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J Neuroimmune Pharmacol [journal]
- Robert J. Cotter (1943-2012): From Mass Spectrometer Development to the Exploration of Life. [JOURNAL ARTICLE]
- J Neuroimmune Pharmacol 2013 Jun 15.
- The Roles of PDGF in Development and During Neurogenesis in the Normal and Diseased Nervous System. [JOURNAL ARTICLE]
- J Neuroimmune Pharmacol 2013 Jun 15.
The four platelet-derived growth factor (PDGF) ligands and PDGF receptors (PDGFRs), α and β (PDGFRA, PDGFRB), are essential proteins that are expressed during embryonic and mature nervous systems, i.e., in neural progenitors, neurons, astrocytes, oligodendrocytes, and vascular cells. PDGF exerts essential roles from the gastrulation period to adult neuronal maintenance by contributing to the regulation of development of preplacodal progenitors, placodal ectoderm, and neural crest cells to adult neural progenitors, in coordinating with other factors. In adulthood, PDGF plays critical roles for maintenance of many specific cell types in the nervous system together with vascular cells through controlling the blood brain barrier homeostasis. At injury or various stresses, PDGF modulates neuronal excitability through adjusting various ion channels, and affecting synaptic plasticity and function. Furthermore, PDGF stimulates survival signals, majorly PI3-K/Akt pathway but also other ways, rescuing cells from apoptosis. Studies imply an involvement of PDGF in dendrite spine morphology, being critical for memory in the developing brain. Recent studies suggest association of PDGF genes with neuropsychiatric disorders. In this review, we will describe the roles of PDGF in the nervous system, from the discovery to recent findings, in order to understand the broad spectrum of PDGF in the nervous system. Recent development of pharmacological and replacement therapies targeting the PDGF system is discussed.
- Commentary on Special Issue: CNS Diseases and the Immune System. [JOURNAL ARTICLE]
- J Neuroimmune Pharmacol 2013 Jun 12.
In an increasing number of central nervous system (CNS) diseases a pathogenic contribution of the immune system is proposed. However, the exact underlying mechanisms are often poorly understood. The collection of articles in this special issue presents a state-of-the-art review of adaptive and innate immune mechanisms and their main players in number CNS disorders. The aim of these articles is to stimulate discussion on the question whether the immune system may be a feasible target of therapy for diseases where currently no effective treatment exists.
- Functional Brain Abnormalities During Finger-Tapping in HIV-Infected Older Adults: A Magnetoencephalography Study. [JOURNAL ARTICLE]
- J Neuroimmune Pharmacol 2013 Jun 9.
Despite the availability of combination antiretroviral therapy, at least mild cognitive dysfunction is commonly observed in HIV-infected patients, with an estimated prevalence of 35-70 %. Neuropsychological studies of these HIV-associated neurocognitive disorders (HAND) have documented aberrations across a broad range of functional domains, although the basic pathophysiology remains unresolved. Some of the most common findings have been deficits in fine motor control and reduced psychomotor speed, but to date no neuroimaging studies have evaluated basic motor control in HAND. In this study, we used magnetoencephalography (MEG) to evaluate the neurophysiological processes that underlie motor planning in older HIV-infected adults and a matched, uninfected control group. MEG is a noninvasive and direct measure of neural activity with good spatiotemporal precision. During the MEG recording, participants fixated on a central crosshair and performed a finger-tapping task with the dominant hand. All MEG data was corrected for head movements, preprocessed, and imaged in the time-frequency domain using beamforming methodology. All analyses focused on the pre-movement beta desynchronization, which is known to be an index of movement planning. Our results demonstrated that HIV-1-infected patients have deficient beta desynchronization relative to controls within the left/right precentral gyri, and the supplementary motor area. In contrast, HIV-infected persons showed abnormally strong beta responses compared to controls in the right dorsolateral prefrontal cortex and medial prefrontal areas. In addition, the amplitude of beta activity in the primary and supplementary motor areas correlated with scores on the Grooved Pegboard test in HIV-infected adults. These results demonstrate that primary motor and sensory regions may be particularly vulnerable to HIV-associated damage, and that prefrontal cortices may serve a compensatory role in maintaining motor performance levels in infected patients.
- Apolipoprotein E-Dependent Differences in Innate Immune Responses of Maturing Human Neuroepithelial Progenitor Cells Exposed to HIV-1. [JOURNAL ARTICLE]
- J Neuroimmune Pharmacol 2013 Jun 7.
