The astrocyte in multiple sclerosis revisited

Among the constituent cell types of the multiple sclerosis (MS) plaque, the astrocyte has been the least considered as a player in the pathogenesis of the lesion. Traditionally, it has been assigned a secondary scarring role with little or no role in lesion formation or repair. However, the recent upsurge of interest in the demyelinating condition neuromyelitis optica (NMO) has resulted in NMO being identified as the first disease of myelin in which primary damage to astrocytes, resulting from a humoral immune response that forms against the water channel aquaporin‐4, has been documented. This finding in NMO prompted us to re‐examine data and material from cases of MS displaying active lesions. Our reappraisal revealed unambiguous early damage to perivascular astrocyte end‐feet and to hypertrophic astrocytes in the adjacent parenchyma, but whether this was a primary event was difficult to evaluate due to concomitant edema and inflammation in these acute lesions. The astrocyte damage was long‐lasting since resolving lesions displaying remyelination also showed defects in the integrity of the astrocytic covering around blood vessels. Analysis of our findings and of the astrocytic literature supports multiple roles for the astrocyte in the evolution of changes encountered in MS depending upon lesion stage and lesion topography. At variance with the somewhat inhibitory role of the astrocyte is the abundant and growing evidence for this cell to actively participate in both lesion development and repair. We propose that the unequivocal selective early involvement of the astrocyte in MS lesions may have therapeutic relevance. © 2013 Wiley Periodicals, Inc.     

Preoperative embolisation of brain arteriovenous malformations: a systematic review and meta-analysis

Preoperative embolisation is a commonly performed adjunct to microsurgical excision of brain arteriovenous malformations (bAVMs), with aims such as lessening the technical difficulty of the microsurgical procedure, reducing operative time, decreasing blood loss, and improving patient functional outcomes. We aim to perform a systematic review of randomised trials and cohort studies evaluating preoperative embolisation of bAVMs published between 01 January 2000 and 31 March 2021 and appraise its role in clinical practice. A MEDLINE search was performed, and articles reporting on outcomes following preoperative embolisation, as an adjunct to microsurgery, were eligible for inclusion. PRISMA reporting and Cochrane Handbook guidelines were followed. The primary outcome measure was the risk of complications associated with preoperative embolisation. The study was registered with PROSPERO (CRD42021244231). Of the 1661 citations, 8 studies with 588 patients met predefined inclusion criteria. No studies specifically compared outcomes of surgical excision of bAVMs between those with and without preoperative embolisation. Spetzler Martin (SM) grading was available in 301 cases. 123 of 298 (41?28%) patients presented with haemorrhage. Complications related to embolisation occurred in 175/588 patients (29.4%, 95% CI 19.6–40.2). Permanent neurological deficits occurred in 36/541 (6%, 95% CI 3.9–8.5) and mortality in 6/588 (0.41%, 95% CI 0–1.4). This is the first systematic review evaluating preoperative embolisation of bAVMs. Existing studies assessing this intervention are of poor quality. Associated complication rates are significant. Based on published literature, there is currently insufficient evidence to recommend preoperative embolisation of AVMs. Further studies are required to ascertain if there are benefits of this procedure and if so, in which cases.

     

IL-10 fails to abrogate experimental autoimmune encephalomyelitis

Mice adoptively-sensitized to develop chronic relapsing experimental autoimmune encephalomyelitis (EAE), a model for the human demyelinating condition, multiple sclerosis (MS), were given injections of recombinant human IL-10 at various timepoints post-sensitization in an attempt to abrogate disease development. IL-10 is a Th2 immunomodulatory cytokine with known down-regulatory effects upon Th1 responses and macrophages. Contrary to a previous report on EAE and the predicted outcome, after repeated experiments, IL-10 was found to elicit a worsening or no effect upon EAE in the mouse. Animals were studied clinically, histopathologically and immunocytochemically. On no occasion was disease ameliorated by IL-10. Pretreatment with IL-10 of lymph node cells used to transfer EAE had no effect upon disease outcome, indicating that the cells were already committed effectors. Administration of anti-IL-10 monoclonal antibody before onset of signs had no effect when given early post-sensitization and caused marked worsening when given immediately before onset of signs. In the context of this autoimmune demyelinating model, these results suggest that IL-10 alone is insufficient to reverse the effector response and indeed may serve to enhance the cascade of events in EAE. © 1996 Wiley-Liss, Inc.     

Inhibition of medium and short-chain fatty acid oxidation in rat heart mitochondria by dichloroacetate

The effect of dichloroacetate (DCA) on the oxidation of medium-chain and short-chain fatty acids was studied in rat heart mitochondria. Dichloroacetate (1–10 mM) markedly decreased medium-chain and short-chain fatty acid oxidation (oxygen uptake and release of ¹⁴CO₂ from labelled fatty acids) by heart mitochondria; the oxidation of long-chain fatty acid, however, was unaffected by the compound. The oxidation of acylcarnitines was not influenced by DCA. Dichloroacetate inhibited medium-chain and short-chain fatty acid oxidation by inhibiting the activity of mitochondrial acyl-CoA synthases. Inhibition of the enzyme activity by DCA was rapid and not due to its effect on pyruvate dehydrogenase.     

