Wenbin Deng

Glutamate Receptor-Mediated Oligodendrocyte Toxicity in Periventricular Leukomalacia: A Protective Role for Topiramate

Periventricular leukomalacia is a form of hypoxic–ischemic cerebral white matter injury seen most commonly in premature infants and is the major antecedent of cerebral palsy. Glutamate receptor-mediated excitotoxicity is a predominant mechanism of hypoxic–ischemic injury to developing cerebral white matter. We have demonstrated previously the protective effect of AMPA–kainate-type glutamate receptor blockade in a rodent model of periventricular leukomalacia. The present study explores the therapeutic potential of glutamate receptor blockade for hypoxic–ischemic white matter injury. We demonstrate that AMPA receptors are expressed on developing human oligodendrocytes that populate fetal white matter at 23–32 weeks gestation, the period of highest risk for periventricular leukomalacia. We show that the clinically available anticonvulsant topiramate, when administered post-insult in vivo, is protective against selective hypoxic–ischemic white matter injury and decreases the subsequent neuromotor deficits. We further demonstrate that topiramate attenuates AMPA–kainate receptor-mediated cell death and calcium influx, as well as kainate-evoked currents in developing oligodendrocytes, similar to the AMPA–kainate receptor antagonist 6-nitro-7-sulfamoylbenzo-(f)quinoxaline-2,3-dione (NBQX). Notably, protective doses of NBQX and topiramate do not affect normal maturation and proliferation of oligodendrocytes either in vivo or in vitro. Taken together, these results suggest that AMPA–kainate receptor blockade may have potential for translation as a therapeutic strategy for periventricular leukomalacia and that the mechanism of protective efficacy of topiramate is caused at least in part by attenuation of excitotoxic injury to premyelinating oligodendrocytes in developing white matter.

Calcium-permeable AMPA/kainate receptors mediate toxicity and preconditioning by oxygen-glucose deprivation in oligodendrocyte precursors

Hypoxic–ischemic brain injury in premature infants results in cerebral white matter lesions with prominent oligodendroglial injury and loss, a disorder termed periventricular leukomalacia (PVL). We have previously shown that glutamate receptors mediate hypoxic–ischemic injury to oligodendroglial precursor cells (OPCs) in a model of PVL in the developing rodent brain. We used primary OPC cultures to examine the mechanism of cellular toxicity induced by oxygen–glucose deprivation (OGD) to simulate brain ischemia. OPCs were more sensitive to OGD-induced toxicity than mature oligodendrocytes, and OPC toxicity was attenuated by nonselective [2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline (NBQX), 6-cyano-7-nitroquinoxaline-2,3-dione], α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-preferring (GYKI 52466), kainate-preferring (γ-d-glutamylaminomethanesulfonic acid), or Ca2+-permeable AMPA/kainate receptor antagonists (joro spider toxin, JSTx) administered either during or after OGD. Furthermore, NBQX or JSTx blocked OGD-induced Ca2+ influx. Relevant to recurrent hypoxic–ischemic insults in developing white matter, we examined the effects of sublethal OGD preconditioning. A prior exposure of OPCs to sublethal OGD resulted in enhanced vulnerability to subsequent excitotoxic or OGD-induced injury associated with an increased Ca2+ influx. AMPA/kainate receptor blockade with NBQX or JSTx either during or after sublethal OGD prevented its priming effect. Furthermore, OGD preconditioning resulted in a down-regulation of the AMPA receptor subunit GluR2 on cell surface that increased Ca2+ permeability of the receptors. Overall, these data suggest that aberrantly enhanced activation of Ca2+-permeable AMPA/kainate receptors may be a major mechanism in acute and repeated hypoxic–ischemic injury to OPCs in disorders of developing cerebral white matter, such as PVL.

Prospects for Minocycline Neuroprotection

Minocycline is a clinically available antibiotic and anti-inflammatory drug that also demonstrates neuroprotective properties in a variety of experimental models of neurological diseases. There have thus far been more than 300 publications on minocycline neuroprotection, including a growing number of human studies. Our objective is to critically review the biological basis and translational potential of this action of minocycline on the nervous system.

