathways. Attention is devoted to the tailored conjugation of targeting ligands (e.g., enzymes, antibodies, peptides) to drug carrier systems. Similarly, the approaches toward controlled drug release are discussed. Various polymer–drug conjugates based, for example, on polyethylene glycol (PEG), N-(2-hydroxypropyl)methacrylamide (HPMA), polymeric micelles, and nanoparticle carriers are explored with respect to absorption, distribution, metabolism, and excretion (ADME scheme) of administrated drug. Design and structure of superparamagnetic iron oxide nanoparticles (SPION) and condensed magnetic clusters are classified according to the mechanism of noncovalent drug loading involving...

Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors

Abstract: Porphyromonas gingivalis, the keystone pathogen in chronic periodontitis, was identified in the brain of Alzheimer's disease patients. Toxic proteases from the bacterium called gingipains were also identified in the brain of Alzheimer's patients, and levels correlated with tau and ubiquitin pathology. Oral P. gingivalis infection in mice resulted in brain colonization and increased production of Aβ1-42, a component of amyloid plaques. Further, gingipains were neurotoxic in vivo and in vitro, exerting detrimental effects on tau, a protein needed for normal neuronal function. To block this neurotoxicity, we designed and synthesized small-molecule inhibitors targeting gingipains. Gingipain inhibition reduced the bacterial load of an established P. gingivalis brain infection, blocked Aβ1-42 production, reduced neuroinflammation, and rescued neurons in the hippocampus. These data suggest that gingipain inhibitors could be valuable for treating P. gingivalis brain colonization and neurodegeneration in Alzheimer's disease.