Improved Visualization of Neuronal Injury Following Glial Activation by Manganese Enhanced MRI

Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
Journal of Neuroimmune Pharmacology (Impact Factor: 4.11). 06/2013; 8(4). DOI: 10.1007/s11481-013-9475-3
Source: PubMed


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.

14 Reads
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Manganese enhanced magnetic resonance imaging (MEMRI) is a method used primarily in basic science experiments to advance the understanding of information processing in central nervous system pathways. With this mechanistic approach, manganese (Mn2+) acts as a calcium surrogate, whereby voltage-gated calcium channels allow for activity driven entry of Mn2+ into neurons. The detection and quantification of neuronal activity via Mn2+ accumulation is facilitated by “hemodynamic-independent contrast” using high resolution MRI scans. This review emphasizes initial efforts to-date in the development and application of MEMRI for evaluating tinnitus (the perception of sound in the absence of overt acoustic stimulation). Perspectives from leaders in the field highlight MEMRI related studies by comparing and contrasting this technique when tinnitus is induced by high-level noise exposure and salicylate administration. Together, these studies underscore the considerable potential of MEMRI for advancing the field of auditory neuroscience in general and tinnitus research in particular. Because of the technical and functional gaps that are filled by this method and the prospect that human studies are on the near horizon, MEMRI should be of considerable interest to the auditory research community.
    Hearing research 05/2014; 311. DOI:10.1016/j.heares.2014.02.003 · 2.97 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Neurologist-assessed parkinsonism signs are prevalent among workers exposed to manganese (Mn)-containing welding fume. Neuroinflammation may possibly play a role. Inducible nitric oxide synthase, coded by NOS2, is involved in inflammation, and particulate exposure increases the gene's expression through methylation of CpG sites in the 5' region. Methods: We assessed DNA methylation at three CpG sites in the NOS2 exon 1 from blood from 201 welders. All were non-Hispanic Caucasian men 25-65 years old who were examined by a neurologist specializing in movement disorders. We categorized the workers according to their Unified Parkinson Disease Rating Scale motor subsection 3 (UPDRS3) scores as parkinsonism cases (UPDRS3 ≥ 15; n = 49), controls (UPDRS3 < 6; n = 103), or intermediate (UPDRS3 ≥ 6 to < 15; n = 49). Results: While accounting for age, examiner and experimental plate, parkinsonism cases had lower mean NOS2 methylation than controls (p-value for trend = 0.04), specifically at CpG site 8329 located in an exonic splicing enhancer of NOS2 (p-value for trend = 0.07). These associations were not observed for the intermediate UPDRS3 group (both p-value for trend ≥ 0.59). Conclusions: Inflammation mediated by inducible nitric oxide synthase may possibly contribute to the association between welding fume and parkinsonism, but requires verification in a longitudinal study.
    Occupational and Environmental Medicine 06/2014; 71 Suppl 1(4):A32. DOI:10.1136/oemed-2014-102362.100 · 3.27 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The long term impact of neuroflammation induced by systemic inflammation on astroglial transcription factor nuclear factor (NF)-kappaB activation in the sub-region of hippocampus as well as its' association with the ultra-structural changes in brain cells are yet unknow. In this study, rats received 10 mg/kg of lipopolysaccharide (LPS, ip injection) and NF-kappaBp65 expression on the astroglia as well as the neuronal and astroglial ultra-structural changes and/or death and microvasculature damage were assessed with immunofluorescence and transmission electron microscopy respectively up to 16 days after treatment. The results showed that in the CA1 and CA3 region of the hippocampus, the fluorescence intensity of NF-kappaBp65 was increased from day 1 after LPS injection, reaching a peak at day 3, and stayed at higher level when compared to the control up to 16 days after LPS treatment (P<0.05). Electron microscopy studies revealed sustainable substructural alterations, injury or even death of astrocytes, neurons and capillaries even after 16 days post LPS injection. Our study demonstrated that long-term sustainable activation of astroglial NF-kappaB following systemic inflammation was associated with brain cell and microvasculature injury in the sub-region of the hippocampus which ultimately likely results in brain functional impairment.
    Acta neurobiologiae experimentalis 09/2014; 74(3):298-306. · 1.29 Impact Factor

Similar Publications