Translocator Protein/Peripheral Benzodiazepine Receptor Is Not Required for Steroid Hormone Biosynthesis

Molecular events that regulate cellular biosynthesis of steroid hormones have been a topic of intense research for more than half a century. It has been established that transport of cholesterol into the mitochondria forms the rate-limiting step in steroid hormone production. In current models, both the steroidogenic acute regulatory protein (StAR) and the translocator protein (TSPO) have been implicated to have a concerted and indispensable effort in this cholesterol transport. Deletion of StAR in mice resulted in a critical failure of steroid hormone production, but deletion of TSPO in mice was found to be embryonic lethal. As a result, the role of TSPO in cholesterol transport has been established only using pharmacologic and genetic tools in vitro. To allow us to explore in more detail the function of TSPO in cell type-specific experimental manipulations in vivo, we generated mice carrying TSPO floxed alleles (TSPOfl/fl). In this study we made conditional knockout mice (TSPOcΔ/Δ) with TSPO deletion in testicular Leydig cells by crossing with an anti-Mullerian hormone receptor type II cre/+ mouse line. Genetic ablation of TSPO in steroidogenic Leydig cells in mice did not affect testosterone production, gametogenesis, and reproduction. Expression of StAR, cytochrome P450 side chain cleavage enzyme, 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase type I, and TSPO2 in TSPOcΔ/Δ testis was unaffected. These results challenge the prevailing dogma that claims an essential role for TSPO in steroid hormone biosynthesis and force reexamination of functional interpretations made for this protein. This is the first study examining conditional TSPO gene deletion in mice. The results show that TSPO function is not essential for steroid hormone biosynthesis.

Stimuli-responsive cross-linked micelles for on-demand drug delivery against cancers

Stimuli-responsive cross-linked micelles (SCMs) represent an ideal nanocarrier system for drug delivery against cancers. SCMs exhibit superior structural stability compared to their non-cross-linked counterpart. Therefore, these nanocarriers are able to minimize the premature drug release during blood circulation. The introduction of environmentally sensitive cross-linkers or assembly units makes SCMs responsive to single or multiple stimuli present in tumor local microenvironment or exogenously applied stimuli. In these instances, the payload drug is released almost exclusively in cancerous tissue or cancer cells upon accumulation via enhanced permeability and retention effect or receptor mediated endocytosis. In this review, we highlight recent advances in the development of SCMs for cancer therapy. We also introduce the latest biophysical techniques, such as electron paramagnetic resonance (EPR) spectroscopy and fluorescence resonance energy transfer (FRET), for the characterization of the interactions between SCMs and blood proteins.

Progress in Periventricular Leukomalacia

Periventricular leukomalacia (PVL) is the predominant form of brain injury and the leading known cause of cerebral palsy and cognitive deficits in premature infants. The number of low-birth-weight infants who survive to demonstrate these neurologic deficts is increasing. Magnetic resonance imaging-based neuroimaging techniques provide greater diagnostic sensitivity for PVL than does head ultrasonography and often document the involvement of telencephalic gray matter and long tracts in addition to periventricular white matter. The neuropathologic hallmarks of PVL are microglial activation and focal and diffuse periventricular depletion of premyelinating oligodendroglia. Premyelinating oligodendroglia are highly vulnerable to death caused by glutamate, free radicals, and proinflammatory cytokines. Studies in animal models of PVL suggest that pharmacologic interventions that target these toxic molecules will be useful in diminishing the severity of PVL.

Neurobiology of injury to the developing brain

Owing to improved survival rates of premature newborns, the number of very low birth weight infants is rising. Preterm infants display a greater propensity for brain injury caused by hypoxic or ischemic events, infection and/or inflammation that results in prominent white matter injury (WMI) than infants carried to full term. The intrinsic vulnerability of developing oligodendroglia to excitotoxic, oxidative and inflammatory forms of injury is a major factor in the pathogenesis of this condition. Furthermore, activated microglia and astrogliosis are critically involved in triggering WMI. Currently, no specific treatment is available for this kind of injury. Injury to the premature brain can substantially influence brain development and lead to disability. Impairment of the main motor pathways, such as the corticospinal tract, in the perinatal period contributes substantially to clinical outcome. Advanced neuroimaging techniques have led to greater understanding of the nature of both white and gray matter injury in preterm infants. Further research is warranted to examine the translational potential of preclinical therapeutic strategies for controlling such injury and preserving the integrity of motor pathways in preterm infants.