HIV enters the brain early during infection and induces a chronic inflammatory state that can result in neurological abnormalities in a subset of infected individuals. To investigate the effects of HIV exposure on neurogenesis and neuronal survival in the brain, we have used a model system consisting of human neuroepithelial progenitor (NEP) cells that undergo directed differentiation into astrocytes and neurons in vitro. Changes in gene expression in NEP cultures as a result of HIV exposure were investigated using gene expression microarrays with the Illumina HT-12 V4_0_R1 platform array. Through this approach, we identified a group of genes specifically upregulated by exposure to virus that are strongly related to interferon induced responses and antigen presentation. When the data were stratified by their apolipoprotein genotype, this innate immune response was more robust in the apolipoprotein E3/E3 genotype cultures than in the apolipoprotein E3/E4 counterparts. Biological processes as defined by the gene ontology (GO) program were also differently affected upon virus exposure in cultures of the two genotypes, particularly those related to antigen presentation and the actions of interferons. Differences occurred in both in numbers of genes affected and their significance in the GO processes in which they participate, with apoE3/E3 > apoE3/E4. These data suggest that maturing NEP cultures recognize HIV and respond to it by mounting an innate immune response with a vigor that is influenced by the apolipoprotein E genotype of the cells.
- The Blood-Brain Barrier. [JOURNAL ARTICLE]
- J Neuroimmune Pharmacol 2013 Jun 6.
The concept of a blood-brain barrier (BBB) dates back to experiments performed by Paul Ehrlich. Using "intravital tracers" which change their color depending on their oxidative state, he intended to estimate the oxygen consumption of the bodily organs. An important prerequisite of this approach, however, would have been an equal distribution of these tracers at the beginning of the experiment, but this was not what he found: Hydrophilic dyes uniformly did not reach the parenchyma, which led his student, the Berlin physician Lewandowski to claim that the capillary wall provides a barrier for certain molecules in the brain, but it was not before the golden era of electron microscopy that Reese and Karnovsky detected what they called "morphological barriers" of the BBB. In this article, we provide an overview of what maintains barrier function for blood-molecules, clarify that a BBB for solutes is neither mechanistically equal to a barrier for immune cells nor in regard to the sites of entry (capillaries versus post-capillary venules), formulate areas of lack of knowledge and consequently, raise open questions to be addressed in the future.
- Wnt Signaling in the Pathogenesis of Human HIV-Associated Pain Syndromes. [JOURNAL ARTICLE]
- J Neuroimmune Pharmacol 2013 Jun 5.
Many synaptic plasticity-related signaling pathways have been identified as important regulators of the pathogenesis of chronic pain in animal models. However, their relevance to human pathological pain is rarely confirmed rigorously. Recent studies suggest that Wnt signaling plays critical roles in synaptic plasticity and is dysregulated in the spinal cord dorsal horn (SDH) of different mouse pain models. In this study, we compared the protein levels of Wnt ligands, Wnt receptors and their downstream effector proteins in the SDH from non-HIV patients, HIV patients who developed chronic pain ('pain-positive' HIV patients), and HIV patients who did not develop chronic pain ('pain-negative' HIV patients). Our results indicate that many Wnt ligands and downstream effector proteins were specifically up-regulated in the SDH of 'pain-positive' HIV patients but not in the 'pain-negative' HIV patients. These findings describe an HIV pain-associated activation of Wnt signaling in the SDH of human patients. Given the established role of Wnt signaling in the regulation of synaptic plasticity, these results suggest that the activated Wnt signaling might contribute to the expression of the synaptic plasticity in the SDH during the pathogenesis of HIV-associated chronic pain.
- Improved Visualization of Neuronal Injury Following Glial Activation by Manganese Enhanced MRI. [JOURNAL ARTICLE]
- J Neuroimmune Pharmacol 2013 Jun 1.
