Experimental mouse model of NMOSD produced by facilitated brain delivery of NMO-IgG by microbubble-enhanced low-frequency ultrasound in experimental allergic encephalomyelitis mice

Luo, Jiaying; Xie, Chong; Zhang, Wei; Cai, Yu; Ding, Jie; Wang, Yishu; Hao, Yong; Zhang, Ying; Guan, Yangtai

doi:10.1016/j.msard.2020.102473

Cited by 6 publications

(5 citation statements)

References 24 publications

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“…NMO-IgG and complement were obtained as described previously ( 8 , 17 ). Briefly, serum was obtained from NMOSD patients seropositive for NMO-IgG.…”

Section: Methodsmentioning

confidence: 99%

“…Complement was collected from human volunteers. Blood samples were obtained and prepared as described previously ( 8 ). Informed consent was obtained from all subjects.…”

Section: Methodsmentioning

confidence: 99%

“…), 200 ng of pertussis toxin (List Biological) was injected intraperitoneally. Then, on Day 15 p.i., the BBB was opened by microbubble-enhanced low-frequency ultrasound (MELFUS) ( 8 ). Briefly, mice were anesthetized and their hair on the targeted area was removed with depilatory cream.…”

Section: Methodsmentioning

confidence: 99%

“…Spinal cords, optic nerves and brains were harvested for pathological assessment. H&E staining and Luxol fast blue (LFB) staining were conducted as previously described ( 8 , 17 ). The percentage of infiltration was calculated as the number of inflammatory cells in different groups relative to control group, while the demyelination severity was expressed as the relative percentage of reduced blue area to the control group.…”

Section: Methodsmentioning

confidence: 99%

“…Our previous study established an animal model of NMOSD by additionally compromising the blood-brain barrier (BBB) with low-frequency ultrasound to enable efficient access for NMO-IgG and complement to enter the CNS of experimental autoimmune encephalomyelitis (EAE) mice. Our NMOSD model was able to induce the pathogenesis of NMOSD with an amount of NMO-IgG as low as 100 μg ( 8 ). We have also successfully demonstrated inflammatory demyelination concomitant with the loss of AQP4 and glial fibrillary acidic protein (GFAP) expression in the spinal cord, brain and optic nerve.…”

Section: Introductionmentioning

confidence: 99%

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Low Frequency Ultrasound With Injection of NMO-IgG and Complement Produces Lesions Different From Experimental Autoimmune Encephalomyelitis Mice

et al. 2021

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Neuromyelitis optica spectrum disorder (NMOSD), a relapsing autoimmune disease of the central nervous system, mainly targets the optic nerve and spinal cord. To date, all attempts at the establishment of NMOSD animal models have been based on neuromyelitis optica immunoglobulin G antibody (NMO-IgG) and mimic the disease in part. To solve this problem, we developed a rodent model by opening the blood-brain barrier (BBB) with low frequency ultrasound, followed by injection of NMO-IgG from NMOSD patients and complement to mice suffering pre-existing neuroinflammation produced by experimental autoimmune encephalomyelitis (EAE). In this study, we showed that ultrasound with NMO-IgG and complement caused marked inflammation and demyelination of both spinal cords and optic nerves compared to blank control group, as well as glial fibrillary acidic protein (GFAP) and aquaporin-4 (AQP4) loss of spinal cords and optic nerves compared to EAE mice and EAE mice with only BBB opening. In addition, magnetic resonance imaging (MRI) revealed optic neuritis with spinal cord lesions. We further demonstrated eye segregation defects in the dorsal lateral geniculate nucleus (dLGN) of these NMOSD mice.

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“…NMO-IgG and complement were obtained as described previously ( 8 , 17 ). Briefly, serum was obtained from NMOSD patients seropositive for NMO-IgG.…”

Section: Methodsmentioning

confidence: 99%

“…Complement was collected from human volunteers. Blood samples were obtained and prepared as described previously ( 8 ). Informed consent was obtained from all subjects.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Low Frequency Ultrasound With Injection of NMO-IgG and Complement Produces Lesions Different From Experimental Autoimmune Encephalomyelitis Mice

et al. 2021

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Ultrasound-mediated blood–brain barrier opening: An effective drug delivery system for theranostics of brain diseases

Wang

Pan

et al. 2022

Advanced Drug Delivery Reviews

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The Temporal Dynamics of Pathological Profile and Functional Impairment in Neuromyelitis Optica Spectrum Disorders associated Optic Neuritis

Yang,

Yao,

Chan

et al. 2024

Preprint

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Background Optic neuritis (ON) linked to Neuromyelitis Optica Spectrum Disorders (NMOSD), particularly in Asians, causes irreversible vision loss. The lack of comprehensive analysis that tracks the progression of changes over time hinders the identification of optimal timeframes for observation and intervention of the disease. Our aim is to map disease progression histologically and functionally in an optimized Neuromyelitis Optica Spectrum Disorders associated Optic Neuritis (NMOSD-ON) animal model.Materials and Methods The animals in the NMOSD-ON group involved the injections of aquaporin-4-immunoglobulin G (AQP4-IgG) and human complement into the posterior optic nerve, separated by 24 hours, repeated twice. The control group received injections of normal immunoglobulin G (normal IgG) and human complement. Histological analyses examined the immunoreactivity of aquaporin-4 (AQP4) protein, glial fibrillary acidic protein (GFAP) protein (maker of astrocytes), microglial activation, myelin oligodendrocyte glycoprotein (MOG) (maker of myelin sheath), and degeneration of retinal ganglion cells (RGCs), along with gene expression profiling of inflammatory cytokines at various time points (Baseline, Day 2, Week 1, Week 2, Week 4). In-vivo visual functional and retinal structural assessments were performed weekly up to Week 4 to track disease progression.Results Administration of AQP4-IgG and human complement triggered a series of events in mice with NMOSD-ON, leading to early changes in astrocyte pathology (loss of AQP4 and GFAP staining), upregulation of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), CXCL10, brain-derived neurotrophic factor (BDNF) and microglia activation in Week 1. This was followed by demyelination, culminating in damage to RGCs and nerve fibers in Week 2. Functionally, the delays of visual evoked potential N1 latency were detectable from Week 2, with reduced N1P1 amplitudes by Week 2. For the electroretinogram, the postive scotopic threshold response (pSTR) amplitude decreased at Week 2, while scotopic a- and b-wave amplitudes remained unchange, which corresponded to the retinal nerve fibre layer thinning in the in-vivo retinal structural scan commencing at Week 2.Conclusion This study outlines the progression timeline of NMOSD-ON disease and connects histological and molecular findings to retinal structural changes, in-vivo functional impariment following NMOSD-ON onset in an optimized animal model.

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Experimental mouse model of NMOSD produced by facilitated brain delivery of NMO-IgG by microbubble-enhanced low-frequency ultrasound in experimental allergic encephalomyelitis mice

Cited by 6 publications

References 24 publications

Low Frequency Ultrasound With Injection of NMO-IgG and Complement Produces Lesions Different From Experimental Autoimmune Encephalomyelitis Mice

Low Frequency Ultrasound With Injection of NMO-IgG and Complement Produces Lesions Different From Experimental Autoimmune Encephalomyelitis Mice

Ultrasound-mediated blood–brain barrier opening: An effective drug delivery system for theranostics of brain diseases

The Temporal Dynamics of Pathological Profile and Functional Impairment in Neuromyelitis Optica Spectrum Disorders associated Optic Neuritis

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