Role of mitogen-activated protein kinases in inducible nitric oxide synthase and TNFalpha expression in human fetal astrocytes

Astrocytes are important sources of proinflammatory mediators such as iNOS and TNFalpha in the diseased central nervous system. In previous studies, we showed that the cytokine IL-1 plays a critical role in the activation of human astrocytes to express TNFalpha and the inducible form of nitric oxide synthase (iNOS). In the present study, we have addressed the role of the MAP-kinase pathway in the signaling events leading to the induction of these genes. Treatment with SB203580, a specific inhibitor of p38 mitogen-activated protein kinases (MAPK), potently inhibited IL-1-mediated induction of iNOS and TNFalpha in cultures of human fetal astrocytes. In contrast, PD98059, an upstream inhibitor of the extracellular regulated kinase (ERK)1/2 pathway, had little or no effect. Interestingly, SB203580 reduced the mRNA expression for iNOS, TNFalpha, and IL-6, indicating inhibition prior to translation. Transfection of astrocytes with a dominant-negative Jun-NH(2)-terminal kinase (JNK) construct also reduced iNOS expression. Western blot analysis showed phosphorylated p38 and JNK in IL-1-activated astrocytes, and phosphorylated ERK in both resting and activated cells. Electrophoretic mobility shift assay (EMSA) showed that IL-1 induced NF-kappaB and AP-1 DNA complex formation in astrocytes, and that SB203580 inhibited AP-1 complex formation. Taken together, these results demonstrate the differential roles played by the three MAP kinases in human astrocyte inflammatory gene activation and point to a crucial function of p38 and JNK MAP kinases in IL-1-mediated astrocyte activation.     

Differential induction of chemokines in human microglia by type I and II interferons

Chemokines are secreted proteins that function as chemoattractants, mediating the recruitment of specific subsets of leukocytes to sites of tissue damage and immunological reactions. Chemokines may also function as antiviral agents, since viruses such as human immunodeficiency virus type 1 (HIV-1) use chemokine receptors as co-receptors for viral entry. This study examines whether virus-induced interferon, IFNbeta, or immune-related interferon, IFNgamma, affects the production of beta-chemokines by CNS microglia and peripheral monocytes. When IFNbeta was used as the stimulus, induction of MIP-1alpha, MIP-1beta, MCP-1, and RANTES mRNA and protein was observed within 12 h of stimulation in microglia. By contrast, when IFNgamma was used as the stimulus, only MCP-1 was induced. IFNbeta stimulation of blood monocytes resulted in upregulation of MIP-1alpha, MIP-1beta, and MCP-1. Thus, type I and II interferons differentially regulate beta-chemokines in human fetal microglia and peripheral blood monocytes. These observations may have relevance for the therapeutic activity of IFNbeta in multiple sclerosis and for the antiviral effects of IFNbeta for HIV-1 infection of monocytes and microglia.     

Hypothalamic-pituitary dysfunction associated with Moyamoya disease in children

Moyamoya disease is a rare cerebral vascular disease that results in narrowing of the vessels of the circle of Willis and the formation of a network of collateral vessels at the base of the brain for compensatory perfusion. Moyamoya disease has the highest incidence during the first decade of life, and children present most frequently with transient ischemic attacks. We present two cases of Moyamoya disease in children with associated hypothalamic-pituitary dysfunction. Both children presented to the endocrinologist for decreased growth velocity. One child had hypothyroidism and both had growth hormone deficiency. A review of the literature reveals a few isolated case reports of hypothalamic-pituitary dysfunction occurring with Moyamoya disease and with other states of cerebral vascular insufficiency. We suggest that children with compromise of cerebral vascular perfusion be monitored closely for clinical signs and symptoms of hypothalamic-pituitary dysfunction.     

Canonical transient receptor potential channel 4 (TRPC4) co-localizes with the scaffolding protein ZO-1 in human fetal astrocytes in culture

Members of the mammalian transient receptor potential (TRP) family form cation-permeable channels at the plasma membrane implicated in capacitative calcium influx after activation by either second-messenger-mediated pathways or store depletion, or both. This study shows that with the use of RT-PCR, Western blotting, and immunohistochemistry, resting astrocytes express TRPC4 at the cell membrane, particularly at sites of cell-to-cell contact. By confocal imaging and immunoelectron microscopy, we detected co-localization of TRPC4 with the scaffolding protein zonula occludens 1 (ZO-1), and demonstrated that immunoprecipitation with antibodies to ZO-1 brought down TRPC4, and vice-versa. It has been proposed that the targeting of TRPC4 to the cell membrane is dependent on the interaction of the C-terminal TRL motif with PDZ domains. Using transfection of astrocytes with myc-tagged TRPC4 or TRL-motif truncated TRPC4 (deltaTRL), we found that deltaTRL localized predominantly to a juxtanuclear compartment, whereas the wild-type protein showed cell surface distribution. Deletion of the TRL motif also reduced plasma membrane expression as assessed by cell surface biotinylation experiments. Using GST fusion proteins, we found that TRPC4 interacted with the PDZ1 domain of ZO-1 and that this was also dependent on the TRL motif. Thus, our data demonstrate that the PDZ-interacting domain of TRPC4 controls its cell surface localization. These data implicate TRPC4 in the regulation of calcium homeostasis in astrocytes, particularly as part of a signaling complex that forms at junctional sites between astrocytes.