Role of astroglia in Down’s syndrome revealed by patient-derived human-induced pluripotent stem cells

Down’s syndrome (DS), caused by trisomy of human chromosome 21, is the most common genetic cause of intellectual disability. Here we use induced pluripotent stem cells (iPSCs) derived from DS patients to identify a role for astrocytes in DS pathogenesis. DS astroglia exhibit higher levels of reactive oxygen species and lower levels of synaptogenic molecules. Astrocyte-conditioned medium collected from DS astroglia causes toxicity to neurons, and fails to promote neuronal ion channel maturation and synapse formation. Transplantation studies show that DS astroglia do not promote neurogenesis of endogenous neural stem cells in vivo. We also observed abnormal gene expression profiles from DS astroglia. Finally, we show that the FDA-approved antibiotic drug, minocycline, partially corrects the pathological phenotypes of DS astroglia by specifically modulating the expression of S100B, GFAP, inducible nitric oxide synthase, and thrombospondins 1 and 2 in DS astroglia. Our studies shed light on the pathogenesis and possible treatment of DS by targeting astrocytes with a clinically available drug. Down’s syndrome is characterized by intellectual disability and other neuropathological symptoms. Here, the authors show that astroglia derived from induced pluripotent stem cells from Down’s syndrome patients impair the development of neurons, and that this can be attenuated with the drug minocycline.

Switching cell fate: the remarkable rise of induced pluripotent stem cells and lineage reprogramming technologies

Cell reprogramming, in which a differentiated cell is made to switch its fate, is an emerging field with revolutionary prospects in biotechnology and medicine. The recent discovery of induced pluripotency by means of in vitro reprogramming has made way for unprecedented approaches for regenerative medicine, understanding human disease and drug discovery. Moreover, recent studies on regeneration and repair by direct lineage reprogramming in vivo offer an attractive novel alternative to cell therapy. Although we continue to push the limits of current knowledge in the field of cell reprogramming, the mechanistic elements that underlie these processes remain largely elusive. This article reviews landmark developments in cell reprogramming, current knowledge, and technological developments now on the horizon with significant promise for biomedical applications.

Oligodendroglia in developmental neurotoxicity.

The developing nervous system has been long recognized as a primary target for a variety of toxicants. To date, most efforts to understand the impact of neurotoxic agents on the brain have focused primarily on neurons and to a lesser degree astroglia as cellular targets. The role of oligodendroglia, the myelin-forming cells in the central nervous system (CNS), in developmental neurotoxicity has been emphasized only in recent years. Oligodendrocytes originate from migratory, mitotic progenitors that mature progressively into postmitotic myelinating cells. During differentiation, oligodendroglial lineage cells pass through a series of distinct phenotypic stages that are characterized by different proliferative capacities and migratory abilities, as well as dramatic changes in morphology with sequential expression of unique developmental markers. In recent years, it has become appreciated that oligodendrocyte lineage cells have important functions other than those related to myelin formation and maintenance, including participation in neuronal survival and development, as well as neurotransmission and synaptic function. Substantial knowledge has accumulated on the control of oligodendroglial survival, migration, proliferation, and differentiation, as well as the cellular and molecular events involved in oligodendroglial development and myelin formation. Recently, studies have been initiated to address the role of oligodendrocyte lineage cells in neurotoxic processes. This article examines recent progress in oligodendroglial biology, focuses attention on the characteristic features of the oligodendrocyte developmental lineage as a model system for neurotoxicological studies, and explores the role of oligodendrocyte lineage cells in developmental neurotoxicity. The potential role of oligodendroglia in environmental lead neurotoxicity is presented to exemplify this thesis.