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Background: Neuromyelitis optica (NMO) is an autoimmune disorder of the central nervous system, which is characterized by autoantibodies directed against the water channel aquaporin-4 (AQP4). As one of the main water regulators in the central nervous system, APQ4 is supposed to be involved in the dynamics of brain edema. Cerebral edema seriously affects clinical outcome after ischemic stroke; we therefore aimed to investigate whether NMO-antibodies may exert the same functional effects as an AQP4-inhibitor in-vivo in acute ischemic stroke., Methods: Sixteen male Wistar rats were randomized into two groups twice receiving either purified NMO-IgG or immune globulin from healthy controls, 24 hours and 30 minutes before middle cerebral artery occlusion (MCAO) was performed. T2-weighted MRI was carried out 24 hours after MCAO., Results: MRI-examination showed a significant increase of infarct size in relation to the cerebral hemisphere volume with NMO-IgG treated animals (27.1% ± 11.1% vs. 14.3% ± 7.2%; p < 0.05) when corrected for the space-occupying effect of vasogenic edema formation and similar results without edema correction (34.4% ± 16.4% vs. 17.5% ± 9.3%; p < 0.05). Furthermore, T2-RT revealed a significant increase in cortical brain water content of the treatment group (19.5 ms ± 9.7 ms vs. 9.2 ms ± 5.2 ms; p < 0.05)., Conclusions: These results support the functional impact of NMO-antibodies and also offer an in-vivo-applicable animal model to investigate the properties of AQP4 in ischemic stroke.

Background: Cerebral air microembolization (CAM) is a frequent side effect of diagnostic or therapeutic interventions. Besides reduction of the amount of bubbles, filter systems in the clinical setting may also lead to a dispersion of large gas bubbles and therefore to an increase of the gas-liquid-endothelium interface. We evaluated the production and application of different strictly defined bubble diameters in a rat model of CAM and assessed functional outcome and infarct volumes in relation to the bubble diameter., Methods: Gas emboli of defined number and diameter were injected into the carotid artery of rats. Group I (n = 7) received 1800 air bubbles with a diameter of 45 μm, group II (n = 7) 40 bubbles of 160 μm, controls (n = 6) saline without gas bubbles; group I and II yielded the same total injection volume of air with 86 nl. Functional outcome was assessed at baseline, after 4 h and 24 h following cerebral MR imaging and infarct size calculation., Results: Computer-aided evaluation of bubble diameters showed high constancy (group I: 45.83 μm ± 2.79; group II: 159 μm ± 1.26). Animals in group I and II suffered cerebral ischemia and clinical deterioration without significant difference. Infarct sizes did not differ significantly between the two groups (p = 0.931 u-test)., Conclusions: We present further development of a new method, which allows reliable and controlled CAM with different bubble diameters, producing neurological deficits due to unilateral cerebral damage. Our findings could not display a strong dependency of stroke frequency and severity on bubble diameter.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor protein predominantly expressed in microglia within the central nervous system (CNS). TREM2 regulates multiple microglial functions, including lipid metabolism, immune reaction, inflammation, and microglial phagocytosis. Recent studies have found that TREM2 is highly expressed in activated microglia after ischemic stroke. However, the role of TREM2 in the pathologic response after stroke remains unclear. Herein, TREM2-deficient microglia exhibit an impaired phagocytosis rate and cholesteryl ester (CE) accumulation, leading to lipid droplet formation and upregulation of Perilipin-2 (PLIN2) expression after hypoxia. Knockdown of TREM2 results in increased lipid synthesis (PLIN2, SOAT1) and decreased cholesterol clearance and lipid hydrolysis (LIPA, ApoE, ABCA1, NECH1, and NPC2), further impacting microglial phenotypes. In these lipid droplet-rich microglia, the TGF-β1/Smad2/3 signaling pathway is downregulated, driving microglia towards a pro-inflammatory phenotype. Meanwhile, in a neuron-microglia co-culture system under hypoxic conditions, we found that microglia lost their protective effect against neuronal injury and apoptosis when TREM2 was knocked down. Under in vivo conditions, TREM2 knockdown mice express lower TGF-β1 expression levels and a lower number of anti-inflammatory M2 phenotype microglia, resulting in increased cerebral infarct size, exacerbated neuronal apoptosis, and aggravated neuronal impairment. Our work suggests that TREM2 attenuates stroke-induced neuroinflammation by modulating the TGF-β1/Smad2/3 signaling pathway. TREM2 may play a direct role in the regulation of inflammation and also exert an influence on the post-ischemic inflammation and the stroke pathology progression via regulation of lipid metabolism processes. Thus, underscoring the therapeutic potential of TREM2 agonists in ischemic stroke and making TREM2 an attractive new clinical target for the treatment of ischemic stroke and other inflammation-related diseases. [Display omitted] • TREM2 regulates multiple microglial functions including lipid metabolism, inflammation, and microglial phagocytosis. • TREM2-deficient microglia exhibit an impaired phagocytosis rate and lipid droplet accumulation. • TREM2 knockdown leads lower TGF-β1 levels and less anti-inflammatory M2 phenotype microglia. • TREM2-deficient microglia display a lower neuroprotective potential. • TREM2 regulates post-ischemic inflammation in both a direct and an indirect way by modulating lipid metabolism. [ABSTRACT FROM AUTHOR]