Research directed at anatomical, integrative and functional activities of the central nervous system (CNS) can be realized through bioimaging. A wealth of data now demonstrates the utility of magnetic resonance imaging (MRI) towards unraveling complex neural connectivity operative in health and disease. A means to improve MRI sensitivity is through contrast agents and notably manganese (Mn(2+)). The Mn(2+) ions enter neurons through voltage-gated calcium channels and unlike other contrast agents such as gadolinium, iron oxide, iron platinum and imaging proteins, provide unique insights into brain physiology. Nonetheless, a critical question that remains is the brain target cells serving as sources for the signal of Mn(2+) enhanced MRI (MEMRI). To this end, we investigated MEMRI's abilities to detect glial (astrocyte and microglia) and neuronal activation signals following treatment with known inflammatory inducing agents. The idea is to distinguish between gliosis (glial activation) and neuronal injury for the MEMRI signal and as such use the agent as a marker for neural activity in inflammatory and degenerative disease. We now demonstrate that glial inflammation facilitates Mn(2+) neuronal ion uptake. Glial Mn(2+) content was not linked to its activation. MEMRI performed on mice injected intracranially with lipopolysaccharide was associated with increased neuronal activity. These results support the notion that MEMRI reflects neuronal excitotoxicity and impairment that can occur through a range of insults including neuroinflammation. We conclude that the MEMRI signal enhancement is induced by inflammation stimulating neuronal Mn(2+) uptake.
- Riluzole Partially Rescues Age-Associated, but not LPS-Induced, Loss of Glutamate Transporters and Spatial Memory. [JOURNAL ARTICLE]
- J Neuroimmune Pharmacol 2013 May 25.
Impaired memory may result from synaptic glutamatergic dysregulation related to chronic neuroinflammation. GLT1 is the primary excitatory amino acid transporter responsible for regulating extracellular glutamate levels in the hippocampus. We tested the hypothesis that if impaired spatial memory results from increased extracellular glutamate due to age or experimentally induced chronic neuroinflammation in the hippocampus, then pharmacological augmentation of the glutamate transporter GLT1 will attenuate deficits in a hippocampal-dependent spatial memory task. The profile of inflammation-related genes and proteins associated with normal aging, or chronic neuroinflammation experimentally-induced via a four-week LPS infusion into the IV(th) ventricle, were correlated with performance in the Morris water maze following treatment with Riluzole, a drug that can enhance glutamate clearance by increasing GLT1 expression. Age-associated inflammation was qualitatively different from LPS-induced neuro-inflammation in young rats. LPS produced a pro-inflammatory phenotype characterized by increased IL-1ß expression in the hippocampus, whereas aging was not associated with a strong central pro-inflammatory response but with a mixed peripheral immune phenotype. Riluzole attenuated the spatial memory impairment, the elevation of serum cytokines and the decrease in GLT1 gene expression in Aged rats, but had no effect on young rats infused with LPS. Our findings highlight the therapeutic potential of reducing glutamatergic function upon memory impairment in neurodegenerative diseases associated with aging.
- Combinatorial assessments of brain tissue metabolomics and histopathology in rodent models of human immunodeficiency virus infection. [JOURNAL ARTICLE]
- J Neuroimmune Pharmacol 2013 May 24.
Metabolites are biomarkers for a broad range of central nervous system disorders serving as molecular drivers and byproducts of disease pathobiology. However, despite their importance, routine measures of brain tissue metabolomics are not readily available based on the requirements of rapid tissue preservation. They require preservation by microwave irradiation, rapid freezing or other methods designed to reduce post mortem metabolism. Our research on human immunodeficiency virus type one (HIV-1) infection has highlighted immediate needs to better link histology to neural metabolites. To this end, we investigated such needs in well-studied rodent models. First, the dynamics of brain metabolism during ex vivo tissue preparation was shown by proton magnetic resonance spectroscopy in normal mice. Second, tissue preservation methodologies were assessed using liquid chromatography tandem mass spectrometry and immunohistology to measure metabolites and neural antigens. Third, these methods were applied to two animal models. In the first, immunodeficient mice reconstituted with human peripheral blood lymphocytes then acutely infected with HIV-1. In the second, NOD scid IL2 receptor gamma chain knockout mice were humanized with CD34+ human hematopoietic stem cells and chronically infected with HIV-1. Replicate infected animals were treated with nanoformulated antiretroviral therapy (nanoART). Results from chronic infection showed that microgliosis was associated with increased myoinostitol, choline, phosphocholine concentrations and with decreased creatine concentrations. These changes were partially reversed with nanoART. Metabolite responses were contingent on the animal model. Taken together, these studies integrate brain metabolomics with histopathology towards uncovering putative biomarkers for neuroAIDS.