ORCID Profile
0000-0002-3677-2198
Current Organisation
University of Oxford
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Publisher: Wiley
Date: 17-06-2023
Abstract: Abnormal myelination underlies the pathology of white matter diseases such as preterm white matter injury and multiple sclerosis. Osteopontin (OPN) has been suggested to play a role in myelination. Murine OPN mRNA is translated into a secreted isoform (sOPN) or an intracellular isoform (iOPN). Whether there is an isoform‐specific involvement of OPN in myelination is unknown. Here we generated mouse models that either lacked both OPN isoforms in all cells (OPN‐KO) or lacked sOPN systemically but expressed iOPN specifically in oligodendrocytes (OLs‐iOPN‐KI). Transcriptome analysis of isolated oligodendrocytes from the neonatal brain showed that genes and pathways related to increase of myelination and altered cell cycle control were enriched in the absence of the two OPN isoforms in OPN‐KO mice compared to control mice. Accordingly, adult OPN‐KO mice showed an increased axonal myelination, as revealed by transmission electron microscopy imaging, and increased expression of myelin‐related proteins. In contrast, neonatal oligodendrocytes from OLs‐iOPN‐KI mice compared to control mice showed differential regulation of genes and pathways related to the increase of cell adhesion, motility, and vasculature development, and the decrease of axonal/neuronal development. OLs‐iOPN‐KI mice showed abnormal myelin formation in the early phase of myelination in young mice and signs of axonal degeneration in adulthood. These results suggest an OPN isoform‐specific involvement, and a possible interplay between the isoforms, in myelination, and axonal integrity. Thus, the two isoforms of OPN need to be separately considered in therapeutic strategies targeting OPN in white matter injury and diseases.
Publisher: Elsevier BV
Date: 12-2014
Publisher: Society for Neuroscience
Date: 17-07-2013
Publisher: Frontiers Media SA
Date: 11-07-2017
Publisher: SAGE Publications
Date: 31-01-2017
Abstract: Infection and inflammation are known risk factors for neonatal brain injury. Mycoplasma and Gram-positive bacteria, for which Toll-like receptor 2 (TLR2) plays a key role in recognition and inflammatory response, are among the most common pathogens in the perinatal period. Here, we report that systemic activation of TLR2 by Pam3CSK4 (P3C) increases neural tissue loss and demyelination induced by subsequent hypoxia–ischemia (HI) in neonatal mice. High-resolution respirometry of brain isolated mitochondria revealed that P3C suppresses ADP-induced oxidative phosphorylation, the main pathway of cellular energy production. The results suggest that infection and inflammation might contribute to HI-induced energy failure.
Publisher: Elsevier BV
Date: 07-2019
Publisher: Oxford University Press (OUP)
Date: 04-08-2016
Abstract: Inflammation is a significant risk factor for brain injury in the perinatal period. In this study, we tested the hypothesis that activation of peripheral TLR induces inflammation in the brain, including leukocyte trafficking. Postnatal day 8 mice were injected intraperitoneally with a TLR1/2 (Pam3CSK4, P3C), TLR2/6 (FSL-1) or TLR4 (LPS) agonist, and the peripheral and central cytokine and chemokine response was determined. Infiltration of immune cells to the CSF and brain was examined by flow cytometry, and brain permeability was investigated by radioactively labeled sucrose. We report that peripheral administration of P3C to neonatal mice induces significant influx of leukocytes, mainly neutrophils and monocytes, to the CSF and brain. Infiltration of leukocytes was TLR2 and MyD88 dependent, but largely absent after administration of LPS or FSL-1. PC3-mediated accumulation of immune cells in the brain was observed in classic CNS-leukocyte gateways, the subarachnoid space and choroid plexus, as well as in the median eminence. Although P3C and LPS induced a similar degree of peripheral inflammatory responses, P3C provoked a distinct brain chemokine response and increased permeability, in particular, of the blood-CSF barrier. Collectively, our results do not support the hypothesis that TLR activation, in general, induces immune cell infiltration to the brain. Instead, we have discovered a specific TLR2-mediated mechanism of CNS inflammation and leukocyte invasion into the neonatal brain. This interaction between peripheral and central immune responses is to a large extent via the blood-CSF barrier.
Publisher: Elsevier BV
Date: 03-2019
DOI: 10.1016/J.JCHEMNEU.2018.12.009
Abstract: The developing brain is very susceptible to environmental insults, and very immature infants often suffer from long-term neurological syndromes associated with white matter injuries such as periventricular leukomalacia. Infection and inflammation are important risk factors for neonatal brain white matter injuries, but the evaluation of white matter injury in animal models, especially the quantification of myelinated axons, has long been problematic due to the lack of ideal measurement methods. Here, we present an automated segmentation method, which we call MyelinQ, for the quantification of myelinated white matter in immunohistochemical DAB-stained sections of the neonatal mouse brain. Using MyelinQ, we show that a viral infection mimic agent, the Toll-like receptor 3 ligand Poly I:C, causes significant hypomyelination of white matter in the cortical and hippoc al fimbria regions, but not in the striatal caudoputamen region. We showed that MyelinQ can reliably produce results that are comparable to a method used in our previous publications. However, in comparison to the conventional method, MyelinQ has the advantages of being automated, objective and accurate. MyelinQ can analyze white matter in various specific brain regions and therefore provides a useful platform for the quantification of myelin and the evaluation of white matter injuries in animal models. MyelinQ and its code together with instructions for use can be found at: arham-ap/myelinq.
Publisher: Springer Science and Business Media LLC
Date: 30-10-2018
Publisher: American Society for Microbiology
Date: 21-02-2020
DOI: 10.1128/AAC.02003-19
Abstract: Infection is correlated with increased risk of neurodevelopmental sequelae in preterm infants. In modeling neonatal brain injury, Toll-like receptor agonists have often been used to mimic infections and induce inflammation. Using the most common cause of bacteremia in preterm infants, Staphylococcus epidermidis , we present a more clinically relevant neonatal mouse model that addresses the combined effects of bacterial infection together with subsequent hypoxic-ischemic brain insult.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Amin Mottahedin.